Coupling Interval Research Articles

Polymorphic ventricular tachycardia, ischaemic ventricular fibrillation, and torsade de pointes: importance of the QT and the coupling interval in the differential diagnosis.

Distinctive types of polymorphic ventricular tachycardia (VT) respond differently to different forms of therapy. We therefore performed the present study to define the electrocardiographic characteristics of different forms of polymorphic VT. We studied 190 patients for whom the onset of 305 polymorphic VT events was available. The study group included 87 patients with coronary artery disease who had spontaneous polymorphic VT triggered by short-coupled extrasystoles in the absence of myocardial ischaemia. This group included 32 patients who had a long QT interval but nevertheless had their polymorphic VT triggered by ectopic beats with short coupling interval, a subcategory termed 'pseudo-torsade de pointes] (TdP). For comparison, we included 50 patients who had ventricular fibrillation (VF) during acute myocardial infarction ('ischaemic VF' group) and 53 patients with drug-induced TdP ('true TdP' group). The QT of patients with pseudo-TdP was (by definition) longer than that of patients with polymorphic VT and normal QT (QTc 491.4 ± 25.2 ms vs. 447.3 ± 55.6 ms, P < 0.001). However, their QT was significantly shorter than that of patients with true TdP (QTc 564.6 ± 75.6 ms, P < 0.001). Importantly, the coupling interval of the ectopic beat triggering the arrhythmia was just as short during pseudo-TdP as during polymorphic VT with normal QT (359.1 ± 38.1 ms vs. 356.6 ± 39.4 ms, P = 0.467) but was much shorter than during true TdP (581.2 ± 95.3 ms, P < 0.001). The coupling interval helps discriminate between polymorphic VT that occurs despite a long QT interval (pseudo-TdP) and polymorphic arrhythmias striking because of a long QT (true TdP).

New composite index has superior sensitivity in prediction of PVC-induced tachycardiomyopathy in patients with intermediate arrhythmic burden

Aims – Frequent premature ventricular complexes (PVCs) may induce/aggravate LV systolic dysfunction (LVD) by tachy(dyssynchrono)cardiomyopathy (tCMP) in patients with/without previous structural heart disease. High arrhythmic burden (i.e. &gt;26%) is the main predictor of tCMP development in patients with previously normal LV function. However, its predictive power is reduced once the arrhythmic burden is below 26%, with considerable overlap between patients at risk for tCMP and those who will maintain normal LV function. We sought to evaluate the predictive power of a composite index that includes PVC burden, PVC duration and PVC coupling interval. Methods – 61 patients referred for radiofrequency ablation (RFA), with frequent PVCs refractory to at least one antiarrhythmic drug (AAD), symptomatic and/or with LV systolic dysfunction (LVEF &lt; 50%) were retrospectively studied. Patients with structural lesions on transthoracic echocardiography (TTE) and/or cardiac magnetic resonance imaging (c-MRI), with sustained ventricular tachycardia/supraventricular tachycardia or severe valvular disease were excluded. A composite parameter dependent on PVC burden, PVC duration and PVC coupling interval was defi ned. Results – Mean PVC burden was 25.80% ± 11.64 (35% ± 8.16 in tCMP subgroup). Chronic PVC suppression was achieved in 89.6% of patients with a mean of 1.44 ± 0.7 procedures with 86.4% of patients requiring one procedure. Septal right ventricular outfl ow tract (RVOT) was the most frequent PVC origin (36.1%). Mean left ventricular ejection fraction (LVEF) in the tCMP group (7 patients) was 38% ± 5.26 which increased 1 month after RF ablation to 54.6% ± 3.64 (87.35% of recovered LVEF), at 3 months to 56% ± 2.23 and at 6 months 57% ± 2.73. LVEF recovery was also present in non-tCMP subgroup, yet statistically insignifi cant. There was no procedure-related mortality. Retrograde ventriculo-atrial (VA) conduction, male gender, non-sustained VT (NSVT), a higher BMI and a higher PVC burden were associated with tCMP development. ROC curve analysis appears to demonstrate higher sensitivity of tCMP prediction by the composite index in comparison to PVC burden in patients with 16.93-25.93% PVCs (i.e. below the formerly described tCMP PVC% cut-off). Conclusions – In patients with a PVC burden lower than the previously described cut offs (i.e. with ~17-25% PVCs) PVC mediated systolic dysfunction seems to be predicted with higher sensitivity by a composite index accounting for PVC burden, PVC duration and PVC coupling interval.

