Journal: Circ Arrhythm Electrophysiol

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Abstract

Heterogeneity in Conduction Underlies Obesity Related Atrial Fibrillation Vulnerability.

Schram-Serban C, Heida A, Roos-Serote MC, Knops P, ... Bogers AJJC, de Groot NMS

- Obese patients are more vulnerable to development of atrial fibrillation (AF) but pathophysiology underlying this relation is only partly understood. The aim of this study is to compare the severity and extensiveness of conduction disorders between obese patients and non-obese patients measured at a high-resolution scale.- Patients (N=212) undergoing cardiac surgery (male:161, 63±11years) underwent epicardial mapping of the right atrium (RA), Bachmann\'s bundle (BB) and left atrium (LA) during sinus rhythm. Conduction delay (CD) was defined as inter-electrode conduction time (CT) of 7-11ms and conduction block (CB) as CT ≥12ms. Prevalence of CD/CB, continuous CDCB (cCDCB), length of CD/CB/cCDCB lines, and severity of CB were analyzed.- In obese patients, the overall incidence of CD (3.1% versus 2.6%, p=0.002), CB (1.8% versus 1.2%, p<0.001) and cCDCB (2.6% versus 1.9%, p<0.001) was higher and CD (p=0.012) and cCDCB (p<0.001) lines are longer. There were more conduction disorders at BB and this area has a higher incidence of CD (4.4% versus 3.3%, p=0.002), CB (3.1% versus 1.6%, p<0.001), cCDCB (4.6% versus 2.7%, p<0.001) and longer CD (p<0.001) or cCDCB (p=0.017) lines. The severity of CB is also higher, particularly in the BB (p=0.008) and PV (p=0.020) areas. In addition, obese patients have a higher incidence of early de-novo post-operative AF (PoAF) (p=0.003). BMI (p=0.037) and the overall amount of CB (p=0.012) were independent predictors for incidence of early PoAF.- Compared to non-obese patients, obese patients have higher incidences of conduction disorders which are also more extensive and more severe. These differences in heterogeneity in conduction are already present during SR and may explain the higher vulnerability to AF of obese patients.



Circ Arrhythm Electrophysiol: 16 Apr 2020; epub ahead of print
Schram-Serban C, Heida A, Roos-Serote MC, Knops P, ... Bogers AJJC, de Groot NMS
Circ Arrhythm Electrophysiol: 16 Apr 2020; epub ahead of print | PMID: 32301327
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Abstract

Ablation of Supraventricular Tachycardias From Concealed Left-sided Nodoventricular And Nodofascicular Accessory Pathways.

Cardona-Guarache R, Han FT, Nguyen DT, Chicos AB, ... Heaven D, Scheinman MM

- Nodoventricular (NV) and nodofascicular (NF) accessory pathways (AP) are uncommon connections between the AV node and the fascicles or ventricles.- Five patients with NF or NV tachycardia were studied.- We identified 5 patients with concealed, left-sided NV (n=4) and NF (n=1) AP. We proved the participation of AP in tachycardia by delivering His-synchronous PVCs that either delayed the subsequent atrial electrogram or terminated the tachycardia (n=3), and by observing an increase in VA interval coincident with left bundle branch block (LBBB) (n=2). The APs were not atrioventricular pathways because the septal VA interval during tachycardia was <70ms in 3, 1 had spontaneous AV dissociation, and in 1 the atria were dissociated from the circuit with atrial overdrive pacing. Entrainment from the right ventricle showed ventricular fusion in 4 out of 5 cases. A left-sided origin of the AP was suspected after failed ablation of the right inferior extension of AV node in 3 cases and by observing a VA increase with LBBB in 2 cases. The NF and 3 of the NV AP were successfully ablated from within the proximal coronary sinus (CS) guided by recorded potentials at the roof of the CS, and 1 NV AP was ablated via a transseptal approach near the CS os.- Left-sided NF and NV AP appear to connect the ventricles with the CS musculature in the region of the CS os. Mapping and successful ablation sites can be guided by recording potentials within or near the CS os.



Circ Arrhythm Electrophysiol: 13 Apr 2020; epub ahead of print
Cardona-Guarache R, Han FT, Nguyen DT, Chicos AB, ... Heaven D, Scheinman MM
Circ Arrhythm Electrophysiol: 13 Apr 2020; epub ahead of print | PMID: 32286853
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Abstract

Impact of Cardiac Implantable Electronic Device Infection: A Clinical and Economic Analysis of the WRAP-IT Trial.

Wilkoff BL, Boriani G, Mittal S, Poole JE, ... Willey S, Tarakji KG

- Current understanding of the impact of cardiac implantable electronic device (CIED) infection is based on retrospective analyses from medical records or administrative claims data. The WRAP-IT trial offers an opportunity to evaluate the clinical and economic impacts of CIED infection from the hospital, payer, and patient perspectives in the US healthcare system.- This was a pre-specified, as-treated analysis evaluating outcomes related to major CIED infections: mortality, QOL, disruption of CIED therapy, HCU, and costs. Payer costs were assigned using Medicare FFS national payments, while Medicare Advantage, hospital, and patient costs were derived from similar hospital admissions in administrative datasets.- Major CIED infection was associated with increased all-cause mortality (12-month risk-adjusted HR 3.41; 95% CI, 1.81 to 6.41; P<0.001), an effect that sustained beyond 12 months (HR through all follow-up 2.30; 95% CI, 1.29 to 4.07; P=0.004). QOL was reduced (P=0.004) and did not normalize for 6 months. Disruptions in CIED therapy were experienced in 36% of infections for a median duration of 184 days. Mean costs were $55,547 ± $45,802 for the hospital, $26,867 ± $14,893, for Medicare FFS and $57,978 ± $29,431 for Medicare Advantage (mean hospital margin of -$30,828 ± $39,757 for Medicare FFS and -$6,055 ± $45,033 for Medicare Advantage). Mean out-of-pocket costs for patients were $2,156 ± $1,999 for Medicare FFS, and $1,658 ± $1,250 for Medicare Advantage.- This large, prospective analysis corroborates and extends understanding of the impact of CIED infections as seen in real-world datasets. CIED infections severely impact mortality, QOL, HCU, and cost in the US healthcare system.- ClinicalTrials.org; Unique Identifier: NCT02277990.



Circ Arrhythm Electrophysiol: 11 Apr 2020; epub ahead of print
Wilkoff BL, Boriani G, Mittal S, Poole JE, ... Willey S, Tarakji KG
Circ Arrhythm Electrophysiol: 11 Apr 2020; epub ahead of print | PMID: 32281393
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Abstract

Factors Associated with Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).

Steinberg BA, Holmes DN, Pieper K, Allen LA, ... Peterson ED, Piccini JP

- Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described.- We assessed factors associated with a 1-year increase in AFEQT of 1 standard deviation (≥18 points; 3x clinically important difference), among outpatients in the ORBIT-AF I registry.- Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 vs. 74, p=0.3), equally likely to be female (44% vs. 48%, p=0.3), but more likely to have newly-diagnosed AF at baseline (18% vs. 8%; p=0.0004), prior antiarrhythmic drug use (52% vs. 40%, 0.005), baseline antiarrhythmic drug use (34.8% vs, 26.8%, p=0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% vs. 2.0%, p=0.003; cardioversion:12.2% vs. 5.9% p=0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR 2.41, p=0.01) and increased baseline diastolic BP (adjusted OR 1.23 per 10-point increase and >65 mm Hg, p=0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/TIA, COPD, and PAD were less likely to improve (p<0.05 for each).- In this national registry of AF patients, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient reported outcomes in AF.- clinicaltrials.gov.; Unique Identifier: NCT01165710.



Circ Arrhythm Electrophysiol: 15 Apr 2020; epub ahead of print
Steinberg BA, Holmes DN, Pieper K, Allen LA, ... Peterson ED, Piccini JP
Circ Arrhythm Electrophysiol: 15 Apr 2020; epub ahead of print | PMID: 32298144
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Abstract

Irrigated Microwave Catheter Ablation Can Create Deep Ventricular Lesions Through Epicardial Fat with Relative Sparing of Adjacent Coronary Arteries.

