Successful Cardiac Resynchronization Therapy Reduces Negative Septal Work in Patient-Specific Models of Dyssynchronous Heart Failure.

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches.

Characterizing cardiac contractile motion for noninvasive radioablation of ventricular tachycardia.

Background: Respiratory motion management strategies are used to minimize the effects of breathing on the precision of stereotactic ablative radiotherapy for ventricular tachycardia, but the extent of cardiac contractile motion of the human heart has not been systematically explored. Objective: We aim to assess the magnitude of cardiac contractile motion between different directions and locations in the heart. Methods: Patients with intracardiac leads or valves who underwent 4-dimensional cardiac computed tomography (CT) prior to a catheter ablation procedure for atrial or ventricular arrhythmias at 2 medical centers were studied retrospectively. The displacement of transvenous right atrial appendage, right ventricular (RV) implantable cardioverter-defibrillator, coronary sinus lead tips, and prosthetic cardiac devices across the cardiac cycle were measured in orthogonal 3-dimensional views on a maximal-intensity projection CT reconstruction. Results: A total of 31 preablation cardiac 4-dimensional cardiac CT scans were analyzed. The LV lead tip had significantly greater motion compared with the RV lead in the anterior-posterior direction (6.0 ± 2.2 mm vs 3.8 ± 1.7 mm; P = .01) and superior-inferior direction (4.4 ± 2.9 mm vs 3.5 ± 2.0 mm; P = .049). The prosthetic aortic valves had the least movement of all fiducials, specifically compared with the RV lead tip in the left-right direction (3.2 ± 1.2 mm vs 6.1 ± 3.8 mm, P = .04) and the LV lead tip in the anterior-posterior direction (3.8 ± 1.7 mm vs 6.0 ± 2.2 mm, P = .03). Conclusion: The degree of cardiac contractile motion varies significantly (1 mm to 15.2 mm) across different locations in the heart. The effect of contractile motion on the precision of radiotherapy should be assessed on a patient-specific basis.

Impact of artificial intelligence arrhythmia mapping on time to first ablation, procedure duration, and fluoroscopy use.

INTRODUCTION: Artificial intelligence (AI) ECG arrhythmia mapping provides arrhythmia source localization using 12-lead ECG data; whether this information impacts procedural efficiency is unknown. We performed a retrospective, case-control study to evaluate the hypothesis that AI ECG mapping may reduce time to ablation, procedural duration, and fluoroscopy. MATERIALS AND METHODS: Cases in which system output was used were retrospectively enrolled according to IRB-approved protocols at each site. Matched control cases were enrolled in reverse chronological order beginning on the last day for which the technology was unavailable. Controls were matched based upon physician, institution, arrhythmia, and a predetermined complexity rating. Procedural metrics, fluoroscopy data, and clinical outcomes were assessed from time-stamped medical records. RESULTS: The study group consisted of 28 patients (age 65 ± 11 years, 46% female, left atrial dimension 4.1 ± 0.9 cm, LVEF 50 ± 18%) and was similar to 28 controls. The most common arrhythmia types were atrial fibrillation (n = 10), premature ventricular complexes (n = 8), and ventricular tachycardia (n = 6). Use of the system was associated with a 19.0% reduction in time to ablation (133 ± 48 vs. 165 ± 49 min, p = 0.02), a 22.6% reduction in procedure duration (233 ± 51 vs. 301 ± 83 min, p < 0.001), and a 43.7% reduction in fluoroscopy (18.7 ± 13.3 vs. 33.2 ± 18.0 min, p < 0.001) versus controls. At 6 months follow-up, arrhythmia-free survival was 73.5% in the study group and 63.3% in the control group (p = 0.56). CONCLUSION: Use of forward-solution AI ECG mapping is associated with reductions in time to first ablation, procedure duration, and fluoroscopy without an adverse impact on procedure outcomes or complications.

Successful Noninvasive 12-Lead ECG Mapping-Guided Radiotherapy of Inaccessible Ventricular Tachycardia Substrate Due to Mechanical Valves.

In patients presenting with refractory ventricular tachycardia (VT) and aortic and mitral mechanical prosthetic valves, traditional catheter ablation is challenging. We describe a case in which a novel noninvasive computational electrocardiogram mapping algorithm localized VT sources originating from substrate near the mechanical valves, in which stereotactic ablative radiotherapy eliminated VT in 1.5-year follow-up. (Level of Difficulty: Advanced.).

Stochastic termination of spiral wave dynamics in cardiac tissue.

