Artificial intelligence-adjudicated spatiotemporal dispersion: A patient-unique fingerprint of persistent atrial fibrillation.

BACKGROUND: Spatiotemporal dispersion-guided ablation is a tailored approach for patients in persistent atrial fibrillation (PsAF). The characterization of dispersion extent and distribution and its association with common clinical descriptors of PsAF patients has not been studied. OBJECTIVES: Artificial intelligence-adjudicated dispersion extent and distribution (AI-DED) was obtained with a machine/deep learning classifier (VX1 Software, Volta Medical) in PsAF patients undergoing ablation. The purpose of this study was to test the hypothesis that AI-DED is unique to each patient and independent of common procedural and clinical parameters. METHODS: In a subanalysis of the Ev-AIFib study (NCT03434964), spatiotemporal dispersion maps were built with VX1 software in 78 consecutive persistent and long-standing PsAF patients. AI-DED was quantified using 2 distinct approaches (visual regional characterization or automated global quantification of AI-DED). RESULTS: AI-DED paired-subregion Euclidean distance measurements between 78 patients (average distance 5.07 ± 0.60; min 2.23; max 9.75) demonstrate that AI-DED is a patient-unique characteristic of PsAF. Importantly, both AF type and AF history do not correlate with AI-DED levels (R2 = 0.006, P = .53; and R2 = 0.03, P = .25, respectively). The most extensive AI-DED levels are not associated with poorer procedural (83%, 81%, and 83% of AF termination in low, medium, and high dispersion groups, respectively; P = .954) and long-term (88%, 75%, and 91% of freedom from AF/atrial tachycardia after multiple procedures; P = .517) outcomes. CONCLUSION: The atrial distribution and extent of multipolar electrogram spatiotemporal dispersion follow a nonrandom, albeit patient-unique, distribution in PsAF patients. AI-DED may represent a procedure-implementable fingerprint of the PsAF substrate.

Right atrial appendage firing in atrial fibrillation.

Background: The role of atrial fibrillation (AF) drivers located at the left atrium, superior vena cava, crista terminalis and coronary sinus (CS) is well established. While these regions are classically targeted during catheter ablation, the role of right atrial appendage (RAA) drivers has been incompletely investigated. Objective: To determine the prevalence and electrophysiological characteristics of AF driver's arising from the RAA. Materials and methods: We conducted a retrospective analysis of clinical and procedural data of 317 consecutive patients who underwent an AF ablation procedure after bi-atrial mapping (multipolar catheter). We selected patients who presented with a per-procedural RAA firing (RAAF). RAAF was defined as the recording of a sustained RAA EGM with a cycle length shorter than 120 ms or 120 < RAAF CL ≤ 130 ms and ratio RAA CL/CS CL ≤ 0.75. Results: Right atrial/atrium appendage firing was found in 22 patients. The prevalence was estimated at 7% (95% CI, 4-10). These patients were mostly men (72%), median age: 66 yo ± 8 without structural heart disease (77%). RAAFs were predominantly found in paroxysmal AF patients (63%, 32%, and 5% for paroxysmal, short standing and long-standing AF, respectively, p > 0.05). RAAF median cycle length was 117 ms ± 7 while CS cycle length was 180 ms ± 10 (p < 0.01). Conclusion: In 317 consecutive AF ablation patients (22 patients, 7%) the presence of a high-voltage short-cycle-length right atrial appendage driver (RAAF) may conclusively be associated with AF termination. This case series exemplifies the not-so-uncommon role of the RAA in the perpetuation of AF.

Artificial intelligence software standardizes electrogram-based ablation outcome for persistent atrial fibrillation.

