Spontaneous Ventricular Tachycardia Research Articles

The importance of scar border zone size in VT presentation and recurrence in post MI patients

Abstract Introduction Available mapping data in post-myocardial infarction patients describe ventricular tachycardia (VT) re-entry circuit characteristics of slow VT, that are typically related to transmural scars. Fast VTs with cycle lengths close to the refractory period may be related to functional re-entry in the scar border zone. Functional re-entry related border zone VTs may be difficult to control by ablation. Purpose The aims of this study are (1) to describe electroanatomical voltage map (EAVM) characteristics in post myocardial infarction (MI) patients with spontaneous and inducible fast VTs and (2) to assess the relation between scar border zone size and ablation outcomes. Methods Consecutive post-MI patients undergoing VT ablation at a tertiary referral center from January 2012 to November 2018 were included. Fast VT was defined as a VT cycle length (VTCL) = ventricular refractory period + max. 30ms. Areas of scar border zone (using 0.5 – 2.1mV/3.0mV cut-offs (according to LV remodeling stage; LVEF<47% and LV end-systolic volume index of >50 ml/m2)) were measured on the EAVM and correlated with clinical outcomes. Results In total, 138 patients were included (86% male; left ventricular ejection fraction 35±10%; 86% remodeled LV). Twenty-three patients (17%) had ≥1 fast VT (mean VTCL 275±52ms) at presentation, mean VTCL of the remaining patients 397±88ms). The median scar border zone size was 27% [IQR 20-38] of the left ventricular endocardial surface. Patients who presented with a spontaneous fast VT had a larger border zone than patients with slower VT (32% [IQR 28 – 41] vs. 25% [IQR 16 – 36], p=0.01). After ablation, 79 (57%) patients remained inducible for any VT, including 59/79 (75%) for a fast VT (median VTCL fast VT 260ms [IQR 236 -280]). Patients who remained inducible for fast VTs had a larger border zone than patients who remained inducible for slower VTs (35% [IQR 27 – 44] vs. 26% [IQR 20 – 36], p<0.001). During a median follow-up of 26 months [IQR 8 – 47], 45 patients (33%) had a VT recurrence (mean VTCL 357±98ms). Patients with a below median (27%) scar border zone area had a lower VT recurrence rate compared to patients with an above median scar border zone area (recurrence rate: 16/66 (24%) vs. 29/72 (40%), p=0.03). Kaplan-Meier survival analysis showed better free VT survival in the below median border zone patients (Log-rank: p<0.05) (Figure 1). Conclusion Patients who present with spontaneous fast VTs or who remain inducible for fast VTs after ablation have larger scar border zones during EAVM compared to patients with presenting or remaining slower VTs. A larger border zone appeared to be associated with higher VT-recurrence rates. The scar border zone may play an important role as VT substrate for (fast) VTs and may not be easily targeted by current ablation techniques.VT-free survival stratified by median BZ

Ventricular tachycardia mapping and ablation using MIXture of well-established approaches. The MIX-VT study

Abstract Introduction Ablation for ventricular tachycardia (VT) is still challenging despite impressive technology development, especially in mid- or low-volume centers. The most frequently used approach is homogenization of scar area responsible for VT, combined with standard electrophysiological (EP) approaches such as VT inducibility and mapping. However, in real life long-term efficacy of VT ablation in such centers does not exceed 50%. We hypothesized that an approach consisting of the mixture of various well-established parameters would be more effective than scar homogenization and VT non-inducibility as the endpoints. Purpose To compare the outcome of VT ablation using the standard approach (scar homogenization) and a more complex approach, called the MIX-VT protocol, using late potential mapping + pace mapping with rapid change of VT morphology to localize the critical isthmus + core isolation. All procedures were performed using the 3D mapping system, Pentaray mapping catheter, Smart-Touch ablation catheter and intracardiac echocardiography (ICE). Methods 48 consecutive patients (41 male, mean age 71.5 years) with ischemic cardiopathy referred for urgent VT ablation were included: 23 patients underwent "standard" VT ablation between December 2018 and December 2019, whereas the next 25 patients underwent ablation using the MIX-VT protocol between January 2020 and December 2020. First step in the MIX-VT group was to perform ICE imaging of the scar area from the right ventricle. Next, left ventricular maps were created during rhythm at which spontaneous VT occurred (sinus or paced). Areas of late potentials were identified to localize the critical isthmus where the abrupt change in the paced-QRS axis was seen. Finally, areas delineated by these two above-mentioned maneuvers where ablated in order to achieve core isolation (Figure 1). The patients were followed for 12 months in the outpatient clinic during ICD examination. The composite end-point for follow-up was VT recurrences terminated by anty-tachycardia pacing (ATP) or shock, or death. Results Clinical and demographic variables were similar between the two groups (Figure 2), except for a higher prevalence of diabetes mellites and number of previous ablations in the standard group (4/25 [16%] vs 10/23 [43%], p=0.03 and 2/24 vs 8/23 [34.8], p=0.03, respectively). Three patients from the MixVT group and one patient from the standard group were lost to follow-up. During follow-up, VT recurrences were significantly less frequent in the MIX-VT group (3/22 [13.6] vs 10/22 [45.4]. p=0.02. It was mostly driven by less ATP therapy. (Figure 2). One patient from the standard approach groups died. Conclusion Ablation for VT in low- or medium volume centers using the combination of well-established various EP approaches resulted in the improvement in overall survival and arrythmia-free survival. The presented approach does not involve additional resource utilization.