Optimising the Predictive Value of Ventricular Tachycardia Testing with Electrophysiology Studies: Which Minimum Coupling Interval Should be Used?

It is unknown whether the use of coupling intervals limited only by refractory period at electrophysiology study (EPS) to induce ventricular tachycardia (VT) in patients soon after ST-elevation myocardial infarction (STEMI) carries predictive value for ventricular tachyarrhythmia recurrence. There is also the concern that coupling intervals of <200ms might induce ventricular tachyarrhythmia, which may not have predictive value.

The effect of basic cycle length stimuli on effective refractory period measurement

Background: Refractory periods are measured by the extrastimulus technique, whereby a single extrastimulus is introduced at progressively shorter coupling intervals until a response is no longer elicited. Purpose: As refractoriness of cardiac tissues depends on prior cycle length, refractory periods should be determined at a fixed cycle length within the physiologic range. The extrastimulus is delivered after a train of 8 to 10 paced complexes to allow time for reasonable stabilization of refractoriness, which is usually accomplished after the first 3 or 4 paced beats. Objectives: We conducted this study to compare the effect of 6 vs 8 stimuli in basic cycle length (BCL) in measurement of effective refractory period (ERP). Materials and Methods: During electrophysiologic study (EPS) of 100 consecutive patients, anterograde and retrograde ERP of atrioventricular node (AVN) were measured by introduction of 6 vs 8 stimuli in BCL and premature beat, then the results were compared. Results: Recorded anterograde and retrograde ERP of AVN applying 6 vs 8 stimuli in BCL were compared and no difference was detected. Conclusion: We concluded that for ERP measurement of AVN, 6 stimuli in BCL is comparable to 8 stimuli in reaching the steady state.

BOUSSINESQ MODELING OF COMBINED STORM SURGE AND WAVES OVER WETLANDS FORCED BY WIND

Coastal wetlands protect the shoreline and infrastructure by attenuating wind waves and reducing storm surge. It is of importance to accurately quantify the flood protection provided by vegetation. Existing numerical models for hurricane waves and storm surge are based on the phase-averaged wave action balance equation and the nonlinear shallow water equations, respectively, with the wind forcing and vegetal drag as the free surface and bottom boundary conditions. To consider the interaction of waves and surge, the phase-averaged short wave and long wave (storm surge) models can be coupled in a staggered fashion. If the time step of the wave model and storm surge model are 30 minutes and 1 s, respectively, both models would exchange information every 30 minutes. There is no iteration between the wave and surge models at each coupling interval. An alternative to this state-of-the-practice of hurricane wave and storm surge modeling is to simulate the combined wave and surge motion driven by wind and attenuated by wetland vegetation using a phase-resolving Boussinesq model. The objective of this study is threefold: 1) to demonstrate the capability of modeling wave growth by wind, wave reduction by vegetation, and the total water level (wave setup, wind setup and wave runup) using the extended FUNWAVE-TVD model; 2) to analyze the energy balance of the combined wave and surge motion; 3) to examine the momentum balance with an emphasis on the vegetal drag owing to the combined wave orbital velocity and wind-driven current velocity.Recorded Presentation from the vICCE (YouTube Link): https://youtu.be/-o_kx4hPvC8

Antegrade slow pathway mapping of typical atrioventricular nodal reentrant tachycardia based on direct slow pathway capture.