Rotating spiral waves are self-organized features in spatially extended excitable media and may play an important role in cardiac arrhythmias including atrial fibrillation (AF). In homogeneous media, spiral wave dynamics are perpetuated through spiral wave breakup, leading to the continuous birth and death of spiral waves, but have a finite probability of termination. In non-homogeneous media, however, heterogeneities can act as anchoring sources that result in sustained spiral wave activity. It is thus unclear how and if AF may terminate following the removal of putative spiral wave sources in patients. Here, we address this question using computer simulations in which a stable spiral wave is trapped by an heterogeneity and is surrounded by spiral wave breakup. We show that, following ablation of spatial heterogeneity to render that region of the medium unexcitable, termination of spiral wave dynamics is stochastic and Poisson-distributed. Furthermore, we show that the dynamics can be accurately described by a master equation using birth and death rates. To validate these predictions in vivo, we mapped spiral wave activity in patients with AF and targeted the locations of spiral wave sources using radiofrequency ablation. Targeted ablation was indeed able to terminate AF, but only after a variable delay of up to several minutes. Furthermore, and consistent with numerical simulations, termination was not accompanied by gradual temporal or spatial organization. Our results suggest that spiral wave sources and tissue heterogeneities play a critical role in the maintenance of AF and that the removal of sources results in spiral wave dynamics with a finite termination time, which could have important clinical implications.

Forward-Solution Noninvasive Computational Arrhythmia Mapping: The VMAP Study.

BACKGROUND: The accuracy of noninvasive arrhythmia source localization using a forward-solution computational mapping system has not yet been evaluated in blinded, multicenter analysis. This study tested the hypothesis that a computational mapping system incorporating a comprehensive arrhythmia simulation library would provide accurate localization of the site-of-origin for atrial and ventricular arrhythmias and pacing using 12-lead ECG data when compared with the gold standard of invasive electrophysiology study and ablation. METHODS: The VMAP study (Vectorcardiographic Mapping of Arrhythmogenic Probability) was a blinded, multicenter evaluation with final data analysis performed by an independent core laboratory. Eligible episodes included atrial and ventricular: tachycardia, fibrillation, pacing, premature atrial and ventricular complexes, and orthodromic atrioventricular reentrant tachycardia. Mapping system results were compared with the gold standard site of successful ablation or pacing during electrophysiology study and ablation. Mapping time was assessed from time-stamped logs. Prespecified performance goals were used for statistical comparisons. RESULTS: A total of 255 episodes from 225 patients were enrolled from 4 centers. Regional accuracy for ventricular tachycardia and premature ventricular complexes in patients without significant structural heart disease (n=75, primary end point) was 98.7% (95% CI, 96.0%-100%; P<0.001 to reject predefined H0 <0.80). Regional accuracy for all episodes (secondary end point 1) was 96.9% (95% CI, 94.7%-99.0%; P<0.001 to reject predefined H0 <0.75). Accuracy for the exact or neighboring segment for all episodes (secondary end point 2) was 97.3% (95% CI, 95.2%-99.3%; P<0.001 to reject predefined H0 <0.70). Median spatial accuracy was 15 mm (n=255, interquartile range, 7-25 mm). The mapping process was completed in a median of 0.8 minutes (interquartile range, 0.4-1.4 minutes). CONCLUSIONS: Computational ECG mapping using a forward-solution approach exceeded prespecified accuracy goals for arrhythmia and pacing localization. Spatial accuracy analysis demonstrated clinically actionable results. This rapid, noninvasive mapping technology may facilitate catheter-based and noninvasive targeted arrhythmia therapies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04559061.

Characteristics and outcomes of recurrent atrial fibrillation after prior failed pulmonary vein isolation.

BACKGROUND: The mechanisms for atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) catheter ablation are unclear. Non-PV organized atrial arrhythmias (PAC, AT, macro-reentrant AFL) are possible contributors; however the prevalence and effect of their ablation on recurrent AF are unknown. We hypothesize that the identification and ablation of non-PV organized atrial arrhythmias were associated with less AF recurrence. METHODS: Patients who underwent repeat ablation for recurrent AF after prior PVI were retrospectively enrolled. The prevalence and characteristics of PV reconnections and non-PV organized atrial arrhythmias were identified. The outcomes of time to clinical AF recurrence, heart failure (HF) hospitalization, and mortality were analyzed in patients using multivariable adjusted Cox regression. RESULTS: In 74 patients with recurrent AF (age 66 ± 9 years, left atrial volume index 38 ± 10 ml/m2, 59% persistent AF), PV reconnections were found in 46 patients (61%), macro-reentrant atrial flutter in 27 patients (36%), and focal tachycardia in 12 patients (16%). Mapping and ablation of non-PV organized atrial arrhythmias were associated with a reduced recurrence of late clinical AF (adjusted HR 0.26, CI 0.08-0.85, p = 0.03) and the composite outcome of recurrence of late AF, HF hospitalization, and mortality (adjusted HR 0.38, CI 0.17-0.85, p = 0.02), with median follow-up of 1.6 (IQR 0.7-6.3) years. The presence of PV reconnections or empiric linear ablation was not associated with reduction in clinical AF or composite endpoints. CONCLUSION: The ablation of non-PV organized atrial arrhythmias resulted in a reduction of late clinical AF recurrence and composite outcome. In this challenging population, alternate mechanisms beyond PV reconnections need to be considered. Prospective studies are needed.