Systematic right ventricular electrophysiologic evaluation in patients with repaired tetralogy of Fallot before pulmonary valve replacement

Abstract Introduction Adults with repaired tetralogy of Fallot (rToF) are prone to develop ventricular tachycardia (VT) in adulthood, due to reentry related to slowly conducting anatomical isthmuses (SCAI). Pulmonary valve replacement (PVR) in patients without history of VT, may lead to obliteration of unrecognized SCAI with subsequent catheter ablation failure; electrophysiologic study is thus recommended before PVR. A systematic evaluation of the topology of SCAI in this population is, however, scant. Methods Consecutive rToF patients undergoing PVR with native right ventricular outflow tract were studied with pre-PVR EPS. Electroanatomical mapping with systematic evaluation of all possible anatomical isthmuses (AI) with pacemapping, activation mapping in sinus/paced rhythm and bipolar voltage mapping was performed (AI1: anterior scar/patch to tricuspid annulus; AI2: anterior scar to pulmonary annulus; AI3: pulmonary annulus to ventricular septal defect – VSD- patch; AI4: VSD to tricuspid annulus). Conduction velocity (CV) across all documented AI was calculated (ratio between the distance among the nearest point with bipolar voltage >1.5 mV and their difference in activation timing). Ventricular programmed stimulation was performed at 2 sites (apex and outflow tract) with drive train ad 600/400 ms, up to three extrastimuli until refractoriness or induction, during baseline and isoproterenol infusion. Radiofrequency catheter ablation (RFCA) was performed in all patients with inducible VT and/or SCAI, aiming at conduction block across the SCAI validated with differential pacing. Results Between May 2023 and November 2023, 10 patients with rToF and 1 double outlet right ventricle were studied (73% males, age 46±10 years; 54% with a previous shunt, 46% with a previous transannular patch, 27% pulmonary valvotomy and infundibular boring; median age at surgery 4 years, interquartile range 3-6). EPS was positive for inducible VT in 4 patients (mean cycle length 297 ms, 3 with left bundle branch morphology and 1 right bundle branch morphology, all inferior axis) and polymorphic VT in 1. AI1 was present in 5 patients, AI2 in 5, AI3 in 7, AI 4 in 2. At least 1 SCAI was present in 7 patients (64%), 2 SCAI in 3 patients (43% of patients with SCAI; in every patient SCAI3+SCAI2 in 2 and SCAI 4 in 1 patient). There were no SCAI1; there were 3 SCAI 2 (mean CV 0.43 m/s), 4 SCAI 3 (mean CV 0.3 m/s), 1 SCAI 4 (CV 0.4 m/s). RFCA was performed in 8 patients; acute success was achieved in all patients, achieving bidirectional conduction block across treated SCAI and non-inducibility of VT. Conclusions SCAI are often present in rToF candidate to PVR and without clinical history of spontaneous VT, involving prevalently SCAI3 and SCAI2. Inducible VT is not sufficient as a marker of arrhythmic risk and SCAI should be better sought for. RFCA of SCAI with bidirectional conduction block is acutely highly efficacious.

Inhibition of IL-1 Ameliorates Cardiac Dysfunction and Arrhythmias in a Murine Model of Kawasaki Disease.

Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1β and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.

Automated isochronal late activation mapping for substrate characterization in patients with repaired tetralogy of Fallot.

Slow conduction (SC) anatomical isthmuses (AIs) are the dominant substrate for monomorphic ventricular tachycardia (VT) in patients with repaired tetralogy of Fallot (rTF). This study aimed to evaluate the utility of automated propagational analysis for the identification of SC-AI in patients with rTF. Consecutive rTF patients undergoing VT substrate characterization were included. Automated isochronal late activation maps (ILAM) were obtained with multielectrode HD Grid Catheter. Identified deceleration zones (DZs) were compared with both SC-AI defined by conduction velocity (CV) (<0.5 m/s) and isthmuses of induced VT for mechanistic correlation. Fourteen patients were included (age 48; p25-75 35-52 years; 57% male), 2 with spontaneous VT and 12 for risk stratification. Nine VTs were inducible in seven patients. Procedure time was 140 (p25-75 133-180) min and mapping time 29.5 (p25-75 20-37.7) min, using a median of 2167 points. All the patients had at least one AI by substrate mapping, identifying a total of 27 (11 SC-AIs). Isochronal late activation maps detected 10 DZs mostly in the AI between ventricular septal defect and pulmonary valve (80%). Five patients had no DZs. A significant negative correlation between number of isochrones/cm and CV was observed (rho -0.87; P < 0.001). Deceleration zones correctly identified SC-AI (90% sensitivity; 100% specificity; 0.94 accuracy) and was related to VT inducibility (P = 0.006). Deceleration zones co-localized to the critical isthmus of induced VTs in 88% of cases. No complications were observed. Deceleration zones displayed by ILAM during sinus rhythm accurately identify SC-AIs in rTF patients allowing a safe and short-time VT substrate characterization procedure.