INTRODUCTION: Multiple groups have reported on the usefulness of ablating in atrial regions exhibiting abnormal electrograms during atrial fibrillation (AF). Still, previous studies have suggested that ablation outcomes are highly operator- and center-dependent. This study sought to evaluate a novel machine learning software algorithm named VX1 (Volta Medical), trained to adjudicate multipolar electrogram dispersion. METHODS: This study was a prospective, multicentric, nonrandomized study conducted to assess the feasibility of generating VX1 dispersion maps. In 85 patients, 8 centers, and 17 operators, we compared the acute and long-term outcomes after ablation in regions exhibiting dispersion between primary and satellite centers. We also compared outcomes to a control group in which dispersion-guided ablation was performed visually by trained operators. RESULTS: The study population included 29% of long-standing persistent AF. AF termination occurred in 92% and 83% of the patients in primary and satellite centers, respectively, p = 0.31. The average rate of freedom from documented AF, with or without antiarrhythmic drugs (AADs), was 86% after a single procedure, and 89% after an average of 1.3 procedures per patient (p = 0.4). The rate of freedom from any documented atrial arrhythmia, with or without AADs, was 54% and 73% after a single or an average of 1.3 procedures per patient, respectively (p < 0.001). No statistically significant differences between outcomes of the primary versus satellite centers were observed for one (p = 0.8) or multiple procedures (p = 0.4), or between outcomes of the entire study population versus the control group (p > 0.2). Interestingly, intraprocedural AF termination and type of recurrent arrhythmia (i.e., AF vs. AT) appear to be predictors of the subsequent clinical course. CONCLUSION: VX1, an expertise-based artificial intelligence software solution, allowed for robust center-to-center standardization of acute and long-term ablation outcomes after electrogram-based ablation.

Emerging role of artificial intelligence in cardiac electrophysiology.

Artificial intelligence (AI) and machine learning (ML) have significantly impacted the field of cardiovascular medicine, especially cardiac electrophysiology (EP), on multiple fronts. The goal of this review is to familiarize readers with the field of AI and ML and their emerging role in EP. The current review is divided into 3 sections. In the first section, we discuss the definitions and basics of AI, ML, and big data. In the second section, we discuss their application to EP in the context of detection, prediction, and management of arrhythmias. Finally, we discuss the regulatory issues, challenges, and future directions of AI in EP.

Localized Atrial Tachycardia and Dispersion Regions in Atrial Fibrillation: Evidence of Spatial Concordance.

INTRODUCTION: During atrial fibrillation (AF) ablation, it is generally considered that atrial tachycardia (AT) episodes are a consequence of ablation. Objective: To investigate the spatial relationship between localized AT episodes and dispersion/ablation regions during persistent AF ablation procedures. Methods: We analyzed 72 consecutive patients who presented for an index persistent AF ablation procedure guided by the presence of spatiotemporal dispersion of multipolar electrograms. We characterized spontaneous or post-ablation ATs' mechanism and location in regard to dispersion regions and ablation lesions. RESULTS: In 72 consecutive patients admitted for persistent AF ablation, 128 ATs occurred in 62 patients (1.9 ± 1.1/patient). Seventeen ATs were recorded before any ablation. In a total of 100 ATs with elucidated mechanism, there were 58 localized sources and 42 macro-reentries. A large number of localized ATs arose from regions exhibiting dispersion during AF (n = 49, 84%). Importantly, these ATs' locations were generally remote from the closest ablation lesion (n = 42, 72%). CONCLUSIONS: In patients undergoing a persistent AF ablation procedure guided by the presence of spatiotemporal dispersion of multipolar electrograms, localized ATs originate within dispersion regions but remotely from the closest ablation lesion. These results suggest that ATs represent a stabilized manifestation of co-existing AF drivers rather than ablation-induced arrhythmias.

Atrial Infarction-Induced Spontaneous Focal Discharges and Atrial Fibrillation in Sheep: Role of Dantrolene-Sensitive Aberrant Ryanodine Receptor Calcium Release.