BackgroundRadiofrequency (RF) ablation of typical atrioventricular nodal reentrant tachycardia (tAVNRT) is performed without revealing out the location of antegrade slow pathway (ASp). In this study, we studied a new electrophysiological method of identifying the site of ASp.MethodsThis study included 19 patients. Repeated series of very high‐output single extrastimulations (VhoSESts) were delivered at the anatomical slow pathway region during tAVNRT. Tachycardia cycle length (TCL), coupling interval (CI), and return cycle (RC) were measured and the prematurity of VhoSESts [ΔPM (= TCL – CI)] and the prolongation of RCs [ΔPL (= RC – TCL)] were calculated. Pacing sites were classified into two categories: (i) ASp capture sites [DSPC(+) sites], where two different RCs were shown, and ASp non‐capture sites [DSPC(‐) sites], where only one RC was shown. RF ablation was performed at DSPC(+) sites and/or sites with catheter‐induced mechanical trauma (CIMT) to ASp.ResultsDSPC(+) sites were shown in 13 patients (68%). RF ablation was successful in all patients without any degree of atrioventricular block nor recurrence. Total number of RF applications was 1.8 ± 1.1. Minimal distance between successful ablation sites and DSPC(+)/CIMT sites and His bundle (HB) electrogram recording sites was 1.9 ± 0.8 mm and 19.8 ± 6.1 mm, respectively. ΔPL of more than 92.5 ms, ΔPL/TCL of more than 0.286, and ΔPL/ΔPM of more than 1.565 could identify ASp with sensitivity of 100%, 91.1%, and 88.9% and specificity of 92.9%, 97.0%, and 97.6%, respectively.ConclusionsSites with ASp capture and CIMT were close to successful ablation sites and could be useful indicators of tAVNRT ablation.

Management optimization of nonpoint source pollution considering the risk of exceeding criteria under uncertainty

Management of nonpoint source (NPS) pollution is highly important in watershed water environmental and ecological security. However, the many complexities and uncertainties that exist in the processes of export and management of NPS pollution exert substantial influences on the reliability of multiple management practices. This study developed an inexact multiobjective possibilistic mean-variance mixed-integer programming (IMPMMP) model for NPS pollution management through optimization of watershed land use pattern and livestock production structure. By coupling interval parameter programming, mixed-integer programming, multiobjective programming, and an export coefficient model within a general possibilistic mean-variance model framework, the IMPMMP model deals effectively with system uncertainties and complexities. Moreover, the risk of exceeding criteria (REC) in NPS pollution management systems can be considered. The proposed IMPMMP model was applied to a real-world case study in the Xinfengjiang Reservoir watershed in South China. Results showed that the preference of decision makers regarding land use adjustment plays a decisive role in determining model feasibility. The area provided for each land use type that could be adjusted has to reach a certain threshold to achieve the goals of reduced pollution load and REC control. The NPS pollution loads after optimization would be exported primarily from different land uses and the human population. Compared with NPS nitrogen pollution management, it is more difficult to reduce the NPS phosphorus load and to manage the corresponding REC through adjustment of the land use pattern and livestock production structure. Moreover, it is difficult to simultaneously reduce the NPS nitrogen and phosphorus pollution loads and REC in each subbasin. The model, which can provide policy makers with a series of schemes for optimization of land use pattern and livestock production structure, has satisfactory applicability and could be used for watershed NPS pollution management.

Novel Score to Predict Very Late Recurrences After Catheter Ablation of Atrial Fibrillation

Various predictors of atrial fibrillation (AF) recurrence have been shown based on the baseline characteristics before catheter ablation (CA). This study aimed to develop a novel scoring system for predicting very late recurrences of AF (VLRAFs) after an initial CA, taking the postprocedural clinical data into account and reassessing VLRAFs in 12-month patients' condition using previously known preprocedural predictors of AF recurrences. We retrospectively studied 327 patients who underwent an initial CA with freedom from AF for over 12 months. We elucidated the predictors of VLRAFs and created a new score to predict VLRAFs in the discovery AF cohort (n = 181). Thereafter, we investigated whether the new scoring system could accurately predict VLRAFs in the validation AF cohort (n = 146). In the discovery AF cohort, VLRAFs were observed in 53 patients (29%) during the follow-up period (mean follow-up duration: 55 months). The univariate and multivariate Cox proportional-hazards model demonstrated that non-pulmonary vein foci, early recurrences of AF (ERAFs), atrial premature contraction (APC) burden ≥ 142/24 hours, and minimum prematurity index of the APCs ≤ 48% were associated with VLRAFs after CA. We created a new scoring system to predict VLRAFs, the n-PReDCt score (non-pulmonary vein: 1 point, early recurrences of AFs (Recurrences of AF in early phase after CA): 1 point, APC burden ≥ 142/24 hours: 1 point, and minimum prematurity index (= Coupling interval) of the APCs of ≤ 48%: 1 point). The n-PReDCt score was significantly associated with VLRAFs by a Kaplan-Meier analysis in the discovery AF and validation AF cohorts (p < 0.0001 and p < 0.0001, respectively).