Machine learning-derived cycle length variability metrics predict spontaneously terminating ventricular tachycardia in implantable cardioverter defibrillator recipients.

Implantable cardioverter defibrillator (ICD) therapies have been associated with increased mortality and should be minimized when safe to do so. We hypothesized that machine learning-derived ventricular tachycardia (VT) cycle length (CL) variability metrics could be used to discriminate between sustained and spontaneously terminating VT. In this single-centre retrospective study, we analysed data from 69 VT episodes stored on ICDs from 27 patients (36 spontaneously terminating VT, 33 sustained VT). Several VT CL parameters including heart rate variability metrics were calculated. Additionally, a first order auto-regression model was fitted using the first 10 CLs. Using features derived from the first 10 CLs, a random forest classifier was used to predict VT termination. Sustained VT episodes had more stable CLs. Using data from the first 10 CLs only, there was greater CL variability in the spontaneously terminating episodes (mean of standard deviation of first 10 CLs: 20.1 ± 8.9 vs. 11.5 ± 7.8 ms, P < 0.0001). The auto-regression coefficient was significantly greater in spontaneously terminating episodes (mean auto-regression coefficient 0.39 ± 0.32 vs. 0.14 ± 0.39, P < 0.005). A random forest classifier with six features yielded an accuracy of 0.77 (95% confidence interval 0.67 to 0.87) for prediction of VT termination. Ventricular tachycardia CL variability and instability are associated with spontaneously terminating VT and can be used to predict spontaneous VT termination. Given the harmful effects of unnecessary ICD shocks, this machine learning model could be incorporated into ICD algorithms to defer therapies for episodes of VT that are likely to self-terminate.

Effects of Mesenchymal Stem Cell Injection into Healed Myocardial Infarction Scar Border Zone on the Risk of Ventricular Tachycardia.

The scar border zone is a main source of reentry responsible for ischemic ventricular tachycardia (VT). We evaluated the effects of mesenchymal stem cell (MSC) injection into the scar border zone on arrhythmic risks in a post-myocardial infarction (MI) animal model. Rabbit MI models were generated by left descending coronary artery ligation. Surviving rabbits after 4 weeks underwent left thoracotomy and autologous MSCs or phosphate-buffered saline (PBS) was administered to scar border zones in two rabbits in each group. Another rabbit without MI underwent a sham procedure (control). An implantable loop recorder (ILR) was implanted in the left chest wall in all animals. Four weeks after cell injections, ventricular fibrillation was induced in 1/2 rabbit in the PBS group by electrophysiologic study, and no ventricular arrhythmia was induced in the MSC group or control. Spontaneous VT was not detected during ILR analysis in any animal for 4 weeks. Histologic examination showed restoration of connexin 43 (Cx43) expression in the MSC group, which was higher than in the PBS group and comparable to the control. In conclusion, MSC injections into the MI scar border zone did not increase the risk of VT and were associated with favorable Cx43 expression and arrangement.

Ventricular tachycardia substrates in young patients with repaired tetralogy of fallot