BACKGROUND: The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI). METHODS AND RESULTS: LAMI was created by ligating the atrial branch of the left anterior descending coronary artery. ECG loop recorders were implanted to monitor AF episodes. In 7 sheep, dantrolene-a ryanodine receptor blocker-was administered in vivo during the 8-day observation period (LAMI-D, 2.5 mg/kg, IV, BID). LAMI animals experienced numerous spontaneous AF episodes during the 8-day monitoring period that were suppressed by dantrolene (LAMI, 26.1±5.1; sham, 4.3±1.1; LAMI-D, 2.8±0.8; mean±SEM episodes per sheep, P<0.01). Optical mapping showed spontaneous focal discharges (SFDs) originating from the ischemic/normal-zone border. SFDs were calcium driven, rate dependent, and enhanced by isoproterenol (0.03 µmol/L, from 210±87 to 3816±1450, SFDs per sheep) but suppressed by dantrolene (to 55.8±32.8, SFDs per sheep, mean±SEM). SFDs initiated AF-maintaining reentrant rotors anchored by marked conduction delays at the ischemic/normal-zone border. NOS1 (NO synthase-1) protein expression decreased in ischemic zone myocytes, whereas NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) oxidase and xanthine oxidase enzyme activities and reactive oxygen species (DCF [6-carboxy-2',7'-dichlorodihydrofluorescein diacetate]-fluorescence) increased. CaM (calmodulin) aberrantly increased [3H]ryanodine binding to cardiac RyR2 (ryanodine receptors) in the ischemic zone. Dantrolene restored the physiological binding of CaM to RyR2. CONCLUSIONS: Atrial ischemia causes spontaneous AF episodes in sheep, caused by SFDs that initiate reentry. Nitroso-redox imbalance in the ischemic zone is associated with intense reactive oxygen species production and altered RyR2 responses to CaM. Dantrolene administration normalizes the CaM response, prevents LAMI-related SFDs, and AF initiation. These findings provide novel insights into the mechanisms underlying ischemia-related atrial arrhythmias.

AF Ablation Guided by Spatiotemporal Electrogram Dispersion Without Pulmonary Vein Isolation: A Wholly Patient-Tailored Approach.

BACKGROUND: The use of intracardiac electrograms to guide atrial fibrillation (AF) ablation has yielded conflicting results. OBJECTIVES: The authors evaluated the usefulness of spatiotemporal dispersion, a visually recognizable electric footprint of AF drivers, for the ablation of all forms of AF. METHODS: The authors prospectively enrolled 105 patients admitted for AF ablation. AF was sequentially mapped in both atria with a 20-pole PentaRay catheter. The authors tagged and ablated only regions displaying electrogram dispersion during AF. Results were compared to a validation set in which a conventional ablation approach was used (pulmonary vein isolation/stepwise approach). To establish the mechanism underlying spatiotemporal dispersion of AF electrograms, the authors conducted realistic numerical simulations of AF drivers in a 2-dimensional model and optical mapping of ovine atrial scar-related AF. RESULTS: Ablation at dispersion areas terminated AF in 95% of the 105 patients. After ablation of 17 ± 10% of the left atrial surface and 18 months of follow-up, the atrial arrhythmia recurrence rate was 15% after 1.4 ± 0.5 procedures per patient versus 41% in the validation set after 1.5 ± 0.5 procedures per patient (arrhythmia free-survival: 85% vs. 59%; log-rank p < 0.001). Compared with the validation set, radiofrequency times (49 ± 21 min vs. 85 ± 34.5 min; p = 0.001) and procedure times (168 ± 42 min vs. 230 ± 67 min; p < 0.0001) were shorter. In simulations and optical mapping experiments, virtual PentaRay recordings demonstrated that electrogram dispersion is mostly recorded in the vicinity of a driver. CONCLUSIONS: The clustering of intracardiac electrograms exhibiting spatiotemporal dispersion is indicative of AF drivers. Their ablation allows for a nonextensive and patient-tailored approach to AF ablation. (Substrate Ablation Guided by High Density Mapping in Atrial Fibrillation [SUBSTRATE HD]; NCT02093949).