Qian PC, Barry MA, Tran VT, Lu J, ... Thiagalingam A, Thomas SP

- Radiofrequency ablation depth can be inadequate to reach intramural or epicardial substrate, and energy delivery in the pericardium is limited by penetration through epicardial fat and coronary anatomy. We hypothesized that open irrigated microwave catheter ablation can create deep myocardial lesions endocardially and epicardially though fat while acutely sparing nearby the coronary arteries.- In-house designed and constructed irrigated microwave catheters were tested in in-vitro phantom models and in 15 sheep. Endocardial ablations were performed at 140-180W for 4min; epicardial ablations via subxiphoid access were performed at 90-100W for 4min at sites near coronary arteries.- Epicardial ablations at 90-100W produced mean lesion depth of 10±4mm, width 18±10mm, and length 29±8mm through median epicardial fat thickness of 1.2mm. Endocardial ablations at 180W reached depths of 10.7±3.3mm, width of 16.6±5mm, and length of 20±5mm. Acute coronary occlusion or spasm was not observed at a median separation distance of 2.7mm (IQR 1.2-3.4mm). Saline electrodes recorded unipolar and bipolar electrograms; microwave ablation caused reductions in voltage and changes in electrogram morphology with loss of pace-capture. In-vitro models demonstrated the heat sink effect of coronary flow, as well as preferential microwave coupling to myocardium and blood as opposed to lung and epicardial fat phantoms.- Irrigated microwave catheter ablation may be an effective ablation modality for deep ventricular lesion creation with capacity for fat penetration and sparing of nearby coronary arteries due to cooling endoluminal flow. Clinical translation could improve the treatment of ventricular tachycardia arising from mid myocardial or epicardial substrates.



Circ Arrhythm Electrophysiol: 15 Apr 2020; epub ahead of print
Qian PC, Barry MA, Tran VT, Lu J, ... Thiagalingam A, Thomas SP
Circ Arrhythm Electrophysiol: 15 Apr 2020; epub ahead of print | PMID: 32299229
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Abstract

Ablation at Right Coronary Cusp as an Alternative and Favorable Approach to Eliminate Premature Ventricular Complexes Originating from the Proximal Left Anterior Fascicle.

Chen S, Lu X, Peng S, Xue Y, ... Ouyang F, Liu S

- Premature ventricular complexes (PVC) with narrow QRS duration originating from proximal left anterior fascicle (LAF) is challenging for ablation. This study was performed to evaluate the safety and feasibility of ablation from right coronary sinus (RCC) for proximal LAF-PVC and to investigate this PVC\'s characteristics.- Mapping at RCC and left ventricle and electrocardiogram analysis were performed in 20 patients with LAF-PVC.- The earliest activation site (EAS), with Purkinje-potential during both PVC and sinus rhythm (SR), was localized at proximal LAF in 8 patients (proximal-group) and at non-proximal LAF in 12 patients (non-proximal-group). The Purkinje-potentials preceding PVC-QRS at the EAS in proximal-group (32.6±2.5ms) was significantly earlier than that in non-proximal-group (28.3±4.5ms, P=0.025). Similar difference in the Purkinje-potentials preceding SR-QRS at the EAS was also observed between proximal and non-proximal-group (35.1±4.7ms vs. 25.2±5.0ms, P<0.001). In proximal-group, the distance between the EAS to left His-bundle and to RCC were shorter than that of non-proximal-group (12.3±2.8mm vs. 19.7±5.0mm, P=0.002; and 3.9±0.8mm vs. 15.7±7.8, P<0.001, respectively). No difference in the distance from RCC to proximal LAF was identified between the two groups. PVCs were successfully eliminated from RCC for all proximal-group but at left ventricular EAS for non-proximal-group. The radiofrequency application times, ablation time and procedure time of non-proximal-group were longer than that of proximal-group. Electrocardiographic analysis showed that, when compared to non-proximal-group, the PVCs of proximal-group had narrower QRS duration; smaller S-wave in lead I, V5 and V6; lower R-wave in lead I, aVR, aVL, V1, V2 and V4; and smaller q-wave in lead III and aVF. The QRS duration difference (PVC-QRS and SR-QRS) <15ms predicted the proximal LAF origin with high sensitivity and specificity.- PVCs originating from proximal LAF, with unique electrocardiographic characteristics, could be eliminated safely from RCC.



Circ Arrhythm Electrophysiol: 16 Apr 2020; epub ahead of print
Chen S, Lu X, Peng S, Xue Y, ... Ouyang F, Liu S
Circ Arrhythm Electrophysiol: 16 Apr 2020; epub ahead of print | PMID: 32302210
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Abstract

Catheter Ablation in Patients with Cardiogenic Shock and Refractory Ventricular Tachycardia.

Ballout JA, Wazni OM, Tarakji KG, Saliba WI, ... Lindsay BD, Hussein AA

- There is paucity of data regarding radiofrequency ablation for ventricular tachycardia (VT) in patients with cardiogenic shock and concomitant VT refractory to antiarrhythmic drugs on mechanical support.- Patients undergoing VT ablation at our center were enrolled in a prospectively maintained registry and screened for the current study (2010-2017).All 21 consecutive patients with cardiogenic shock and concomitant refractory ventricular arrhythmia undergoing \"bailout\" ablation due to inability to wean off mechanical support were included. Median age was 61 years, 86% were males, median LVEF was 20%, 81% had ischemic cardiomyopathy, and PAINESD score was 18 ± 5. The type of mechanical support in place prior to the procedure was intra-aortic balloon pump (IABP) in 14 patients (67%), Impella CP in 2, ECMO in 2, ECMO and IABP in 2, and ECMO and Impella CP in 1. Endocardial voltage maps showed myocardial scar in 19 patients (90%). The clinical VTs were inducible in 13 patients (62%), whereas 6 patients had PVC induced VF/VT (29%), and VT could not be induced in 2 patients (9%). Activation mapping was possible in all 13 with inducible clinical VTs. Substrate modification was performed in 15 patients with scar (79%). After ablation and scar modification, the arrhythmia was non-inducible in 19 patients (91%). Seventeen (81%) were eventually weaned off mechanical support successfully, but 6 (29%) died during the index admission from persistent cardiogenic shock. Patients who had ventricular arrhythmia and cardiogenic shock on presentation had a trend towards lower in-hospital mortality compared to those who presented with cardiogenic shock and later developed ventricular arrhythmia.- \"Bailout\" ablation for refractory ventricular arrhythmia in cardiogenic shock allowed successful weaning from mechanical support in a large proportion of patients. Mortality remains high, but the majority of patients were discharged home and survived beyond 1 year.



Circ Arrhythm Electrophysiol: 11 Apr 2020; epub ahead of print
Ballout JA, Wazni OM, Tarakji KG, Saliba WI, ... Lindsay BD, Hussein AA
Circ Arrhythm Electrophysiol: 11 Apr 2020; epub ahead of print | PMID: 32281407
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Abstract

The Year in Review in Cardiac Electrophysiology.

Kapa S, Chung MK, Gopinathannair R, Noseworthy PA, ... Wan E, Wang PJ

In the past year there have been numerous advances in our understanding of arrhythmia mechanisms, diagnosis, and new therapies. We have seen advances in basic cardiac electrophysiology with data suggesting that secretoneurin may be a biomarker for patients at risk of ventricular arrhythmias and we have learned of the potential role of a natriuretic peptide receptor-C in atrial fibrosis and the role of an atrial specific two-pore potassium channel TASK-1 as a therapeutic target for atrial fibrillation. We have seen studies demonstrating role of sensory neurons in sleep apnea-related atrial fibrillation and the association between bariatric surgery and atrial fibrillation ablation outcomes. Artificial intelligence applied to electrocardiography has yielded estimates of age, gender, and overall health. We have seen new tools for collection of patient-centered outcomes following catheter ablation. There have been significant advances in the ability to identify ventricular tachycardia termination sites through high-density mapping of deceleration zones. We have learned that right ventricular dysfunction may be a predictor of survival benefit after ICD implantation in non-ischemic cardiomyopathy patients. We have seen further insights into the role of His bundle pacing on improving outcomes. As our understanding of cardiac laminopathies advance, we may have new tools to predict arrhythmic event rates in gene carriers. Finally, we have seen numerous advances in the treatment of arrhythmias in patients with congenital heart disease.