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): We acknowledge the support from the Netherlands Cardiovascular Research lnitiative: An initiative with support of the Dutch Heart Foundation and Hartekind. Background Patients with repaired tetralogy of Fallot (rTOF) have a time-dependent increase in risk of ventricular tachycardia (VT) after the age of 30 years (Y), with slow conducting anatomical isthmus (SCAI) 3, located between the pulmonary annulus and the ventricular septal defect (VSD) patch, as dominant VT substrate (1-4). However, SCAI may be already present before 30Y. Purpose To assess (1) the prevalence of SCAI, (2) the associated factors in SCAI development, and (3) the occurrence of clinical VT, in rTOF patients &amp;lt;30Y. Methods From a database of 146 patients with rTOF or related lesions who underwent electroanatomical mapping (EAM) and programmed electrical stimulation (PES) between 2007 and 2022 for treatment of ventricular arrhythmias (VA), risk stratification or before pulmonary valve replacement (PVR), those aged &amp;lt;30Y at time of procedure were selected and analysed. Results Of 146 rTOF patients, 55 (38%) were &amp;lt;30Y (median 16Y [IQR 14-22]); 33/55 (60%) had TOF, 9/55 (16%) TOF with double outlet right ventricle (DORV), and 13/55 (24%) complex TOF variants, including 8 patients with pulmonary atresia with VSD, 2 patients with absent pulmonary valve, and 3 with other variations. Initial intracardiac surgical repair (median age 0.8Y [IQR 0.4-1.4]) was performed via a ventriculotomy in 10/55 (18%) after palliative shunts in 16/55 (29%). An RV to pulmonary artery (RV-PA) conduit was inserted during initial or early after (&amp;lt;1Y) initial repair in 12/55 (22%). In 14/55 (25%) pulmonary valve replacement (PVR) was performed later in life (median age 10.1Y [IQR 2.7-14.3]). Five of 55 (9%) underwent EAM/PES after a spontaneous VA, 40/55 (73%) before PVR, and 10/55 (18%) for risk stratification. Monomorphic VT was inducible in 8/55 (15%), including 4/5 patients with spontaneous VT, and was proven related to a SCAI 3 in 7/8 (88%). In 16/55 (29%) SCAI 3 could be identified; no other SCAI (1,2,4) was present. Of note, 9/16 (56%) of patients with SCAI 3 had initial RV-PA conduit repair/early PVR, in comparison with only 3/39 (8%) of patients without SCAI. In univariable analysis complex TOF (OR 6.8 [95% CI 1.8-26.4]), ventriculotomy (OR 5.3 [95% CI 1.2-22.3]), any prior PVR (OR 4.8 [95% CI 1.4-16.7]), and initial RV-PA conduit/early PVR (OR 15.4 [95% CI 3.3-71.8]) were significantly associated with SCAI 3. In multivariable analysis initial RV-PA conduit/early PVR remained the only independent predictor of SCAI 3 (OR 13.0 [95% CI 1.2-142.4]). Conclusions A SCAI 3 is present in 29% of rTOF patients &amp;lt;30Y referred for EAM/PES and the dominant VT substrate for spontaneous and inducible VTs. RV-PA conduit placement during initial repair or early PVR (&amp;lt;1Y after repair) is associated with SCAI 3 in young rTOF. Whether the early conduit/valve placement causes scarring at the infundibulum with consecutive slow conduction and/or whether the complex variants contribute to SCAI requires additional studies.

Sophoridine manifests as a leading compound for anti-arrhythmia with multiple ion-channel blocking effects

BackgroundSophoridine (SR) has shown the potential to be an antiarrhythmic agent. However, SR's electrophysiological properties and druggability research are relatively inadequate, which limits the development of SR as an antiarrhythmic candidate. PurposeTo facilitate the development process of SR as an antiarrhythmic candidate, we performed integrated studies on the electrophysiological properties of SR in vitro and ex vivo to gain more comprehensive insights into the multi-ion channel blocking effects of SR, which provided the foundation for the further drugability studies in antiarrhythmic and safety studies. Firstly, SR's electrophysiological properties and antiarrhythmic potentials were recorded and assessed at the cell and tissue levels by comprehensively integrating the patch clamp with the Electrical and Optical Mapping systems. Subsequently, the antiarrhythmic effects of SR were validated by aconitine and ouabain-induced arrhythmia in vivo. Finally, the safety of SR as an antiarrhythmic candidate compound was evaluated based on the guidelines of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). Study designThe antiarrhythmic effect of SR was evaluated at the in vitro, ex vivo, and in vivo levels. MethodsIsolated primary cardiomyocytes and stable cell lines were prepared to explore the electrophysiologic properties of being a multiple ion-channel blocker in vitro by whole-cell patch clamp. Using electrical and optical mapping, the negative chronotropic effect of SR was determined in langendorff-perfused rat or guinea-pig hearts.The antiarrhythmic activity of SR was assessed by the ex vivo tachyarrhythmia models induced by left coronary artery ligation (LCAL) and isoproterenol (ISO). Canonical models of aconitine and ouabain-induced arrhythmia were used to verify the antiarrhythmic effects in vivo. Finally, the pro-arrhythmic risk of SR was detected in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hSCCMs) using a Microelectrode array (MEA). ResultsSingle-cell patch assay validated the multiple ion-channel blockers of SR in transient outward current potassium currents (Ito), l-type calcium currents (ICa-l), and rapid activation delayed rectifier potassium currents (IKr). SR ex vivo depressed heart rates (HR) and ventricular conduction velocity (CV) and prolonged Q-T intervals in a concentration-dependent manner. Consistent with the changes in HRs, SR extended the active time of hearts and increased the action potential duration measured at 90% repolarization (APD90). SR could also significantly lengthen the onset time and curtail the duration of spontaneous ventricular tachycardia (VT) in the ex vivo arrhythmic model induced by LCAL. Meanwhile, SR could also significantly upregulate the programmed electrical stimulation (PES) frequency after the ISO challenge in forming electrical alternans and re-entrant excitation. Furthermore, SR exerted antiarrhythmic effects in the tachyarrhythmia models induced by aconitine and ouabain in vivo. Notably, the pro-arrhythmic risk of SR was shallow for a moderate inhibition of the human ether-à-go-go-related gene (hERG) channel. Moreover, SR prolonged field potential duration (FPDc) of hSCCMs in a concentration-dependent manner without early after depolarization (EAD) and arrhythmia occurrence. ConclusionOur results indicated that SR manifested as a multiple ion-channel blocker in the electrophysiological properties and exerts antiarrhythmic effects ex vivo and in vivo. Meanwhile, due to the low pro-arrhythmic risk in the hERG inhibition assay and the induction of EAD, SR has great potential as a leading candidate in the treatment of ventricular tachyarrhythmia.