Abstract 15218: Structural and Functional Alterations in a Premature Ventricular Contractions-induced Cardiomyopathy Model

Introduction: Previous studies of premature ventricular contractions (PVC)-induced cardiomyopathy (PVC-CM) in canines have showed reduction in L-type Ca 2+ current and Ca 2+ transient amplitude in isolated ventricular myocytes, concomitant with eccentric hypertrophy and a decline in left ventricular (LV) ejection fraction. Objectives: Assess potential alterations of PVC-CM related to: 1) the efficiency of the Ca 2+ recycling machinery in the sarcoplasmic reticulum (SR), and 2) the overall ultrastructural integrity of myocytes. Methods: Modified pacemakers were implanted in healthy canines to reproduce PVC-CM after 3 months of bigeminal PVC (50% burden at 200-220 ms coupling interval). Animals were randomized to either 50% PVC or no PVC (sham). Ventricular cardiomyocytes were isolated and paced to measure Ca 2+ transients using Fura2. Permeabilized cardiomyocytes loaded with Fluo-5N were used to assess SERCA2 activity in vitro . Additionally, expression of SERCA2, and phosphorylated versus total phospholamban (PLN) were measured with Western blot (WB). LV wall muscle was fixed, en-block stained with uranyl acetate, and thin-sectioned for electron microscopy (EM). Results: There was a non-statistically significant trend towards a reduction of SR-Ca 2+ reuptake efficiency in PVC-CM vs sham, evidenced by a 21% slower decay of the electrically-evoked cytosolic Ca 2+ transient and a 23% slower maximal rate of SR Ca 2+ uptake (PVC-CM n=42 cells, 4 animals vs sham n=50 cells, 3 animals). WB analysis showed a 23% reduction in SERCA2 expression (0.76 ± 0.18 vs 1 ± 0.25, P =0.002, n=6 animals each), a 40% increase in PLN expression (1.4 ± 0.18 vs 1 ± 0.1, P &lt;0.0001, n= 3 animals each), and a 64% reduction in phospho-PLN (0.35 ± 0.15 vs 1 ± 0.18, P &lt;0.0001, n=3 animals each) in PVC-CM vs sham. In addition, EM showed intact dyads, regularly shaped SR, but noticeable myofibril disorder in the PVC-CM derived samples. Conclusions: In PVC-CM, there is impaired electrically-evoked Ca 2+ cycling due to a combination of reduced L-type Ca 2+ channels and reduced SERCA-mediated SR Ca 2+ uptake. This combined with the apparent ultrastructural remodeling, underscore long-term cellular adaptations leading to LV systolic dysfunction associated to the chronic exposure to PVC.

Ventricular premature contractions coupling interval behavior and efficacy of anti-arrhythmic drugs

Abstract Introduction The Idiopathic ventricular arrhythmias are special type of arrhythmia that occurs in the absence of clinically apparent structural heart. They have different pattern of recurrence sporadic, bigeminy, trigeminy, couplets and Ventricular tachycardia runs. They have special behavior of relatively constant coupling interval and recurrence depending on heart rate variability and autonomic nervous system dominance.Objectives: To assess the effect of Coupling interval on the efficacy of different anti-arrhythmic drug. Methods Each subject among 125 consecutive patients with high ventricular premature contractions burden, 24 h ambulatory electrocardiograms were recorded in the absence of anti-arrhythmic drug (control), and during treatment with various anti-arrhythmic drugs. The ratio of the coupling interval (CI) to the preceding R-R intervals was calculated.Patients were treated by different anti-arrhythmic therapy. Efficacy of anti-arrhythmic therapy was documented by ambulatory electrocardiogram for 24 hour by estimating the reduction of Ventricular arrhythmia burden. Results The burden of ventricular premature contractions was reduced effectively (&amp;gt;70% reduction of PVCs burden) in patients receiving BB with RR interval &amp;lt;680 ms, CI/RR &amp;lt;0.4, (P=0.002) (relative tachycardia), while in patients receiving CCB it was effective with RR 650- 830 ms, CI/RR 0.4–0.7, (P=0.04) (average heart rate). While in patients receiving Flecanide were found to have effective therapy with RR &amp;gt;900 ms, CI/RR&amp;gt;0.7, (relative bradycardia) (P=0.005). Conclusion The coupling interval of ventricular premature contractions can predict the efficacy of anti-arrhythmic drugs. The efficacy of anti-arrhythmic therapy may be dependent on the ventricular arrhythmia behavior of the coupling interval and RR interval of the preceding sinus rhythm. Efficacy of different anti-arrhythmic Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Egyptian Ministry of Higher Education