Circ Arrhythm Electrophysiol: 17 May 2020; epub ahead of print
Kapa S, Chung MK, Gopinathannair R, Noseworthy PA, ... Wan E, Wang PJ
Circ Arrhythm Electrophysiol: 17 May 2020; epub ahead of print | PMID: 32423252
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Abstract

Pulsed-Field Ablation Using a Lattice Electrode for Focal Energy Delivery: Biophysical Characterization, Lesion Durability and Safety Evaluation.

Yavin H, Shapira-Daniels A, Barkagan M, Sroubek J, ... Melidone R, Anter E

- Pulsed field ablation (PFA) is a nonthermal energy that may provide safety advantages over radiofrequency ablation (RFA). One-shot PFA catheters have been developed for pulmonary vein isolation, but they do not permit flexible lesion sets. This study investigated a novel lattice-tip catheter designed for focal RFA or PFA ablation.- The effects of PFA (biphasic, 24 amperes) were investigated in 25 swine using a lattice-tip catheter and system (Affera Inc). Step 1 (n=14) examined the feasibility to create atrial line of block and described its acute effects on the phrenic nerve and esophagus. Step 2 (n=7) examined the subacute effects of PFA on block durability, phrenic nerve and esophagus ≥2 weeks. Step 3 compared the effects of PFA and RFA on the esophagus using a mechanical deviation model approximating the esophagus to the right atrium (n=4) and by direct ablation within its lumen (n=4). The effects of endocardial PFA and RFA on the phrenic nerve were also compared (n=10). Histological analysis was performed.- PFA produced acute block in 100% of lines, achieved with 2.1 (1.3-3.2) applications/cm-line. Histological analysis following [35 (18-37)] days showed 100% transmurality (thickness range 0.4-3.4 mm) with a lesion width of 19.4 (10.9-27.4 mm). PFA selectively affected cardiomyocytes but spared blood vessels and nervous tissue. PFA applied from the posterior atria [23 (21-25) applications] to the approximated esophagus [6 (4.5-14) mm] produced transmural lesions without esophageal injury. PFA [16.5 (15-18) applications)] applied inside the esophageal lumen produced mild edema compared to RFA [13 (12-14) applications] which produced epithelial ulcerations. PFA resulted in no or transient stunning of the phrenic nerve (<5min) without histological changes while RFA produced paralysis.- PFA using a lattice-tip ablation catheter for focal ablation produced durable atrial lesions and showed lower vulnerability to esophageal or phrenic nerve damage compared to RFA.



Circ Arrhythm Electrophysiol: 05 May 2020; epub ahead of print
Yavin H, Shapira-Daniels A, Barkagan M, Sroubek J, ... Melidone R, Anter E
Circ Arrhythm Electrophysiol: 05 May 2020; epub ahead of print | PMID: 32372696
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Abstract

Remote Management of Pacemaker Patients with Biennial In-clinic Evaluation: Continuous Home Monitoring in the Japanese At Home Study - A Randomized Clinical Trial.

Watanabe E, Yamazaki F, Goto T, Asai T, ... Varma N, Ando K

- Current expert consensus recommends remote monitoring (RM) for cardiac implantable electronic devices, with at least annual in-office follow-up. We studied safety and resource consumption of exclusive remote follow-up (RFU) in pacemaker patients for two years.- In Japan, consecutive pacemaker patients committed to RM were randomized to either RFU or conventional in-office follow-up (CFU) at twice-yearly intervals. RFU patients were only seen if indicated by remote monitoring. All returned to hospital after two years. The primary endpoint was a composite of death, stroke, or cardiovascular events requiring surgery, and the primary hypothesis was non-inferiority with 5% margin.- Of 1274 randomized patients (50.4% female, age 77±10 years), 558 (RFU) and 550 (CFU) patients reached either the primary endpoint or 24 months follow-up. The primary endpoint occurred in 10.9% and 11.8%, resp. (P=0.0012 for non-inferiority). The median (IQR) number of in-office follow-ups was 0.50 (0.50 - 0.63) in RFU and 2.01 (1.93 - 2.05) in CFU per patient-year (P<0.001). Insurance claims for follow-ups and directly related diagnostic procedures were 18,800 Yen (16,500 - 20,700 Yen) in RFU and 21,400 Yen (16,700 - 25,900 Yen) in CFU (P<0.001). Only 1.4% of remote follow-ups triggered an unscheduled in-office follow-up, and only 1.5% of scheduled in-office follow-ups were considered actionable.- Replacing periodic in-office follow-ups with remote follow-ups for 2 years in pacemaker patients committed to RM does not increase the occurrence of major cardiovascular events and reduces resource consumption.- The trial was registered at https://clinicaltrials.gov; Unique Identifier: NCT01523704.



Circ Arrhythm Electrophysiol: 27 Apr 2020; epub ahead of print
Watanabe E, Yamazaki F, Goto T, Asai T, ... Varma N, Ando K
Circ Arrhythm Electrophysiol: 27 Apr 2020; epub ahead of print | PMID: 32342703
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Abstract

The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection.

Saleh M, Gabriels J, Chang D, Kim BS, ... Mountantonakis S, Epstein LM

- The novel SARs-CoV-2 coronavirus is responsible for the global COVID-19 pandemic. Small studies have shown a potential benefit of chloroquine/hydroxychloroquine ± azithromycin for the treatment of COVID-19. Use of these medications alone, or in combination, can lead to a prolongation of the QT interval, possibly increasing the risk of Torsade de pointes (TdP) and sudden cardiac death.- Hospitalized patients treated with chloroquine/hydroxychloroquine ± azithromycin from March 1st through the 23rd at three hospitals within the Northwell Health system were included in this prospective, observational study. Serial assessments of the QT interval were performed. The primary outcome was QT prolongation resulting in TdP. Secondary outcomes included QT prolongation, the need to prematurely discontinue any of the medications due to QT prolongation and arrhythmogenic death.- Two hundred one patients were treated for COVID-19 with chloroquine/hydroxychloroquine. Ten patients (5.0%) received chloroquine, 191 (95.0%) received hydroxychloroquine and 119 (59.2%) also received azithromycin. The primary outcome of TdP was not observed in the entire population. Baseline QTc intervals did not differ between patients treated with chloroquine/hydroxychloroquine (monotherapy group) vs. those treated with combination group (chloroquine/hydroxychloroquine and azithromycin) (440.6 ± 24.9 ms vs. 439.9 ± 24.7 ms, p =0.834). The maximum QTc during treatment was significantly longer in the combination group vs the monotherapy group (470.4 ± 45.0 ms vs. 453.3 ± 37.0 ms, p = 0.004). Seven patients (3.5%) required discontinuation of these medications due to QTc prolongation. No arrhythmogenic deaths were reported.- In the largest reported cohort of COVID-19 patients to date treated with chloroquine/hydroxychloroquine {plus minus} azithromycin, no instances of TdP or arrhythmogenic death were reported. Although use of these medications resulted in QT prolongation, clinicians seldomly needed to discontinue therapy. Further study of the need for QT interval monitoring is needed before final recommendations can be made.



Circ Arrhythm Electrophysiol: 28 Apr 2020; epub ahead of print
Saleh M, Gabriels J, Chang D, Kim BS, ... Mountantonakis S, Epstein LM
Circ Arrhythm Electrophysiol: 28 Apr 2020; epub ahead of print | PMID: 32347743
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Abstract

Focal Pulsed Field Ablation for Pulmonary Vein Isolation and Linear Atrial Lesions: A Preclinical Assessment of Safety and Durability.