Antitachycardia pacing success in implantable cardioverter-defibrillators by patient, device, and programming characteristics

Antitachycardia pacing (ATP) is an established implantable cardioverter-defibrillator (ICD) therapy that terminates ventricular tachycardias (VTs) without painful ICD shocks. However, factors influencing ATP success are not well understood. The purpose of this study was to examine ATP success rates by patient, device, and programming characteristics. This retrospective analysis of the PainFree SmartShock Technology study included spontaneous ATP-treated monomorphic VT episodes. ATP success rates were calculated for various factors. Also, the relationship of ATP programming on shock burden and syncope were investigated. Of the 2770 enrolled patients (2200 [79%] male; mean age 65 years), 1699 (61%) received an ICD and 1071 (39%) a cardiac resynchronization therapy - defibrillator. ATP had >80% rate of success for terminating VTs overall, with similar rates observed between ICD and cardiac resynchronization therapy - defibrillator devices (82.2% vs 80.3%, respectively; P = .81) as well as between primary and secondary prevention patients with ICDs (77.2% vs 83.9% respectively; P = .25). Arrhythmias with a median cycle length of ≥320 ms had a significantly higher ATP success rate (88.0%; 95% confidence interval 84.8%-90.6%). The cumulative percentage of ATP success increased from 71% at 1 ATP sequence delivered to 87% at ≥8 sequences delivered. Programming more ATP sequences was associated with lower shock burden (P = .0005). There was no evidence that more sequences were associated with higher rates of syncope (P = .16). Delivering more ATP sequences resulted in a higher overall success of terminating VTs, while programming more ATP was associated with decreased shock burden and no evidence of increased syncope or acceleration. This suggests that more ATP sequences should be programmed when possible, but confirmation in prospective studies will be necessary.

Experimental hypothyroidism induces cardiac arrhythmias and ranolazine reverts and prevents the phenotype

AimsHypothyroidism is associated with an increased risk of cardiovascular disease and enhanced susceptibility to arrhythmias. In our investigation, we evaluated the potential involvement of late sodium current (INa,late) in cardiac arrhythmias in an experimental murine model of hypothyroidism. Main methodsMale Swiss mice were treated with methimazole (0.1 % w/vol, during 21 days) to induce experimental hypothyroidism before ECG, action potential (AP) and intracellular Ca2+ dynamics were evaluated. Susceptibility to arrhythmia was measured in vitro and in vivo. Key findingsThe results revealed that hypothyroid animals presented ECG alterations (e.g. increased QTc) with the presence of spontaneous sustained ventricular tachycardia. These changes were associated with depolarized resting membrane potential in isolated cardiomyocytes and increased AP duration and dispersion at 90 % of the repolarization. Aberrant AP waveforms were related to increased Ca2+ sparks and out-of-pace Ca2+ waves. These changes were observed in a scenario of enhanced INa,late. Interestingly, ranolazine, a clinically used blocker of INa,late, restored the ECG alterations, reduced Ca2+ sparks and aberrant waves, decreased the in vitro events and the severity of arrhythmias observed in isolated cardiomyocytes from hypothyroid animals. Using the in vivo dobutamine + caffeine protocol, animals with hypothyroidism developed catecholaminergic bidirectional ventricular tachycardia, but pre-treatment with ranolazine prevented this. SignificanceWe concluded that animals with hypothyroidism have increased susceptibility to developing arrhythmias and ranolazine, a clinically used blocker of INa,late, is able to correct the arrhythmic phenotype.

Abstract P1085: Transient Receptor Potential Cation Channel Subfamily M Member 7 Deficiency Prevents Ventricular Tachycardia During Myocardial Ischemia Reperfusion