The nature of fast and slow pathway interaction during premature pacing: evaluation with high density mapping

Abstract Background Dual AV Nodal (AVN) inputs are associated with the fast pathway (FPW) superiorly, while the SPW activates inferiorly. In the present study, we evaluate the impact of PES on dual antegrade conduction. Objective To Define Antegrade Conduction Properties of the AV Node during PES Methods High density mapping (Orion, Rhythmia) was performed and analyzed in SR and S2 PES in 12 pts. The FPW activates the AVN and travels inferiorly, there is a point where the activation pivots toward the SPW and travels superiorly along the TV. The distance from the pivot point was measured to the HIS location in sinus rhythm and for each coupling interval. Both the distance and prematurity of the S2 coupling was normalized to the BCL during sinus rhythm. The coupling interval was then plotted vs the HIS-Collision distance. A regression analysis was used to compare data sets with significance defined a &amp;lt;0.05. Results Data was obtained in all 12 patients. In all patients, as pre-maturity of S2 increased, the pivot point moved superiorly until there was block in the FPW and activation to the AV node was entirely from the SPW. There is a functional line of block (LOB) between the FPW and SPW. Comparing normalized data decrement vs change in pivot point: R=0.8 p&amp;lt;0.0001 Conclusion During PES, the F/SPW interaction changes: increasing prematurity causes pivot point to move superiorly until the FPW blocks and AVN activates via the SPW. Decremental antegrade conduction occurs within FPW and is associated with the superior pivot shift toward the AVN suggesting a functional LOB. This relationship is linear. Funding Acknowledgement Type of funding source: None

Short coupling with high burden of atrial ectopy in twenty-four hour holter recording predicts recurrence of atrial arrhythmia after atrial fibrillation ablation

Abstract Background Atrial arrhythmia recurrence is experienced in up to 20% of patients after initially receiving a catheter ablation for atrial fibrillation (AF). Therefore, it is important to define predictors of atrial arrhythmia recurrence. Atrial ectopy (AE) with short coupling interval (S-AE) has been reported to be a trigger of AF. On the other hand, high burden of AE has been reported to be a useful predictor of atrial arrhythmia recurrences after AF ablation. Thus, the combination of the incidence of S-AE and AE burden during a 24-hour Holter recording could be a useful predictor of atrial arrhythmia recurrence after AF ablation. Purpose To investigate this hypothesis, we performed a retrospective case-controlled study. Methods We enrolled 180 patients who underwent their first catheter ablation procedure for AF and performed a 24-hour Holter recording between 90 to 365 days after their ablation procedure. Patients who performed an additional ablation procedure before the Holter recording were excluded. Finally, we analyzed 173 patients (age: 65±10 years, female: 28.3%, non-paroxysmal: 27.7%). The Holter recordings were analyzed by the same experienced technicians. We defined AE as a narrow QRS complex occurring &amp;gt;25% than prior R-R interval, and S-AE as AE occurring &amp;gt;55% earlier than expected. The relationship between the characteristics of AE during the Holter recording and atrial arrhythmia recurrences was investigated. Results The Holter recordings were performed at a median of 103 (IQR: 98–138) days after ablation. The median number of AE were 144 (IQR: 54–699) beats per day, and S-AE was recorded in 49 patients (28.3%). Forty-two patients (24.3%) had a recurrence of atrial arrhythmia during a median 488-day follow up period. Patients with S-AE had a recurrence of atrial arrhythmia more frequently than those without S-AE (44.9% vs 16.1%, p&amp;lt;0.001). We found the cut-off point of AE burden as 241 beats per day by the receiver operating characteristic curve with 74% sensitivity and 70% specificity to predict atrial arrhythmia recurrence. We divided the patients into four groups according to the presence or absence of S-AE and high AE burden. In the Kaplan-Meier analysis, patients with S-AE and high AE burden had the highest atrial arrhythmia recurrence rate (Log-rank test: p&amp;lt;0.001). In the Cox multivariate analysis, S-AE with high AE burden was an independent predictor of atrial arrhythmia recurrence (HR: 4.27, 95% CI: 2.32–7.85, p&amp;lt;0.001). Conclusion For AF patients who underwent their first catheter ablation, S-AE (&amp;gt;55% earlier than expected) with high AE burden (&amp;gt;241 beats per day) during the 24-hour Holter recording predicted recurrences of atrial arrhythmia. These results can help to develop follow-up strategies after AF ablation. Funding Acknowledgement Type of funding source: None