Koruth J, Kuroki K, Kawamura I, Stoffregen WC, ... Neuzil P, Reddy VY

- A novel ablation and mapping system can toggle between delivering biphasic pulsed field (PF) and radiofrequency (RF) energy from a 9mm lattice-tip catheter. We assessed the preclinical feasibility and safety of: i) focal PF-based thoracic vein (TV) isolation and linear ablation, ii) combined PF and RF focal ablation, and iii) PF delivered directly atop the esophagus.- Two cohorts of 6 swine were treated with pulsed fields at low-dose (PF) and high-dose (PF) and followed for 4 and 2 weeks, respectively, to isolate 25 TVs and create 5 right atrial (PF), 6 mitral (PF) and 6 roof lines (RF+PF). Baseline and follow-up voltage mapping, venous potentials, ostial diameters and phrenic nerve viability were assessed. PF and RF lesions were delivered in 4 and 1 swine from the inferior vena cava onto a forcefully deviated esophagus. All tissues were submitted for histopathology.- 100% of TVs (25/25) were successfully isolated with 12.4±3.6 applications/vein with mean PF times of <90 seconds/vein. Durable isolation improved from 61.5 % PF to 100 % with PF (p=0.04), and all linear lesions were successfully completed without incurring venous stenoses or phrenic injury. PF sections had higher transmurality rates than PF (98.3 vs 88.1%; p=0.03) despite greater mean thickness (2.51.3 mm; p<0.001). PF lesions demonstrated homogenous fibrosis without epicardial fat, nerve or vessel involvement. In comparison, RF+PF sections revealed similar transmurality, but expectedly more necrosis, inflammation and epicardial fat, nerve and vessel involvement. Significant ablation-related esophageal necrosis, inflammation and fibrosis were seen in all RF sections, as compared to no PF sections.- The lattice-tip catheter can deliver focal PF to durably isolate veins and create linear lesions with excellent transmurality and without complications. The PF lesions did not damage the phrenic nerve, vessels and the esophagus.



Circ Arrhythm Electrophysiol: 05 May 2020; epub ahead of print
Koruth J, Kuroki K, Kawamura I, Stoffregen WC, ... Neuzil P, Reddy VY
Circ Arrhythm Electrophysiol: 05 May 2020; epub ahead of print | PMID: 32370542
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Ablation of Reentry-Vulnerable-Zones Determined by Left Ventricular Activation from Multiple Directions: A Novel Approach for Ventricular Tachycardia Ablation: A Multicenter Study (PHYSIO-VT).

Anter E, Neuzil P, Reddy VY, Petru J, ... Shen C, Wit AL

- The optimal method to identify the arrhythmogenic substrate of scar-related VT is unknown. Sites of activation slowing during sinus rhythm (SR) often co-localize with the VT circuit. However, the utility and limitations of such approach for guiding ablation is unknown.- We conducted a multicenter study in patients with infarct-related VT. The LV was mapped during activation from 3 directions: SR (or atrial pacing), right ventricular (RV) and left ventricular (LV) pacing at 600 msec. Ablation was applied selectively to the cumulative area of slow activation, defined as the sum of all regions with activation times of ≥40 msec per 10mm. Hemodynamically tolerated VTs were mapped with activation or entrainment. The primary outcome was a composite of appropriate ICD therapies and cardiovascular death.- In 85 patients, the LV was mapped during activation from 2.4±0.6 directions. The direction of LV activation influenced the location and magnitude of activation slowing. The spatial overlap of activation slowing between SR and RV pacing was 84.2%±7.1%, between SR and LV pacing was 61.4%±8.8%, and between RV and LV pacing was 71.3%±9.6% (P<0.05 between all comparisons). Mapping during SR identified only 66.2%±8.2% of the entire area of activation slowing and 58% critical isthmus sites. Activation from other directions by RV and LV stimulation unmasked an additional 33% of slowly conducting zones and 25% critical isthmus sites. The area of maximal activation slowing often corresponded to the site where the wavefront first interacted with the infarct. During a follow-up period of 3.6 years, the primary endpoint occurred in 14/85 (16.5%) patients.- The spatial distribution of activation slowing is dependent on the direction of LV activation with the area of maximal slowing corresponding to the site where the wavefront first interacts with the infarct. This data may have implications for VT substrate mapping strategies.



Circ Arrhythm Electrophysiol: 05 May 2020; epub ahead of print
Anter E, Neuzil P, Reddy VY, Petru J, ... Shen C, Wit AL
Circ Arrhythm Electrophysiol: 05 May 2020; epub ahead of print | PMID: 32372657
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Abstract

A Lattice-Tip Focal Ablation Catheter that Toggles Between Radiofrequency and Pulsed Field Energy to Treat Atrial Fibrillation: A First-in-Human Trial.

Reddy VY, Anter E, Rackauskas G, Peichl P, ... Kautzner J, Neuzil P

- The tissue selectivity of pulsed field ablation (PFA) provides safety advantages over radiofrequency ablation (RFA) in treating atrial fibrillation (AF). \"One-shot\" PFA catheters have been shown capable of performing pulmonary vein isolation (PVI), but not flexible lesion sets such as linear lesions. A novel lattice-tip ablation catheter with a compressible 9-mm nitinol tip is able to deliver either focal RFA or PFA lesions, each in 2-5 seconds.- In a 3-center, single-arm, first-in-human trial, the 7.5-French lattice catheter was used with a custom mapping system to treat paroxysmal or persistent AF. Toggling between energy sources, point-by-point PV encirclement was performed using biphasic PFA posteriorly, and either temperature-controlled irrigated RFA or PFA anteriorly (RF/PF or PF/PF, respectively). Linear lesions were created using either PFA or RFA.- The 76-patient cohort included 55 paroxysmal and 21 persistent AF patients undergoing either RF/PF (40 patients) or PF/PF (36 patients) ablation. The PVI therapy duration time (transpiring from first to last lesion) was 22.6±8.3 min/patient, with a mean of 50.1 RF/PF lesions/patient. Linear lesions included 14 mitral (4 RF / 2 RF+PF / 8 PF), 34 LA roof (12 RF / 22 PF) and 44 CTI (36 RF / 8 PF) lines, with therapy duration times of 5.1±3.5, 1.8±2.3 and 2.4±2.1 min/patient, respectively. All lesion sets were acutely successful, using 4.7±3.5 min of fluoroscopy. There were no device-related complications, including no strokes. Post-procedure esophagogastroduodenoscopy revealed minor mucosal thermal injury in 2 of 36 RF/PF and 0 of 24 PF/PF patients. Post-procedure brain MRI revealed DWI+/FLAIR- and DWI+/FLAIR+ asymptomatic lesions in 5 and 3 of 51 patients, respectively.- A novel lattice-tip catheter could safely and rapidly ablate AF using either a combined RF/PF approach (capitalizing on the safety of PFA and the years of experience with radiofrequency energy) or an entirely PF approach.



Circ Arrhythm Electrophysiol: 07 May 2020; epub ahead of print
Reddy VY, Anter E, Rackauskas G, Peichl P, ... Kautzner J, Neuzil P
Circ Arrhythm Electrophysiol: 07 May 2020; epub ahead of print | PMID: 32383391
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Abstract

Triggered Ca2+ Waves Induce Depolarization of Maximum Diastolic Potential and Action Potential Prolongation in Dog Atrial Myocytes.

Gussak G, Marszalec W, Yoo S, Modi R, ... Burrell AR, Wasserstrom JA

- We have identified a novel form of abnormal Ca2+ wave activity in normal and failing dog atrial myocytes which occurs during the action potential (AP) and is absent during diastole. The goal of this study was to determine if triggered Ca2+ waves affect cellular electrophysiological properties.- Simultaneous recordings of intracellular Ca2+ and APs allowed measurements of maximum diastolic potential (MDP) and AP duration (APD) during TCWs in isolated dog atrial myocytes. Computer simulations then explored electrophysiological behavior arising from TCWs at the tissue scale.- At 3.3-5hz, TCWs occurred during the AP and often outlasted several AP cycles. MDP was reduced and APD was significantly prolonged during TCWs. All electrophysiological responses to TCWs were abolished by SEA0400 and ORM10103, indicating that Na-Ca exchange current caused depolarization. The time constant of recovery from inactivation of Ca2+ current was 40-70ms in atrial myocytes (depending on holding potential) so this current could be responsible for AP activation during depolarization induced by TCWs. Modeling studies demonstrated that the characteristic properties of TCWs are potentially arrhythmogenic by promoting both conduction block and reentry arising from the depolarization induced by TCWs.- Triggered Ca2+ waves activate inward NCX and dramatically reduce atrial MDP and prolong APD, establishing the substrate for reentry which could contribute to the initiation and/or maintenance of atrial arrhythmias.