Introduction: Ventricular arrhythmia caused by myocardial ischemia reperfusion (myo-I/R) remain a substantial challenge worldwide. Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a Ca 2+ -permeable channel, and is involved in cardiogenesis and atrial fibrillation. However, the function of TRPM7 in ventricular arrhythmias during myo-I/R is unknown. Hypothesis: We propose that TRPM7 plays a role in ventricular arrhythmias during myo-I/R, therefore deletion of Trpm7 will protect mice against ventricular arrhythmia during myo-I/R. Methods: We used myo-I/R mouse model, in combination with patch-clamp, and various other techniques to investigate the potential role of TRPM7 in myo-I/R injury. Intracardiac programed electrical stimulation was performed to explore the susceptibility to ventricular arrhythmia, and in vitro assays were used for mechanism investigation. Results: We found that myo-I/R can readily induce spontaneous ventricular tachycardia (VT) in WT mice, whereas global Trpm7 deletion ( Trpm7 -/- ) dramatically reduced incidence of VT by 50.0% ( P &lt;0.05, n =10). In the program induced VT, Trpm7 -/- drastically shortened the duration of VT by 153.5 ± 24.0 (s) ( P &lt;0.05, n=10). As TRPM7 is highly expressed in both myocytes and cardiac fibroblast, we established myocyte-specific Trpm7 deletion and fibroblast-specific Trpm7 deletion mice. We found that TRPM7 in myocytes is responsible for VT induced by myo-I/R. To understand the mechanism by which TRPM7 is involved in VT, we evaluated electrphysiological properties of myocytes. The action potentials (AP) duration of ventricular myocytes isolated from WT mice, which significantly shortened after treatment of oxygen glucose deprivation, whereas Trpm7 -/- restored the AP by prolong the duration without influencing amplitude. Whole-cell patch clamp was performed to record L-type Ca 2+ and K + currents with sodium bisulfite treatment. Interestingly, Trpm7 -/- notably normalized the density of K + current back to the normal level when compared to WT myocytes subjected to oxidative stress. Conclusions: Our results indicate that TRPM7 in myocytes is involved in electrical remodeling during myo-I/R. Inhibition of TRPM7 channel function may serve as a potential target for myo-I/R induced ventricular arrhythmias.

Distinct spectral dynamics of implanted cardiac defibrillator signals in spontaneous termination of polymorphic ventricular tachycardia and fibrillation in patients with electrical and structural diseases.

To determine the spectral dynamics of early spontaneous polymorphic ventricular tachycardia and ventricular fibrillation (PVT/VF) in humans. Fifty-eight self-terminated and 173 shock-terminated episodes of spontaneously initiated PVT/VF recorded by Medtronic implanted cardiac defibrillators (ICDs) in 87 patients with various cardiac pathologies were analyzed by short fast Fourier transform of shifting segments to determine the dynamics of dominant frequency (DF) and regularity index (RI). The progression in the intensity of DF and RI accumulations further quantified the time course of spectral characteristics of the episodes. Episodes of self-terminated PVT/VF lasted 8.6 s [95% confidence interval (CI): 8.1-9.1] and shock-terminated lasted 13.9 s (13.6-14.3) (P < 0.001). Recordings from patients with primarily electrical pathologies displayed higher DF and RI values than those from patients with primarily structural pathologies (P < 0.05) independently of ventricular function or antiarrhythmic drug therapy. Regardless of the underlying pathology, the average DF and RI intensities were lower in self-terminated than shock-terminated episodes [DF: 3.67 (4.04-4.58) vs. 4.32 (3.46-3.93) Hz, P < 0.001; RI: 0.53 (0.48-0.56) vs. 0.63 (0.60-0.65), P < 0.001]. In a multivariate analysis controlled by the type of pathology and clinical variables, regularity remained an independent predictor of self-termination [hazard ratio: 0.954 (0.928-0.980)]. Receiver operating characteristic (ROC) curve analysis of DF and RI intensities demonstrated increased predictability for self-termination in time with 95% CI above the 0.5 cut-off limit at about t = 8.6 s and t = 6.95 s, respectively. Consistent with the notion that fast organized sources maintain PVT/VF in humans, reduction of frequency and regularity correlates with early self-termination. Our findings might help generate ICD methods aiming to reduce inappropriate shock deliveries.

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

Life-threatening ventricular arrhythmia prediction in patients with dilated cardiomyopathy using explainable electrocardiogram-based deep neural networks.

AimsWhile electrocardiogram (ECG) characteristics have been associated with life-threatening ventricular arrhythmias (LTVA) in dilated cardiomyopathy (DCM), they typically rely on human-derived parameters. Deep neural networks (DNNs) can discover complex ECG patterns, but the interpretation is hampered by their ‘black-box’ characteristics. We aimed to detect DCM patients at risk of LTVA using an inherently explainable DNN.Methods and resultsIn this two-phase study, we first developed a variational autoencoder DNN on more than 1 million 12-lead median beat ECGs, compressing the ECG into 21 different factors (F): FactorECG. Next, we used two cohorts with a combined total of 695 DCM patients and entered these factors in a Cox regression for the composite LTVA outcome, which was defined as sudden cardiac arrest, spontaneous sustained ventricular tachycardia, or implantable cardioverter-defibrillator treated ventricular arrhythmia. Most patients were male (n = 442, 64%) with a median age of 54 years [interquartile range (IQR) 44–62], and median left ventricular ejection fraction of 30% (IQR 23–39). A total of 115 patients (16.5%) reached the study outcome. Factors F8 (prolonged PR-interval and P-wave duration, P < 0.005), F15 (reduced P-wave height, P = 0.04), F25 (increased right bundle branch delay, P = 0.02), F27 (P-wave axis P < 0.005), and F32 (reduced QRS-T voltages P = 0.03) were significantly associated with LTVA.ConclusionInherently explainable DNNs can detect patients at risk of LTVA which is mainly driven by P-wave abnormalities.