A novel trigger-substrate mechanism based on clinically concealed repolarization abnormalities underlies idiopathic ventricular fibrillation

Abstract Background Sudden cardiac arrest (SCA) is most often due to ventricular fibrillation (VF). When no cause is found during diagnostic follow-up, fibrillation is classified as idiopathic (iVF). We hypothesize that a critical functional substrate-trigger interaction underlies iVF. Purpose To study electrophysiological triggers and substrate for iVF in a clinical cohort; and seek mechanistic explanations in explanted pig hearts and computer models mimicking trigger-substrate interactions. Methods Repolarization time (RT) isochrones on the epicardium were studied with electrocardiographic imaging (ECGI) in patients with iVF, patients with frequent monomorphic premature ventricular complexes (fmPVC) but no structural disease or SCA, and controls without cardiovascular disease. RT gradients were created in explanted, Langendorff-perfused pig hearts by local infusion of dofetilide (“dof”, 250 nM, delaying RT) and pinacidil (“pin”, 30 μM, shortening RT) in adjacent regions of the heart. Arrhythmia inducibility was tested by programmed stimulation (8 atrial stimuli [S1] followed by one ventricular stimulus [S2] paced at regions of early or late RT). A computational ventricular monodomain model was used to study the location-dependency of trigger-substrate interaction; RT gradients were created by local changes in potassium channel conductance. Results Although QTc values were similar, iVF survivors (n=11) displayed significantly steeper RT gradients than controls (n=10) or fmPVC individuals (n=7): 269±111 vs 179±40 vs 171±76 ms/cm respectively (panel A). Unipolar electrograms (EGMs) at the gradients displayed a change in polarity of the local T wave (B). In iVF, PVCs originated more often from regions with early RT than in fmPVC individuals (yellow circles in A; 64% vs 14%). In the explanted hearts (C), drug infusion resulted in similar RT gradients and polarity changes of EGM T waves (D-E). VF inducibility by pacing of the early RT region (D) increased significantly with steeper RT gradients (baseline: 3/6 hearts inducible, dof+pin: 3/3). Pacing of late RT regions (E) did not induce arrhythmias in baseline (0/6) nor with RT gradients (0/3). For similar pacing intervals at the early RT region, the 12-lead ECG R-on-T morphology was similar but VF only occurred in the presence of RT gradients (F). In the computer model, the number of inducible pacing intervals critically depended on the stimulus location (G). Conclusion Combined, these results demonstrate that R-on-T superposition per se is insufficient to explain arrhythmogenesis. Rather, not only the temporal coupling interval but also the spatial origin of PVCs in relationship to the degree of local repolarization abnormalities are critical elements. In iVF, a substrate of RT gradients (panel H1) with triggers from early RT regions (H2) precipitate reentry (H3). Noninvasive ECGI can uncover these substrate and trigger characteristics in (at least a subset of) iVF survivors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Netherlands Organization for Scientific Research Veni grant TTW 16772, French National Research Agency (ANR-10-IAHU04-LIRYC)

Increased left ventricular stiffness assessed by diastolic wall strain causes symptoms in patients with premature ventricular contraction