Circ Arrhythm Electrophysiol: 19 May 2020; epub ahead of print
Gussak G, Marszalec W, Yoo S, Modi R, ... Burrell AR, Wasserstrom JA
Circ Arrhythm Electrophysiol: 19 May 2020; epub ahead of print | PMID: 32433891
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Abstract

Physical Activity and the Risk for Sudden Cardiac Death in Patients with Coronary Artery Disease.

Tulppo MP, Kiviniemi AM, Lahtinen M, Ukkola O, ... Junttila MJ, Huikuri HV

- The association between leisure time physical activity (LTPA) and the risk of sudden cardiac death (SCD) in coronary artery disease (CAD) patients is not well known. We aim to assess whether there is an association between LTPA and the risk of SCD and non-SCD in CAD patients.- Patients with angiographically verified CAD (n=1,946) underwent a clinical evaluation including filling in a LTPA questionnaire and extensive risk profiling at the baseline. The patients were classified into four groups according to LTPA: 1) Inactive; 2) Irregularly active; 3) Active, exercise regularly 2-3 times weekly; 4) Highly active, exercise regularly four times or more weekly. Age, sex, body mass index (BMI), left ventricular ejection fraction, type 2 diabetes, history of myocardial infarction, Canadian Cardiovascular Society grading of angina pectoris (CCS-class) and exercise capacity were used as covariates in the multivariate Cox regression analysis.- During follow-up (median 6.3 years), 52 SCDs and 49 non-SCDs occurred. Inactive patients had increased risk for SCD compared with active patients (HR: 2.45, 95 % CI: 1.01-5.98, p<0.05). A significant LTPA*CCS-class interaction was observed in SCD risk (p=0.019 in highly active patients). LTPA was not associated with SCD in patients with CCS-class 1 (n=1107, 18 events). Among patients with CCS-class 2 or higher (n=839, 34 events), increased risk for SCD was encountered in highly active patients (HR: 7.46, 95 % CI: 2.32-23.9; p<0.001) and inactive patients (HR: 3.64, 95 % CI: 1.16-11.5; p<0.05) as compared to active patients. A linear association was observed between LTPA and non-SCD, those with high LTPA had the lowest risk for non-SCD.- Inactive CAD patients had increased risk for SCD. In subgroup analysis among symptomatic patients, the risk of SCD was increased in highly active and inactive patients compared with active patients.



Circ Arrhythm Electrophysiol: 19 May 2020; epub ahead of print
Tulppo MP, Kiviniemi AM, Lahtinen M, Ukkola O, ... Junttila MJ, Huikuri HV
Circ Arrhythm Electrophysiol: 19 May 2020; epub ahead of print | PMID: 32433894
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Abstract

Real-Time Closed-Loop Suppression of Repolarization Alternans Reduces Arrhythmia Susceptibility in Vivo.

Merchant FM, Sayadi O, Sohn K, Weiss EH, ... Kulkarni K, Armoundas AA

- Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death.- We have developed a real-time, closed-loop system to record and analyze RA from multiple intra-cardiac leads, and deliver dynamically R-wave triggered pacing stimuli during the absolute refractory period. We have evaluated the ability of this system to control RA and reduce arrhythmia susceptibility, .- R-wave triggered pacing can induce RA, the magnitude of which can be modulated by varying the amplitude, pulse width and size of the pacing vector. Using a swine model (n = 9), we demonstrate that to induce a one μV change in the alternans voltage on the body surface, coronary sinus (CS) and left ventricle (LV) leads, requires a delivered charge of 0.04 ± 0.02, 0.05 ± 0.025 and 0.06 ± 0.033 μC, respectively, while to induce a one unit change of the K, requires a delivered charge of 0.93 ± 0.73, 0.32 ± 0.29 and 0.33 ± 0.37 μC, respectively. For all body surface and intra-cardiac leads, both Δ(Alternans Voltage) and ΔK between baseline and R-wave triggered paced beats increases consistently with an increase in the pacing pulse amplitude, pulse width and vector spacing. Additionally, we show that the proposed method can be used to suppress spontaneously occurring alternans (n = 7), in the presence of myocardial ischemia. Suppression of RA by pacing during the absolute refractory period results in a significant reduction in arrhythmia susceptibility, evidenced by a lower S score during programmed ventricular stimulation compared to baseline prior to ischemia.- We have developed and evaluated a novel closed-loop method to dynamically modulate RA in a swine model. Our data suggest that suppression of RA directly reduces arrhythmia susceptibility and reinforces the concept that RA plays a critical role in the pathophysiology of arrhythmogenesis.



Circ Arrhythm Electrophysiol: 19 May 2020; epub ahead of print
Merchant FM, Sayadi O, Sohn K, Weiss EH, ... Kulkarni K, Armoundas AA
Circ Arrhythm Electrophysiol: 19 May 2020; epub ahead of print | PMID: 32434448
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Abstract

Guidance for rebooting electrophysiology through the COVID-19 pandemic from the Heart Rhythm Society and the American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology.

Lakkireddy DR, Chung MK, Deering TF, Gopinathannair R, ... Wang PJ, Russo AM

Coronavirus disease 2019 (COVID-19) has presented substantial challenges to patient care and impacted health care delivery, including cardiac electrophysiology practice throughout the globe. Based upon the undetermined course and regional variability of the pandemic, there is uncertainty as to how and when to resume and deliver electrophysiology services for arrhythmia patients. This joint document from representatives of the Heart Rhythm Society, American Heart Association, and American College of Cardiology seeks to provide guidance for clinicians and institutions reestablishing safe electrophysiological care. To achieve this aim, we address regional and local COVID-19 disease status, the role of viral screening and serologic testing, return-to-work considerations for exposed or infected health care workers, risk stratification and management strategies based on COVID-19 disease burden, institutional preparedness for resumption of elective procedures, patient preparation and communication, prioritization of procedures, and development of outpatient and periprocedural care pathways.



Circ Arrhythm Electrophysiol: 11 Jun 2020; epub ahead of print
Lakkireddy DR, Chung MK, Deering TF, Gopinathannair R, ... Wang PJ, Russo AM
Circ Arrhythm Electrophysiol: 11 Jun 2020; epub ahead of print | PMID: 32530306
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Abstract

Epicardial Interventions: Impact of Liposomal Bupivacaine on Postprocedural Management (The EPI-LIBRE Study).

Sharma SP, Turagam MK, Mohanty S, Di Biase L, ... Natale A, Lakkireddy D

- Electrophysiological procedures such as epicardial ventricular tachycardia (VT) ablation and Lariat left atrial appendage ligation (LAA) that involve the epicardial space are typically associated with significant postoperative pain due to mechanical irritation and associated inflammation. There is an unmet need for an effective pain management strategy in this group of patients. We studied how this impacts patient comfort and duration of hospitalization and other associated comorbidities related to pericardial access.- This is a multi-center retrospective study including 104 patients who underwent epicardial ventricular tachycardia ablation and Lariat left atrial appendage exclusion. We compared 53 patients who received post-procedural intrapericardial liposomal bupivacaine (LB) + oral colchicine (\"LB group\") and 51 patients who received colchicine alone (\"non-LB group\") between January 2015 and March 2018.- LB was associated with significant lowering of median pain scale at 6 hours [1.0(0-2.0) vs. 8.0(6.0-8.0), p<0.001], 12 hours [1.0(1.0-2.0) vs. 6.0 (5.0-6.0), p<0.001] and up to 48 hours post procedure. Incidence of acute severe pericarditis delayed pericardial effusion and gastrointestinal adverse effects were similar in both groups. Median length of stay was significantly lower in \"LB group\" (2.0 vs. 3.0; adjusted linear coefficient -1, CI -1.3 to -0.6, P<0.001). Subgroup analysis demonstrated similar favorable outcomes in both Lariat and epicardial VT ablation groups.- Addition of intrapericardial post - procedural liposomal bupivacaine to oral colchicine in patients undergoing epicardial access during VT ablation or Lariat procedure is associated with significantly decreased numeric pain score up to 48 hours compared with colchicine alone. It is also associated with significantly shorter length of hospital stay without an increase in the risk of adverse events.