Three-year chronic follow-up from the pilot study of a substernal extravascular implantable cardioverter defibrillator

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Medtronic Background The investigational Extravascular Implantable Cardioverter-Defibrillator (EV ICD) uses a substernal lead and delivers defibrillation and pacing therapies, including antitachycardia pacing (ATP). Objective To characterize EV ICD system performance through 3 years. Methods The prospective, first-in-human EV ICD Pilot study was conducted at 4 sites in Australia and New Zealand. ICD-indicated patients were enrolled July-December of 2018. Defibrillation testing was conducted for all patients at implant, and chronically per physician discretion. Electrical testing was conducted at pre-hospital discharge, 2 weeks, 4-6 weeks and 3 months post-implant, and every 6 months thereafter. Posture effects on pacing and sensing were evaluated through 3 months. Results Of 26 patients enrolled, 21 underwent the EV ICD implant procedure. There were no intraprocedural complications. After successful implantation and testing, 17 of 21 patients entered chronic follow-up. 14 patients continue follow up, representing 523 patient-months. Eight elective chronic defibrillation tests converted 7 of 7 patients with ≤ 40 J (maximum energy). Five episodes of spontaneous ventricular tachycardia (VT) were detected in 1 patient and either self-terminated or successfully defibrillated with appropriate shock. Over the total course of follow-up, 3 patients received an inappropriate shock due to; lead tip displacement with subsequent P-wave oversensing; Electromagnetic interference (EMI) in a ungrounded hot-tub; and EMI while doing plumbing work on unearthed electrical pipes, resulting in an annualized inappropriate shock rate of 6.9%. Pacing capture thresholds remained stable across time (5.1 ± 2.0 V at implant and 5.5 ± 2.7 V at 3 years); similarly, R-wave amplitudes were stable across time (3.4 ±2.0 mV at implant and 4.2 ± 2.7 mV at 3 years). Pacing thresholds tended to be lowest with the patient lying on the right side and pacing threshold often increased relative to supine position for left-side, prone or bending postures. R-wave amplitude tended to be greater when bending forward. There were 10 system or procedure-related adverse events in 8 patients through 3 years, including 3 elective system removals for: a single inappropriate shock (1), chronic defibrillation testing showing no safety margin in a patient with arrhythmogenic right ventricular dysplasia (1), intolerance to ATP (1 - high pacing threshold and frequent VT). Other than the lead tip displacement within the first 3 months, no additional clinically significant lead displacements have been observed through 3 years. Conclusion The EV ICD is a novel platform for delivering high-voltage therapy. There were no procedure and system related complications observed after the first year post-implant. Lead position and chronic system performance have generally remained stable through 3 years with a low rate of adverse events.

Severe coronary artery spasm during left atrial appendage closure plus catheter ablation for atrial fibrillation: case presentation

BackgroundLeft atrial appendage closure (LAAC) combined with radiofrequency catheter ablation (RFCA) as a hybrid procedure is commonly performed to treat atrial fibrillation (AF). Although this treatment carries a low risk of coronary artery spasm (CAS), and has never been observed in LAAC procedure, caution still needed to be taken. We presented a case of CAS that occurred in an AF patient during the hybrid procedure.Case presentationThe patient was a 65-year-old man with paroxysmal AF who developed CAS during RFCA and LAAC. In this case, LAAC was performed ahead of RFCA. After atrial septal puncture, the occluder was advanced into left atrium through delivery sheath, and successfully deployed in the LAA. After verifying the assessment of “PASS” criteria, we decided to release the device. However, before releasing the occluder in LAAC, the patient’s blood pressure (BP) fell to 70/45 mmHg with heart rate (HR) drop and ST-segment elevation in II, III, and aVF and reciprocal ST-segment depression in I and aVL. Isotonic sodium chloride load was administered. After 3 min, the BP and HR raised, and ST-segment returned to normal. The occluder was successfully released after the stable condition of the patient. Then, RFCA was sequentially performed. When isolating the right pulmonary veins, the patient’s BP and HR fell again with ST-segment elevation in inferior leads. Spontaneous ventricular tachycardia and fibrillation developed rapidly and defibrillation was performed immediately with success. Coronary angiography revealed the obstruction of the right coronary artery which disappeared completely after intracoronary nitroglycerin injection (1 mg). Under systemic diltiazem infusion, the RFCA procedure was accomplished. After the procedure, the patient recovered without any neurologic deficit, and CAS has never recurred with isosorbide mononitrate treatment during follow-up.ConclusionsCAS is a rare complication associated with AF hybrid procedure. Attention should be paid to this rare but potentially life-threatening complication.