Abstract Background Premature ventricular contraction (PVC) is one of common arrhythmias and only some patients complain of PVC-related symptoms, however the mechanisms which cause the symptoms remain unclear in patients with PVCs. Purpose We investigated whether the left ventricular (LV) stiffness assessed by diastolic wall strain (DWS) relate symptoms or not in patients with PVC. Methods We studied 109 patients (48 males, age 60±19) with frequent monomorphic PVCs who underwent 12-leads electrocardiogram (ECG), signal-averaged electrocardiogram (SAECG), 24h-Holter ECG recording, and transthoracic echocardiography (TTE). Patients with structural heart disease or other arrhythmias such as atrial fibrillation were excluded. Clinical factors, blood samples for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and filtered QRS duration (f-QRS) and root mean square voltage of the terminal 40ms of the QRS complex (RMS40) obtained by SAECG were evaluated. We assessed PVC-SV (stroke volume during PVC), PVC-CI (CI between the previous sinus beat and VPC), and left ventricular (LV) stiffness assessed by diastolic wall strain (DWS). DWS was calculated from the M-mode echocardiographic measurement of the LV posterior wall thickness at end-systole (PWs) and end-diastole (PWd) during sinus rhythm, and DWS was defined as (PWs − PWd)/PWs. Results 31patients (28%) had PVC-related symptoms (18 palpitation and 13 pulse deficit). Patients with PVC-related symptoms showed shorter PVC coupling interval index (52±10 vs. 58±11%, p=0.0140), reduced PVC-SV (21±12 vs. 29±17ml, p=0.0103) and decreased DWS (0.38±0.06 vs. 0.42±0.06, p=0.0011). Meanwhile, the level of BNP and ANP, f-QRS, RMS40, QRS morphology of PVC and the total number of PVC per day were not associated with PVC-related symptoms. On multivariate analysis, decreased DWS was only independently associated with PVC-related symptoms (p=0.0357, OR 2.3629 for each 0.1 decrease in DWS 95% CI 1.0583–5.5815). Conclusion The reduced diastolic wall strain relates with PVC-related symptoms. The increased left ventricular stiffness might cause symptoms in patients with PVC. Funding Acknowledgement Type of funding source: None

Critical repolarization gradients determine the induction of reentry-based torsades de pointes arrhythmia in models of long QT syndrome

Torsades de pointes arrhythmia is a potentially lethal polymorphic ventricular tachyarrhythmia (pVT) in the setting of long QT syndrome. Arrhythmia susceptibility is influenced by risk factors modifying repolarization. The purpose of this article was to characterize repolarization duration and heterogeneity in relation to pVT inducibility and maintenance. Sotalol was infused regionally or globally in isolated Langendorff blood-perfused pig hearts (N = 7) to create repolarization time (RT) heterogeneities. Programmed stimulation and epicardial activation and repolarization mapping were performed. The role of RT (heterogeneities) was studied in more detail using a computer model of the human heart. pVTs (n = 11) were inducible at a critical combination of RT and RT heterogeneities. The pVT cycle lengths were similar in the short and long RT regions. Short-lasting pVTs were maintained by focal activity while longer-lasting pVTs by reentry wandering along the interface between the 2 regions. Local restitution curves from the long and short RT regions crossed. This was associated with T-wave inversion at coupling intervals at either side of the crossing point. These experimental observations were confirmed by the computer simulations. pVTs are inducible within a critical range of RT and RT heterogeneities and are maintained by reentry wandering along the repolarization gradient. Double potentials localize at the core of the reentrant circuit and reflect phase singularities. RT gradient and T waves invert with short-coupled premature beats in the long RT region as a result of the crossing of the restitution curves allowing reentry initiation.

Determinants of Ca2+ release restitution: Insights from genetically altered animals and mathematical modeling.