Circ Arrhythm Electrophysiol: 03 Jun 2020; epub ahead of print
Sharma SP, Turagam MK, Mohanty S, Di Biase L, ... Natale A, Lakkireddy D
Circ Arrhythm Electrophysiol: 03 Jun 2020; epub ahead of print | PMID: 32496820
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Abstract

Single-molecule Localization of Na1.5 Reveals Different Modes of Reorganization at Cardiomyocyte Membrane Domains.

Vermij SH, Rougier JS, Agulló-Pascual E, Rothenberg E, Delmar M, Abriel H

- Mutations in the gene encoding the sodium channel Na1.5 cause various cardiac arrhythmias. This variety may arise from different determinants of Na1.5 expression between cardiomyocyte domains. At the lateral membrane and T-tubules, Na1.5 localization and function remain insufficiently characterized.- We used novel single-molecule localization microscopy (SMLM) and computational modeling to define nanoscale features of Na1.5 localization and distribution at the lateral membrane (LM), the LM groove, and T-tubules (TT) in cardiomyocytes from wild-type ( = 3), dystrophin-deficient (;= 3) mice, and mice expressing C-terminally truncated Na1.5 (ΔSIV;= 3). We moreover assessed TT sodium current by recording whole-cell sodium currents in control ( = 5) and detubulated ( = 5) wild-type cardiomyocytes.- We show that Na1.5 organizes as distinct clusters in the groove and T-tubules which density, distribution, and organization partially depend on SIV and dystrophin. We found that overall reduction in Na1.5 expression inand ΔSIV cells results in a non-uniform re-distribution with Na1.5 being specifically reduced at the groove of ΔSIV and increased in T-tubules ofcardiomyocytes. A TT sodium current could however not be demonstrated.- Na1.5 mutations may site-specifically affect Na1.5 localization and distribution at the lateral membrane and T-tubules, depending on site-specific interacting proteins. Future research efforts should elucidate the functional consequences of this redistribution.



Circ Arrhythm Electrophysiol: 14 Jun 2020; epub ahead of print
Vermij SH, Rougier JS, Agulló-Pascual E, Rothenberg E, Delmar M, Abriel H
Circ Arrhythm Electrophysiol: 14 Jun 2020; epub ahead of print | PMID: 32536203
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Abstract

A Clinico-pathological \"Bird\'s-Eye\" View of Left Atrial Myocardial Fibrosis in 121 Patients with Persistent Atrial Fibrillation: Developing Architecture and Main Cellular Players.

Callegari S, Macchi E, Monaco R, Magnani L, ... Alfieri O, Corradi D

- Scientific research on atrial fibrosis in atrial fibrillation (AF) has mainly focused on quantitative and/or molecular features. The purpose of this study was to perform a clinico-architectural/structural investigation of fibrosis to provide one key to understanding the electrophysiological/clinical aspects of AF.- We characterized the fibrosis (amount, architecture, cellular components, and ultrastructure) in left atrial biopsies from 121 patients with persistent/long-lasting persistent AF () (59 males; 60±11 years; 91 mitral disease-related AF, 30 non-mitral disease-related AF) and from 39 patients in sinus rhythm with mitral-valve regurgitation (; 32 males; 59±12 years). Ten autopsy hearts served as controls.- Qualitatively, the fibrosis exhibited the same characteristics in all cases and displayed particular architectural scenarios (which we arbitrarily subdivided into four stages) ranging from isolated foci to confluent sclerotic areas. The percentage of fibrosis was larger and at a more advanced stage invs.and, within , in patients with rheumatic disease vs. non-rheumatic cases. In AF patients with mitral disease and no rheumatic disease, the percentage of fibrosis and the fibrosis stages correlated with both left atrial volume index and AF duration. The fibrotic areas mainly consisted of type I collagen with only a minor cellular component (especially fibroblasts/myofibroblasts; average value range 69-150 cells/mm, depending on the areas in AF biopsies). A few fibrocytes-circulating and bone marrow-derived mesenchymal cells-were also detectable. The fibrosis-entrapped cardiomyocytes showed sarcolemmal damage and connexin 43 redistribution/internalization.- Atrial fibrosis is an evolving and inhomogeneous histological/architectural change which progresses through different stages ranging from isolated foci to confluent sclerotic zones which - seemingly - constrain impulse conduction across restricted regions of electrotonically-coupled cardiomyocytes. The fibrotic areas mainly consist of type I collagen extracellular matrix and, only to a lesser extent, mesenchymal cells.



Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print
Callegari S, Macchi E, Monaco R, Magnani L, ... Alfieri O, Corradi D
Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print | PMID: 32538131
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Abstract

Machine Learning of 12-lead QRS Waveforms to Identify Cardiac Resynchronization Therapy Patients with Differential Outcomes.

Feeny AK, Rickard J, Trulock KM, Patel D, ... Madabhushi A, Chung MK

- Cardiac resynchronization therapy (CRT) improves heart failure outcomes but has significant non-response rates, highlighting limitations in ECG selection criteria: QRS duration (QRSd) ≥150 ms and subjective labeling of left bundle branch block (LBBB). We explored unsupervised machine learning of ECG waveforms to identify CRT subgroups that may differentiate outcomes beyond QRSd and LBBB.- We retrospectively analyzed 946 CRT patients with conduction delay. Principal components analysis (PCA) dimensionality reduction obtained a two-dimensional representation of pre-CRT 12-lead QRS waveforms. -means clustering of the two-dimensional PCA representation of 12-lead QRS waveforms identified two patient subgroups (QRS PCA groups). Vectorcardiographic QRS area was also calculated. We examined two primary outcomes: (1) composite endpoint of death, left ventricular assist device, or heart transplant, and (2) degree of echocardiographic left ventricular ejection fraction (LVEF) change after CRT.- Compared to QRS PCA Group 2 (=425), Group 1 (n=521) had lower risk for reaching the composite endpoint (HR 0.44, 95% CI, 0.38-0.53, p<0.001) and experienced greater mean LVEF improvement (11.1±11.7% vs. 4.8±9.7%, p<0.001), even among LBBB patients with QRSd ≥150 ms (HR 0.42, 95% CI, 0.30-0.57, p<0.001; mean LVEF change 12.5±11.8% vs. 7.3±8.1%, p=0.001). QRS area also stratified outcomes but had significant differences from QRS PCA groups. A stratification scheme combining QRS area and QRS PCA group identified LBBB patients with similar outcomes to non-LBBB patients (HR 1.32, 95% CI: 0.93-1.62; difference in mean LVEF change: 0.8%, 95% CI: -2.1%-3.7%). The stratification scheme also identified LBBB patients with QRSd <150 ms with comparable outcomes to LBBB patients with QRSd ≥150 ms (HR: 0.93, 95% CI: 0.67-1.29; difference in mean LVEF change: -0.2%, 95% CI: -2.7%-3.0%).- Unsupervised machine learning of ECG waveforms identified CRT subgroups with relevance beyond LBBB and QRSd. This method may assist in objective classification of bundle branch block morphology in CRT.



Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print
Feeny AK, Rickard J, Trulock KM, Patel D, ... Madabhushi A, Chung MK
Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print | PMID: 32538136
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Abstract

Pre-Procedure Application of Machine Learning and Mechanistic Simulations Predicts Likelihood of Paroxysmal Atrial Fibrillation Recurrence Following Pulmonary Vein Isolation.