Biohybrid cardiac ECM-based hydrogels improve long term cardiac function post myocardial infarction.

Injectable scaffolds for cardiac tissue regeneration are a promising therapeutic approach for progressive heart failure following myocardial infarction (MI). Their major advantage lies in their delivery modality that is considered minimally invasive due to their direct injection into the myocardium. Biomaterials comprising such scaffolds should mimic the cardiac tissue in terms of composition, structure, mechanical support, and most importantly, bioactivity. Nonetheless, natural biomaterial-based gels may suffer from limited mechanical strength, which often fail to provide the long-term support required by the heart for contraction and relaxation. Here we present newly-developed injectable scaffolds, which are based on solubilized decellularized porcine cardiac extracellular matrix (pcECM) cross-linked with genipin alone or engineered with different amounts of chitosan to better control the gel's mechanical properties while still leveraging the ECM biological activity. We demonstrate that these new biohybrid materials are naturally remodeled by mesenchymal stem cells, while supporting high viabilities and affecting cell morphology and organization. They exhibit neither in vitro nor in vivo immunogenicity. Most importantly, their application in treating acute and long term chronic MI in rat models clearly demonstrates the significant therapeutic potential of these gels in the long-term (12weeks post MI). The pcECM-based gels enable not only preservation, but also improvement in cardiac function eight weeks post treatment, as measured using echocardiography as well as hemodynamics. Infiltration of progenitor cells into the gels highlights the possible biological remodeling properties of the ECM-based platform. STATEMENT OF SIGNIFICANCE: This work describes the development of new injectable scaffolds for cardiac tissue regeneration that are based on solubilized porcine cardiac extracellular matrix (ECM), combined with natural biomaterials: genipin, and chitosan. The design of such scaffolds aims at leveraging the natural bioactivity and unique structure of cardiac ECM, while overcoming its limited mechanical strength, which may fail to provide the long-term support required for heart contraction and relaxation. Here, we present a biocompatible gel-platform with custom-tailored mechanical properties that significantly improve cardiac function when injected into rat hearts following acute and chronic myocardial infarction. We clearly demonstrate the substantial therapeutic potential of these scaffolds, which not only preserved heart functions but also alleviated MI damage, even after the formation of a mature scar tissue.

Risk Factors and Genetics of Atrial Fibrillation.

Atrial fibrillation (AF) is by far the most common sustained tachyarrhythmia, affecting 1% to 2% of the general population. AF prevalence and the total annual cost for treatment are alarming, emphasizing the need for an urgent attention to the problem. Thus, having up-to-date information on AF risk factors and appreciating how they promote maintenance of AF maintenance are essential. This article presents a simplified examination of AF risk factors, including emerging genetic risks.

Electrogram Fractionation-Guided Ablation in the Left Atrium Decreases the Frequency of Activation in the Pulmonary Veins and Leads to Atrial Fibrillation Termination: Pulmonary Vein Modulation Rather Than Isolation.