Computational ECG mapping and respiratory gating to optimize stereotactic ablative radiotherapy workflow for refractory ventricular tachycardia.

BACKGROUND: Stereotactic ablative radiotherapy (SAbR) is an emerging therapy for refractory ventricular tachycardia (VT). However, the current workflow is complicated, and the precision and safety in patients with significant cardiorespiratory motion and VT targets near the stomach may be suboptimal. OBJECTIVE: We hypothesized that automated 12-lead electrocardiogram (ECG) mapping and respiratory-gated therapy may improve the ease and precision of SAbR planning and facilitate safe radiation delivery in patients with refractory VT. METHODS: Consecutive patients with refractory VT were studied at 2 hospitals. VT exit sites were localized using a 3-D computational ECG algorithm noninvasively and compared to available prior invasive mapping. Radiotherapy (25 Gy) was delivered at end-expiration when cardiac respiratory motion was ≥0.6 cm or targets were ≤2 cm from the stomach. RESULTS: In 6 patients (ejection fraction 29% ± 13%), 4.2 ± 2.3 VT morphologies per patient were mapped. Overall, 7 out of 7 computational ECG mappings (100%) colocalized to the identical cardiac segment when prior invasive electrophysiology study was available. Respiratory gating was associated with smaller planning target volumes compared to nongated volumes (71 ± 7 vs 153 ± 35 cc, P < .01). In 2 patients with inferior wall VT targets close to the stomach (6 mm proximity) or significant respiratory motion (22 mm excursion), no GI complications were observed at 9- and 12-month follow-up. Implantable cardioverter-defibrillator shocks decreased from 23 ± 12 shocks/patient to 0.67 ± 1.0 (P < .001) post-SAbR at 6.0 ± 4.9 months follow-up. CONCLUSIONS: A workflow including computational ECG mapping and protocol-guided respiratory gating is feasible, is safe, and may improve the ease of SAbR planning. Studies to validate this workflow in larger populations are required.

Electrical Substrate Ablation for Refractory Ventricular Fibrillation: Results of the AVATAR Study.

[Figure: see text].

Machine Learned Cellular Phenotypes in Cardiomyopathy Predict Sudden Death.

RATIONALE: Susceptibility to VT/VF (ventricular tachycardia/fibrillation) is difficult to predict in patients with ischemic cardiomyopathy either by clinical tools or by attempting to translate cellular mechanisms to the bedside. OBJECTIVE: To develop computational phenotypes of patients with ischemic cardiomyopathy, by training then interpreting machine learning of ventricular monophasic action potentials (MAPs) to reveal phenotypes that predict long-term outcomes. METHODS AND RESULTS: We recorded 5706 ventricular MAPs in 42 patients with coronary artery disease and left ventricular ejection fraction ≤40% during steady-state pacing. Patients were randomly allocated to independent training and testing cohorts in a 70:30 ratio, repeated K=10-fold. Support vector machines and convolutional neural networks were trained to 2 end points: (1) sustained VT/VF or (2) mortality at 3 years. Support vector machines provided superior classification. For patient-level predictions, we computed personalized MAP scores as the proportion of MAP beats predicting each end point. Patient-level predictions in independent test cohorts yielded c-statistics of 0.90 for sustained VT/VF (95% CI, 0.76-1.00) and 0.91 for mortality (95% CI, 0.83-1.00) and were the most significant multivariate predictors. Interpreting trained support vector machine revealed MAP morphologies that, using in silico modeling, revealed higher L-type calcium current or sodium-calcium exchanger as predominant phenotypes for VT/VF. CONCLUSIONS: Machine learning of action potential recordings in patients revealed novel phenotypes for long-term outcomes in ischemic cardiomyopathy. Such computational phenotypes provide an approach which may reveal cellular mechanisms for clinical outcomes and could be applied to other conditions.