Shade JK, Ali RL, Basile D, Popescu D, ... Calkins H, Trayanova NA

- Pulmonary vein isolation (PVI) is an effective treatment strategy for patients with atrial fibrillation (AF), but many experience AF recurrence and require repeat ablation procedures. The goal of this study was to develop and evaluate a methodology which combines machine learning (ML) and personalized computational modeling to predict, prior to PVI, which patients are most likely to experience AF recurrence after PVI.- This single-center retrospective proof-of-concept study included 32 patients with documented paroxysmal AF who underwent PVI and had pre-procedural late gadolinium enhanced magnetic resonance imaging (LGE-MRI). For each patient, a personalized computational model of the left atrium simulated AF induction via rapid pacing. Features were derived from pre-PVI LGE-MRI images and from results of simulations (SimAF). The most predictive features were used as input to a quadratic discriminant analysis ML classifier, which was trained, optimized, and evaluated with 10-fold nested cross validation to predict the probability of AF recurrence post-PVI.- In our cohort, the ML classifier predicted probability of AF recurrence with an average validation sensitivity and specificity of 82% and 89%, respectively, and a validation AUC of 0.82. Dissecting the relative contributions of SimAF and raw images to the predictive capability of the ML classifier, we found that when only features from SimAF were used to train the ML classifier, its performance remained similar (validation AUC=0.81). However, when only features extracted from raw images were used for training, the validation AUC significantly decreased (0.47).- ML and personalized computational modeling can be used together to accurately predict, using only pre-PVI LGE-MRI scans as input, whether a patient is likely to experience AF recurrence following PVI, even when the patient cohort is small.



Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print
Shade JK, Ali RL, Basile D, Popescu D, ... Calkins H, Trayanova NA
Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print | PMID: 32536204
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Abstract

Prospective Assessment of An Automated Intraprocedural 12-lead ECG-Based System for Localization of Early Left Ventricular Activation.

Zhou S, AbdelWahab A, Horáček BM, MacInnis PJ, ... Trayanova NA, Sapp JL

- To facilitate ablation of ventricular tachycardia (VT), an automated localization system to identify the site of origin of left ventricular (LV) activation in real time using the 12-lead ECG was developed. The objective of this study was to prospectively assess its accuracy.- The automated site of origin localization (SOLO) system consists of three steps: (1) localization of ventricular segment based on population templates, (2) population-based localization within a segment, and (3) patient-specific site localization. Localization error was assessed by the distance between the known reference site and the estimated site.- In 19 patients undergoing 21 catheter ablation procedures of scar-related VT, SOLO accuracy was estimated using 552 LV endocardial pacing sites pooled together, and 25 VT-exit sites identified by contact mapping. For the 25 VT-exit sites, localization error of the population-based localization steps was within 10 mm. Patient-specific site localization achieved accuracy of within 3.5 mm after including up to 11 pacing (training) sites. Using three remotes (67.8 ± 17.0 mm from the reference VT-exit site), and then 5 close pacing sites, resulted in localization error of 7.2 ± 4.1 mm for the 25 identified VT-exit sites. In two emulated clinical procedure with 2 induced VTs, the SOLO system achieved accuracy within 4 mm.- In this prospective validation study, the automated localization system achieved estimated accuracy within 10 mm and could thus provide clinical utility.



Circ Arrhythm Electrophysiol: 14 Jun 2020; epub ahead of print
Zhou S, AbdelWahab A, Horáček BM, MacInnis PJ, ... Trayanova NA, Sapp JL
Circ Arrhythm Electrophysiol: 14 Jun 2020; epub ahead of print | PMID: 32538133
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Abstract

Clinical Outcomes and Characteristics with Dofetilide in Atrial Fibrillation Patients Considered for Implantable Cardioverter-Defibrillator.

Koene RJ, Menon V, Cantillon DJ, Dresing TJ, ... Lindsay BD, Wazni OM

- Dofetilide is one of the only anti-arrhythmic agents approved for atrial fibrillation (AF) in patients with reduced left ventricular ejection fraction (LVEF). However, post-approval data and safety outcomes are limited. In this study, we assessed the incidence and predictors of LVEF improvement, safety, and outcomes in AF patients with LVEF ≤ 35% without prior implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy (CRT), or AF ablation.- An analysis of 168 consecutive patients from 2007 to 2016 was performed. Incidences of adverse events, drug continuation, ICD and/or CRT implantation, LVEF improvement (>35%) and recovery (≥50%), AF recurrence, and AF ablation were determined. Multivariable regression analysis to identify predictors of LVEF improvement/recovery was performed.- The mean age was 64±12 years. Dofetilide was discontinued prior to hospital discharge in 46 (27%) because of QT prolongation (14%), torsades de pointe or polymorphic ventricular tachycardia/fibrillation (6% [sustained 3%, non-sustained 3%]), ineffectiveness (5%), or other causes (3%). At 1 year, 43% remained on dofetilide. Freedom from AF was 42% at 1 year, and 40% underwent future AF ablation. LVEF recovered (≥ 50%) in 45% and improved to >35% in 73%. Predictors of LVEF improvement included presence of AF during echocardiogram (odds ratio [OR] 4.22, 95% CI, 1.71 - 10.4, p=0.002), coronary artery disease (OR 0.35, 95% CI, 0.16 - 0.79, p=0.01), left atrial diameter (OR 0.52 per 1 cm increase, 95% CI 0.30 - 0.90, p=0.01), and LVEF (OR per 1% increase, 1.09, 95% CI, 1.02 - 1.16, p=0.006). The C-statistic was 0.78.- In patients with LVEF ≤ 35%, who are potential ICD candidates, treated with dofetilide as an initial anti-arrhythmic strategy for AF, drug discontinuation rates were high, and many underwent future AF ablation. However, most patients had improvement in LVEF, obviating the need for primary prevention ICD.



Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print
Koene RJ, Menon V, Cantillon DJ, Dresing TJ, ... Lindsay BD, Wazni OM
Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print | PMID: 32538135
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Abstract

Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome.

Strand S, Strasburger JF, Cuneo BF, Wakai RT
Background
Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth.
Methods
We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP).
Results
Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born.
Conclusions
The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03047161.



Circ Arrhythm Electrophysiol: 29 Apr 2020; 13:e008082
Strand S, Strasburger JF, Cuneo BF, Wakai RT
Circ Arrhythm Electrophysiol: 29 Apr 2020; 13:e008082 | PMID: 32421437
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Abstract

Late I blocker GS967 Suppress Polymorphic VT in a Transgenic Rabbit Model of Long QT Type 2.

Hwang J, Kim TY, Terentyev D, Zhong M, ... Koren G, Choi BR

- Long QT syndrome (LQTS) has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I) may counterbalance the reduced repolarization reserve in LQTS and prevent EADs and PVTs.- We tested the effects of the selective I blocker GS967 on PVT induction in a transgenic rabbit model of LQTS type 2 (LQT2) using intact heart optical mapping, cellular electrophysiology and confocal Ca imaging, and computer modeling.- GS967 reduced (ventricular fibrillation) VF induction under a rapid pacing protocol (n=7/14 hearts in control vs. 1/14 hearts at 100 nM) without altering APD or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca-mediated EADs and focal activity during isoproterenol perfusion (at 30 nM, n=7/12 and 100 nM n=8/12 hearts without EADs and PVTs). Confocal Ca imaging of LQT2 myocytes revealed that GS967 shortened Ca transient duration via accelerating Na/Ca exchanger (I)-mediated Ca efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I potentiates EADs in the LQT2 setting through 1) providing additional depolarizing currents during AP plateau phase, 2) increasing intracellular Na (Na) that decreases the depolarizing I thereby suppressing the AP plateau and delaying the activation of slowly-activating delayed rectifier K channels (I), suggesting important roles of I in regulating Na.- Selective I blockade by GS967 prevents EADs and abolishes PVT in LQT2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na.



Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print
Hwang J, Kim TY, Terentyev D, Zhong M, ... Koren G, Choi BR
Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print | PMID: 32628505
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Abstract

Artificial Intelligence and Machine Learning in Arrhythmias and Cardiac Electrophysiology.

Feeny AK, Chung MK, Madabhushi A, Attia ZI, ... Turakhia MP, Wang PJ

Artificial intelligence (AI) and machine learning (ML) in medicine are currently areas of intense exploration, showing potential to automate human tasks and even perform tasks beyond human capabilities. Literacy and understanding of AI/ML methods are becoming increasingly important to researchers and clinicians. The first objective of this review is to provide the novice reader with literacy of AI/ML methods and provide a foundation for how one might conduct an ML study. We provide a technical overview of some of the most commonly used terms, techniques, and challenges in AI/ML studies, with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology, with emphasis on disease detection and diagnosis, prediction of patient outcomes, and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate validation, adoption, and deployment of AI technologies into clinical practice.



Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print
Feeny AK, Chung MK, Madabhushi A, Attia ZI, ... Turakhia MP, Wang PJ
Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print | PMID: 32628863
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Abstract

Characterization of Lead Adherence Using Intravascular Ultrasound to Assess Difficulty of Transvenous Lead Extraction.

Beaser AD, Aziz Z, Besser SA, Jones CI, ... Tung R, Nayak HM

- Clinical factors associated with development of intravascular lead adherence (ILA) are unreliable predictors. Because vascular injury in the superior vena cava - right atrium (SVC-RA) during transvenous lead extraction (TLE) is more likely to occur in segments with higher degrees of ILA, reliable and accurate assessment of ILA is warranted. We hypothesized that intravascular ultrasound (IVUS) could accurately visualize and quantify ILA and degree of ILA correlates with TLE difficulty.- Serial imaging of leads occurred prior to TLE using IVUS. ILA areas were classified as high or low grade. Degree of extraction difficulty was assessed using 2 metrics and correlated with ILA grade. Lead extraction difficulty (LED) was calculated for each patient and compared to IVUS findings.- 158 vascular segments in 60 patients were analyzed: 141 (89%) low grade versus 17 (11%) high grade. Median extraction time (low=0 versus high grade=97 seconds, p<0.001) and median laser pulsations delivered (low=0 versus high grade=5852, p<0.001) were significantly higher in high grade segments. Most patients with low LED score had low ILA grades. 86% of patients with high LED score had low IVUS grade and the degree of TLE difficulty was similar to patients with low IVUS grades and LED scores.- IVUS is a feasible imaging modality that may be useful in characterizing ILA in the SVC-RA region. An ILA grading system using imaging correlates with extraction difficulty. Most patients with clinical factors associated with higher extraction difficulty may exhibit lower ILA and extraction difficulty based on IVUS imaging.



Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print
Beaser AD, Aziz Z, Besser SA, Jones CI, ... Tung R, Nayak HM
Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print | PMID: 32628867
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Abstract

Electrocardiogram Standards for Children and Young Adults Using Z-scores.

Bratincsák A, Kimata C, Limm-Chan BN, Vincent K, Williams M, Perry JC

- Normative ECG values for children are based on relatively few subjects and are not standardized, resulting in interpersonal variability of interpretation. Recent advances in digital technology allow a more quantitative, reproducible assessment of ECG variables. Our objective was to create the foundation of normative ECG standards in the young utilizing Z-scores.- One-hundred-and-two ECG variables were collected from a retrospective cohort of 27085 study subjects with no known heart condition, ages 0-39 years. The cohort was divided into 16 age groups by gender. Median, interquartile range and range were calculated for each variable adjusted to body surface area.- Normative standards were developed for all 102 ECG variables including heart rate; P, R, and T axis; R-T axis deviation; PR interval, QRS duration, QT and QTc interval; P, Q, R, S, and T amplitudes in 12 leads; as well as QRS and T wave integrals. Incremental Z-score values between -2.5 and 2.5 were calculated to establish upper and lower limits of normal. Historical ECG interpretative concepts were reassessed and new concepts observed.- Electronically acquired ECG values based on the largest pediatric and young adult cohort ever compiled provide the first detailed, standardized, quantitative foundation of traditional and novel ECG variables. Expression of ECG variables by Z-scores lends an objective and reproducible evaluation without interpreter bias that can lead to more confident establishment of ECG-disease correlations and improved automated ECG readings in high volume cardiac screening efforts in the young.



Circ Arrhythm Electrophysiol: 06 Jul 2020; epub ahead of print
Bratincsák A, Kimata C, Limm-Chan BN, Vincent K, Williams M, Perry JC
Circ Arrhythm Electrophysiol: 06 Jul 2020; epub ahead of print | PMID: 32634327
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Abstract

Machine Learning to Classify Intracardiac Electrical Patterns during Atrial Fibrillation.

Alhusseini MI, Abuzaid F, Rogers AJ, Zaman JAB, ... Rappel WJ, Narayan SM

- Advances in ablation for atrial fibrillation (AF) continue to be hindered by ambiguities in mapping, even between experts. We hypothesized that convolutional neural networks (CNN) may enable objective analysis of intracardiac activation in AF, which could be applied clinically if CNN classifications could also be explained.- We performed panoramic recording of bi-atrial electrical signals in AF. We used the Hilbert-transform to produce 175,000 image grids in 35 patients, labeled for rotational activation by experts who showed consistency but with variability (kappa=0.79). In each patient, ablation terminated AF. A CNN was developed and trained on 100,000 AF image grids, validated on 25,000 grids, then tested on a separate 50,000 grids.- In the separate test cohort (50,000 grids), CNN reproducibly classified AF image grids into those with/without rotational sites with 95.0% accuracy (CI 94.8-95.2%). This accuracy exceeded that of support vector machines, traditional linear discriminant and k-nearest neighbor statistical analyses. To probe the CNN, we applied Gradient-weighted Class Activation Mapping which revealed that the decision logic closely mimicked rules used by experts (C-statistic 0.96).- Convolutional neural networks improved the classification of intracardiac AF maps compared to other analyses, and agreed with expert evaluation. Novel explainability analyses revealed that the CNN operated using a decision logic similar to rules used by experts, even though these rules were not provided in training. We thus describe a scaleable platform for robust comparisons of complex AF data from multiple systems, which may provide immediate clinical utility to guide ablation.



Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print
Alhusseini MI, Abuzaid F, Rogers AJ, Zaman JAB, ... Rappel WJ, Narayan SM
Circ Arrhythm Electrophysiol: 05 Jul 2020; epub ahead of print | PMID: 32631100
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Abstract

Endocardial-Epicardial Phase Mapping of Prolonged Persistent Atrial Fibrillation Recordings: High Prevalence of Dissociated Activation Patterns.

Parameswaran R, Kalman JM, Royse A, Goldblatt J, ... Gerstenfeld EP, Lee G

- Endocardial-epicardial dissociation (EED) and focal breakthroughs in humans with atrial fibrillation (AF) have been recently demonstrated using activation mapping of short 10-second AF segments. In the current study we used simultaneous endo-epi phase mapping to characterise endo-epi activation patterns on long segments of human persistent AF (PeAF).- Simultaneous intra-operative mapping of endo- and epicardial lateral RA wall was performed in patients with PeAF using two high-density grid catheters (16 electrodes, 3mm spacing). Filtered unipolar and bipolar electrograms (EGM\'s) of continuous 2-min AF recordings and electrodes locations were exported for phase analyses. We defined EED as phase difference of ≥20ms between paired endo-epi electrodes. Wavefronts (WF) were classified as rotations, single WF (SWF), focal waves or disorganised activity as per standard criteria. Endo-Epi WF patterns were simultaneously compared on dynamic phase maps. Complex fractionated EGM\'s were defined as bipolar EGM\'s with ≥5 directional changes occupying at least 70% of sample duration.- Fourteen patients with PeAF undergoing cardiac surgery were included. EED was seen in 50.3% of phase maps with significant temporal heterogeneity. Disorganised activity (Endo:41.3% vs Epi:46.8%, p=0.0194) and SWF (Endo:31.3% vs Epi:28.1%, p=0.129) were the dominant patterns. Transient rotations (Endo:22% vs Epi:19.2%, p=0.169; mean duration: 590±140ms) and non-sustained focal waves (Endo:1.2% vs Epi:1.6%, p=0.669) were also observed. Apparent transmural migration of rotational activations (n=6) from the epi- to the endocardium was seen in 2 patients. EGM fractionation was significantly higher in the epicardium than endocardium (61.2% vs 51.6%, p<0.0001).- Simultaneous endo-epi phase mapping of prolonged human PeAF recordings shows significant EED marked temporal heterogeneity, discordant and transitioning WF patterns and complex fractionations. No sustained focal activity was observed. Such complex 3D-interactions provide insight into why endocardial mapping alone may not fully characterise the AF mechanism and why endocardial ablation may not be sufficient.



Circ Arrhythm Electrophysiol: 06 Jul 2020; epub ahead of print
Parameswaran R, Kalman JM, Royse A, Goldblatt J, ... Gerstenfeld EP, Lee G
Circ Arrhythm Electrophysiol: 06 Jul 2020; epub ahead of print | PMID: 32634027
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This program is still in alpha version.