OBJECTIVES: This study sought to evaluate the impact of a complex fractionated atrial electrogram (CFAE)-guided ablation strategy on atrial fibrillation (AF) dynamics in patients with persistent AF. BACKGROUND: It is still unclear whether complete pulmonary vein isolation (PVI) is required or if the ablation of well-delineated pulmonary vein (PV) subregions could achieve similar outcomes in persistent AF. METHODS: CFAE-guided ablations were performed in 76 patients (65.2 ± 10 years of age) with persistent AF. In 47 patients, we measured mean PVs and left atrial appendage (LAA) cycle length (CL) values (PV-CL and LAA-CL), before ablation and before AF termination. We defined "active" PVs as PV-CL ≤ LAA-CL, "rapid fires" as PV-CL ≤80% of LAA-CL, and "PV-LAA CL gradient" as a significant CL difference between the 2 regions. RESULTS: AF termination (sinus rhythm [SR] or atrial tachycardia [AT] conversion) occurred in 92% and SR conversion in 75%. The radiofrequency time for AF termination and total radiofrequency time were 26 ± 25 min and 61.1 ± 21.6 min, respectively. Thirty of 47 patients had active PV (with 19 PV "rapid fires"). Ablation significantly increased median CL, both at PVs and LAA from 188 ms (interquartile range [IQR]: 161 to 210 ms) to 227.5 ms (IQR: 200 to 256 ms) (p < 0.0001) and from 197 ms (IQR: 168 to 220 ms) to 224 ms (IQR: 193 to 250 ms) (p < 0001), respectively. After ablation, PV-LAA CL gradients were withdrawn and all PV "rapid fires" were extinguished (without PVI). After 17.2 ± 10 months of follow-up and 1.61 ± 0.75 procedures, 86.3% and 73% of the patients were free from AF and from any arrhythmia (AF/AT), respectively. CONCLUSIONS: CFAE-guided ablation leads to a large decrease in PV frequency of activation, preceding AF termination. A PV modulation approach, rather than complete PVI, may be preferable for persistent AF.

Cell-selective arrhythmia ablation for photomodulation of heart rhythm.

Heart disease, a leading cause of death in the developed world, is overwhelmingly correlated with arrhythmias, where heart muscle cells, myocytes, beat abnormally. Cardiac arrhythmias are usually managed by electric shock intervention, antiarrhythmic drugs, surgery, and/or catheter ablation. Despite recent improvements in techniques, ablation procedures are still limited by the risk of complications from unwanted cellular damage, caused by the nonspecific delivery of ablative energy to all heart cell types. We describe an engineered nanoparticle containing a cardiac-targeting peptide (CTP) and a photosensitizer, chlorin e6 (Ce6), for specific delivery to myocytes. Specificity was confirmed in vitro using adult rat heart cell and human stem cell-derived cardiomyocyte and fibroblast cocultures. In vivo, the CTP-Ce6 nanoparticles were injected intravenously into rats and, upon laser illumination of the heart, induced localized, myocyte-specific ablation with 85% efficiency, restoring sinus rhythm without collateral damage to other cell types in the heart, such as fibroblasts. In both sheep and rat hearts ex vivo, upon perfusion of CTP-Ce6 particles, laser illumination led to the formation of a complete electrical block at the ablated region and restored the physiological rhythm of the heart. This nano-based, cell-targeted approach could improve ablative technologies for patients with arrhythmias by reducing currently encountered complications.

Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture.

BACKGROUND: Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown. OBJECTIVE: To determine the mechanisms underlying electrophysiological effects of palmitic (PA), stearic (SA) and oleic (OA) FFAs on sheep atrial myocytes. METHODS: We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min), short-term (4-6 hour) or 24-hour application of individual FFAs (10 µM) on isolated ovine left atrial myocytes (LAMs). RESULTS: Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs). 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p<0.05) action potential duration at 30% repolarization (APD30). APD50 and APD80 were unchanged. SA had no effect on resting membrane potential but reduced membrane capacitance by 15% (p<0.05), and abbreviated APD at all values measured (p≤0.001). OA did not significantly affect passive or active properties of LAMs. Measurement of the major voltage-gated ion channels in SA treated LAMs showed a ~60% reduction (p<0.01) of the L-type calcium current (ICa-L) and ~30% reduction (p<0.05) in the transient outward potassium current (ITO). A human atrial cell model recapitulated SA effects on APD. Optical imaging showed that SA incubated for 24 hours altered t-tubular structure in isolated cells (p<0.0001). CONCLUSIONS: SA disrupts t-tubular architecture and remodels properties of membrane ionic currents in sheep atrial myocytes, with potential implications in arrhythmogenesis.

Mechanistic Comparison of "Nearly Missed" Versus "On-Target" Rotor Ablation.