Linking Electrical Drivers With Atrial Cardiomyopathy for the Targeted Treatment of Atrial Fibrillation.

The relationship between atrial fibrillation (AF) and underlying functional and structural abnormalities has received substantial attention in the research literature over the past decade. Significant progress has been made in identifying these changes using non-invasive imaging, voltage mapping, and electrical recordings. Advances in computed tomography and cardiac magnetic resonance imaging can now provide insight regarding the presence and extent of cardiac fibrosis. Additionally, multiple technologies able to identify electrical targets during AF have emerged. However, an organized strategy to employ these resources in the targeted treatment of AF remains elusive. In this work, we will discuss the basis for mechanistic importance of atrial fibrosis and scar as potential sites promoting AF and emerging technologies to identify and target these structural and functional substrates in the electrophysiology laboratory. We also propose an approach to the use of such technologies to serve as a basis for ongoing work in the field.

Termination of persistent atrial fibrillation by ablating sites that control large atrial areas.

AIMS: Persistent atrial fibrillation (AF) has been explained by multiple mechanisms which, while they conflict, all agree that more disorganized AF is more difficult to treat than organized AF. We hypothesized that persistent AF consists of interacting organized areas which may enlarge, shrink or coalesce, and that patients whose AF areas enlarge by ablation are more likely to respond to therapy. METHODS AND RESULTS: We mapped vectorial propagation in persistent AF using wavefront fields (WFF), constructed from raw unipolar electrograms at 64-pole basket catheters, during ablation until termination (Group 1, N = 20 patients) or cardioversion (Group 2, N = 20 patients). Wavefront field mapping of patients (age 61.1 ± 13.2 years, left atrium 47.1 ± 6.9 mm) at baseline showed 4.6 ± 1.0 organized areas, each separated by disorganization. Ablation of sites that led to termination controlled larger organized area than competing sites (44.1 ± 11.1% vs. 22.4 ± 7.0%, P < 0.001). In Group 1, ablation progressively enlarged unablated areas (rising from 32.2 ± 15.7% to 44.1 ± 11.1% of mapped atrium, P < 0.0001). In Group 2, organized areas did not enlarge but contracted during ablation (23.6 ± 6.3% to 15.2 ± 5.6%, P < 0.0001). CONCLUSION: Mapping wavefront vectors in persistent AF revealed competing organized areas. Ablation that progressively enlarged remaining areas was acutely successful, and sites where ablation terminated AF were surrounded by large organized areas. Patients in whom large organized areas did not emerge during ablation did not exhibit AF termination. Further studies should define how fibrillatory activity is organized within such areas and whether this approach can guide ablation.

Predictors of rate-adaptive pacing in patients implanted with implantable cardioverter-defibrillator and subsequent differential clinical outcomes.

PURPOSE: Patients with severe cardiomyopathy often have chronotropic incompetence, which is predominantly managed by activating rate-adaptive pacing in patients implanted with an implantable cardioverter-defibrillator (ICD) capable of atrial pacing. The purpose of this study was to determine predictors of rate-adaptive pacing activation, the cumulative incidence of activation, and the association of rate-adaptive pacing activation with subsequent clinical outcomes in an ICD population. METHODS: The authors evaluated 228 patients implanted with an ICD between 2011 and 2015. Multivariable logistic regression was used to evaluate predictors of rate-adaptive pacing activation. Cox proportional-hazards regression was used to examine associations of rate-adaptive pacing activation and clinical outcomes. RESULTS: Rate-adaptive pacing was turned on in 38.5% (n = 88) of patients during follow-up. Several statistically significant predictors of rate-adaptive pacing activation were found, particularly previous atrial fibrillation (odds ratio [OR] = 8.27, 95% confidence interval [CI] = 2.96-23.06, p < 0.001), previous myocardial infarction (OR = 4.17, 95% CI = 1.38-12.58, p = 0.01), and non-ischemic cardiomyopathy (OR = 3.83, 95% CI = 1.22-12.00, p = 0.02). In multivariable adjusted analyses, rate-adaptive pacing activation within 30 days of implantation was not associated with the risk of device therapy for tachyarrhythmias (hazard ratio [HR] = 1.52, 95% CI = 0.71-3.28, p = 0.29), atrial fibrillation (HR = 1.42, 95% CI = 0.71-2.87, p = 0.32), HF re-admission (HR = 1.39, 95% CI = 0.80-2.43, p = 0.25), nor all-cause mortality (HR = 2.34, 95% CI = 0.80-6.84, p = 0.12). CONCLUSIONS: During follow-up, more than one in three HF patients implanted with an ICD developed the need for rate-adaptive pacing. Atrial fibrillation, prior myocardial infarction, and non-ischemic cardiomyopathy were statistically significant baseline clinical predictors of rate-adaptive pacing activation. Rate-adaptive pacing activation was not associated with subsequent adverse clinical outcomes.