Nonsustained Ventricular Tachycardia Is Independently Associated With Sustained Ventricular Arrhythmias in Nonischemic Dilated Cardiomyopathy

Spontaneous nonsustained ventricular tachycardia (NSVT) on Holter, VT inducibility during electrophysiology study, and late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) have been associated with sustained ventricular arrhythmias (SVAs) in nonischemic dilated cardiomyopathy (DCM). This study aimed to analyze whether these parameters carry independent prognostic value for spontaneous SVA in DCM. Between 2011 and 2018, patients with the DCM clinical spectrum and documented SVA, suspected SVA, or considered to be at intermediate or high risk for SVA were enrolled in the prospective Leiden Nonischemic Cardiomyopathy Study. Patients underwent a comprehensive evaluation including 24-hour Holter, LGE-CMR, and electrophysiology study. Holters were assessed for the presence of NSVT (≥3 beats; rate, ≥120 bpm; lasting <30 s) and NSVT characteristics (coupling interval, duration, cycle length, morphology, regularity). Patients were followed at 6 to 12 monthly intervals. Of all 115 patients (age, 59±12 years; 77% men; left ventricular ejection fraction, 33±13%; history of SVA, 36%; LGE in 63%; median LGE mass, 13 g; interquartile range, 8-23 g), 62 (54%) had NSVT on Holter, and sustained monomorphic VT was inducible in 34 of 114 patients (30%). NSVT was not associated with LGE on CMR or VT inducibility during electrophysiology study nor were its features (all P>0.05). During 4.0±1.8 years of follow-up, SVA occurred in 39 patients (34%). NSVT (HR, 4.47 [95% CI, 1.87-10.72]; P=0.001) and VT inducibility (HR, 3.08 [95% CI, 1.08-8.81]; P=0.036) were independently associated with SVA during follow-up. A bivariable model including only noninvasively acquired parameters also allowed identification of a high-risk subgroup (ie, those with both NSVT and LGE on CMR). The findings remained similar when only patients without prior SVA were included. In patients with DCM, NSVT on Holter and VT inducibility during electrophysiology study predict SVA during follow-up independent of LGE on CMR. NSVTs may serve as an initiator, and sustained VT inducibility indicates the presence of the substrate for SVA in DCM. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01940081.

Time-efficient three-dimensional transmural scar assessment provides relevant substrate characterization for ventricular tachycardia features and long-term recurrences in ischemic cardiomyopathy

Delayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging requires novel and time-efficient approaches to characterize the myocardial substrate associated with ventricular arrhythmia in patients with ischemic cardiomyopathy. Using a translational approach in pigs and patients with established myocardial infarction, we tested and validated a novel 3D methodology to assess ventricular scar using custom transmural criteria and a semiautomatic approach to obtain transmural scar maps in ventricular models reconstructed from both 3D-acquired and 3D-upsampled-2D-acquired LGE-CMR images. The results showed that 3D-upsampled models from 2D LGE-CMR images provided a time-efficient alternative to 3D-acquired sequences to assess the myocardial substrate associated with ischemic cardiomyopathy. Scar assessment from 2D-LGE-CMR sequences using 3D-upsampled models was superior to conventional 2D assessment to identify scar sizes associated with the cycle length of spontaneous ventricular tachycardia episodes and long-term ventricular tachycardia recurrences after catheter ablation. This novel methodology may represent an efficient approach in clinical practice after manual or automatic segmentation of myocardial borders in a small number of conventional 2D LGE-CMR slices and automatic scar detection.

My Heart Has Double Outlet What?

The aim of this case is to illustrate the rarity of this condition alongside complications that can occur post-surgical repair. In addition, the patient who generously consented for this case to be written has wished for increased awareness of double outlet right ventricle (DORV) among aspiring paediatricians, surgeons and cardiologists. A 40-year-old British Caucasian male presented with 2 concurrent episodes of chest pains. He has had a complex surgical repair of his DORV at age 32 with a pulmonary valve replacement which was complicated by endocarditis and an out of hospital ventricular tachycardia (VT) arrest at age 34 which resulted in hypoxic brain injury, permanent short term memory loss and an implantable cardioverterdefibrillator (ICD) insertion. Urgent ICD interrogation revealed evidence of spontaneous fast VT which were terminated back to sinus rhythm with 2 shocks. In view of recurring episodes of VT, commenced amiodarone and arranged further regular follow-up. With a birth prevalence of 0.02% based on the UK’s national congenital anomaly statistics, it is one of the less commonly occurring congenital heart defects in the UK. There has been massive advancement in our understanding of the condition and how to treat it which includes surgical intervention. However, the overall risks regarding mortality and complications post-surgery are still not well understood. Long term complications such as VT as demonstrated in this case carries a potential life-threatening risk and more research is needed in understanding how to effectively screen and prevent it.International Journal of Human and Health Sciences Supplementary Issue-2: 2021 Page: S14