OBJECTIVES: This study used advanced optical mapping techniques to examine atrial fibrillation (AF) dynamics before and after 2 distinct electrogram-based ablation strategies: complex fractionated atrial electrograms (CFAEs) and DFmax/rotor ablation. BACKGROUND: Among the electrogram analytical features proposed to unravel the atrial regions that perpetuate AF, CFAEs, highest dominant frequency sites (DFmax), and, more recently, phase analysis-enabled rotor mapping have received the largest attention. Still, the mechanisms by which these approaches modulate AF dynamics and lead to AF termination are unknown. METHODS: In Langendorff-perfused sheep hearts, AF was maintained by the continuous perfusion of acetylcholine and high-resolution endocardial-epicardial optical videos were recorded from the left atrial free wall and the posterior left atrium. Then, DFmax/rotor regions (n = 7), or CFAE regions harboring the highest wavebreak density (HWD) (n = 5), were targeted with a 4F ablation catheter (5 to 15 W, 30 to 60 s/point). Thereafter, we examined the changes in AF dynamics and whether AF terminated. RESULTS: DFmax/rotor point ablation resulted in a significant decrease in DFmax values. In 2 animals AF terminated, whereas in the remaining 5 animals the post-ablation DFmax domain remained in the vicinity of its pre-ablation location. However, after HWD/CFAEs density ablation, DFmax values did not change, AF did not terminate, and post-ablation DFmax domains relocated from the left atrial free wall to the pulmonary vein-posterior left atrium region. In another group of hearts (n = 12), we observed that upon a progressive increase in acetylcholine concentration-mimicking the acute electrophysiological changes occurring after ablation-3-dimensional rotors drifted from one atrial region to another along large gradients of myocardial thickness. CONCLUSIONS: "On-target" DFmax/rotor ablation leads to the annihilation of the fibrillation-driving rotor. This translates into large decreases in AF frequency or AF termination. In contrast, "nearly missed" HWD/CFAEs ablation spares the fibrillation-driving rotor, and set the stage for rotor drift along large myocardial thickness gradients.

Digital resolution enhancement of intracardiac excitation maps during atrial fibrillation.

Atrial fibrillation (AF) is often successfully treated by catheter ablation. Those cases of AF that do not readily succumb to ablation therapy would benefit from improved methods for mapping the complex spatial patterns of tissue activation that typify recalcitrant AF. To this end, the purpose of our study was to investigate the use of numerical deconvolution to improve the spatial resolution of activation maps provided by 2-D arrays of intra-cardiac recording electrodes. We simulated tissue activation patterns and their corresponding electric potential maps using a computational model of cardiac electrophysiology, and sampled the maps over a grid of locations to generate a mapping data set. Following cubic spline interpolation, followed by edge-extension and windowing, we deconvolved the data and compared the results to the model current density fields. We performed a similar analysis on voltage-sensitive dye maps obtained in isolated sheep hearts. For both the synthetic data and the voltage-sensitive dye maps, we found that deconvolution led to visually improved map resolution for arrays of 10×10 up to 30×30 electrodes placed within a few mm of the atrial surface when the activation patterns included 3-4 features that spanned the recording area. Root mean square error was also reduced by deconvolution. Deconvolution of arrays of intracardiac potentials, preceded by appropriate interpolation and edge processing, leads to potentially useful improvements in map resolution that may allow more effective assessment of the spatiotemporal dynamics of tissue excitation during AF.

Risk factors and genetics of atrial fibrillation.

Atrial fibrillation (AF) is by far the most common sustained tachyarrhythmia, affecting 1% to 2% of the general population. AF prevalence and the total annual cost for treatment are alarming, emphasizing the need for an urgent attention to the problem. Thus, having up-to-date information on AF risk factors and appreciating how they promote maintenance of AF maintenance are essential. This article presents a simplified examination of AF risk factors, including emerging genetic risks.