Long-term mode and timing of premature ventricular complex recurrence following successful catheter ablation.

PURPOSE: Catheter ablation of premature ventricular contractions (PVCs) is highly successful and has become the hallmark treatment for symptomatic or highly prevalent cases. However, few studies exist that evaluate the outcomes of ablation and likely mechanisms of PVC recurrence beyond 1 year of follow-up. METHODS: This study is a retrospective analysis of patients who underwent catheter ablation for symptomatic PVCs with acute procedural success and had clinical follow-up ≥ 12 months. RESULTS: Forty-four patients (24 women; age 53.5 ± 4.8 years) following acutely successful PVC ablation with long-term follow-up were studied. At a mean of 36 ± 6 months, overall long-term ablation success was 75% (33/44 patients). Notably, recurrence of the targeted PVC focus was low (6.8%, 3/44 patients); the majority of recurrences were from a new source location (18.2%, 8/44 patients). The time course for targeted versus de novo PVC recurrences was significantly different: recurrence of a PVC similar to the targeted PVC morphology occurred at a mean of 5.0 ± 2.0 months, while recurrence of a PVC different from the index case occurred at a mean of 35.8 ± 17.1 months (p = 0.01). Non-ischemic cardiomyopathy was associated with increased risk of PVC recurrence (odds ratio [OR] 14.50 (95% confidence interval [CI] 1.92-109.33, p = 0.01)) and was a significant negative prognostic factor in multivariate analysis for PVC recurrence survival (hazard ratio [HR] 4.63, 95% CI 1.03-20.74, p = 0.04). CONCLUSIONS: The majority of long-term PVC recurrences occur late in follow-up, at locations remote from the targeted PVC source or sources. Such sites may represent ongoing substrate evolution; additional work is required to determine the precise substrate alterations which promote such arrhythmogenic changes.

Transient complete heart block following catheter ablation of a left lateral accessory pathway.

A 16-year-old female with symptomatic Wolff-Parkinson-White (WPW) syndrome underwent catheter ablation of a left-sided lateral accessory pathway. The accessory pathway was eliminated with the first ablation lesion; however, the patient immediately developed complete heart block (CHB). At first, complete heart block was thought to be due to ablation of left atrial extension of the AV node, and pacemaker therapy was considered. However, careful ECG analysis revealed that the development of CHB was in fact due to bump injury to the AV node during transseptal catheterization. Conservative management allowed resolution of AV nodal conduction without need for a permanent pacemaker.

Interaction of Localized Drivers and Disorganized Activation in Persistent Atrial Fibrillation: Reconciling Putative Mechanisms Using Multiple Mapping Techniques.

BACKGROUND: Mechanisms for persistent atrial fibrillation (AF) are unclear. We hypothesized that putative AF drivers and disorganized zones may interact dynamically over short time scales. We studied this interaction over prolonged durations, focusing on regions where ablation terminates persistent AF using 2 mapping methods. METHODS: We recruited 55 patients with persistent AF in whom ablation terminated AF prior to pulmonary vein isolation from a multicenter registry. AF was mapped globally using electrograms for 360±45 cycles using (1) a published phase method and (2) a commercial activation/phase method. RESULTS: Patients were 62.2±9.7 years, 76% male. Sites of AF termination showed rotational/focal patterns by methods 1 and 2 (51/55 vs 55/55; P=0.13) in spatially conserved regions, yet fluctuated over time. Time points with no AF driver showed competing drivers elsewhere or disordered waves. Organized regions were detected for 61.6±23.9% and 70.6±20.6% of 1 minute per method (P=nonsignificant), confirmed by automatic phase tracking (P<0.05). To detect AF drivers with >90% sensitivity, 8 to 32 s of AF recordings were required depending on driver definition. CONCLUSIONS: Sites at which persistent AF terminated by ablation show organized activation that fluctuate over time, because of collision from concurrent organized zones or fibrillatory waves, yet recur in conserved spatial regions. Results were similar by 2 mapping methods. This network of competing mechanisms should be reconciled with existing disorganized or driver mechanisms for AF, to improve clinical mapping and ablation of persistent AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02997254.