Each heartbeat is followed by a refractory period. Recovery from refractoriness is known as Ca2+ release restitution (CRR), and its alterations are potential triggers of Ca2+ arrhythmias. Although the control of CRR has been associated with SR Ca2+ load and RYR2 Ca2+ sensitivity, the relative role of some of the determinants of CRR remains largely undefined. An intriguing point, difficult to dissect and previously neglected, is the possible independent effect of SR Ca2+ content versus the velocity of SR Ca2+ refilling on CRR. To assess these interrogations, we used isolated myocytes with phospholamban (PLN) ablation (PLNKO), knock-in mice with pseudoconstitutive CaMKII phosphorylation of RYR2 S2814 (S2814D), S2814D crossed with PLNKO mice (SDKO), and a previously validated human cardiac myocyte model. Restitution of cytosolic Ca2+ (Fura-2 AM) and L-type calcium current (ICaL; patch-clamp) was evaluated with a two-pulse (S1/S2) protocol. CRR and ICaL restitution increased as a function of the (S2-S1) coupling interval, following an exponential curve. When SR Ca2+ load was increased by increasing extracellular [Ca2+] from 2.0 to 4.0 mM, CRR and ICaL restitution were enhanced, suggesting that ICaL restitution may contribute to the faster CRR observed at 4.0 mM [Ca2+]. In contrast, ICaL restitution did not differ among the different mouse models. For a given SR Ca2+ load, CRR was accelerated in S2814D myocytes versus WT, but not in PLNKO and SDKO myocytes versus WT and S2814D, respectively. The model mimics all experimental data. Moreover, when the PLN ablation-induced decrease in RYR2 expression was corrected, the model revealed that CRR was accelerated in PLNKO and SDKO versus WT and S2814D myocytes, consistent with the enhanced velocity of refilling, SR [Ca2+] recovery, and CRR. We speculate that refilling rate might enhance CRR independently of SR Ca2+ load.

Mechanism of spontaneous initiation of ventricular fibrillation in patients with implantable defibrillators.

To improve the mechanistic understanding of spontaneous initiation of ventricular fibrillation (VF), we characterized the patterns of premature ventricular complex (PVC) preceding spontaneous VF in primary and secondary implantable cardioverter-defibrillator (ICD) recipients. A single-center, cross-sectional analysis of 1209 patients with primary and secondary prevention ICD identified 190 patients who received ICD therapy (firing or antitachycardia pacing) for VF or monomorphic ventricular tachycardia (MMVT). Initiation was quantified by the coupling interval (CI), the cycle length immediately preceding the CI (CL(-1)), the CI corrected by CL(-1) using Fridericia's formula (CIc), and the prematurity index (PI). In both VF (n = 44; 23%) and MMVT (n = 134; 71%), the most common pattern of initiation was late-coupled PVC, followed by the short-long-short pattern. The parameters such as pre-initiation median CL, CL(-1), CI, and PI were not significantly different between VF and MMVT for any patterns. At least some events (45% of VF and 63% of MMVT) had extremely long CIs beyond the QTc cut-off estimated from the CL(-1), suggestive of initiation by a train of multiple PVCs or nonsustained VT instead of a single PVC. Some spontaneous VF events in ICD recipients appear to be initiated by a train of multiple PVC or nonsustained VT rather than a single PVC. This finding indicates that patterns of a single PVC are not an important determinant of VF initiation and thus account for conflicting results in previous studies.

Design and Construction of High-Frequency Cardiac Defibrillator for Small Animals.

The main goal of this research is to evaluate the defibrillation efficacy with the high-frequency waveform on ventricular fibrillation in small animals. A biphasic defibrillator with adjustable frequency was designed for this study. This custom-designed defibrillator can be adjusted to generate four different frequencies of 125, 250, 500, and 1000 Hz. Six rat hearts were induced VT/VF by electrical induction using the waveform of these four frequencies. Success VT/VF-induction by applying those four frequencies were recorded and observed by optical mapping. The results showed that the VT/VF-induction success rate is increasing along with higher frequencies. The VT/VF-induction success rate is 16% in 125Hz and 250 Hz, 33% in 500 Hz, and 100% in 1000 Hz with S1-S2 protocol at 100 ms coupling interval. Also, using optical mapping technique, shock-induced optical potential showed that only high-frequency waveform exhibited the largest tissue responses in the middle position of the heart. In conclusion, high-frequency (1000Hz) defibrillation waveform has the highest defibrillation efficacy comparing to other lower frequencies used in this study.

Novel Assessment of Accessory Pathway Function in Patients with Wolff-Parkinson-White Syndrome.

Surrogates for the shortest pre-excited R-R interval in atrial fibrillation (SPERRI) such as the accessory pathway effective refractory period (APERP) and shortest pre-excited paced cycle length (SPPCL) are flawed assessments of accessory pathway function in patients with WPW. Multi-extrastimulus pacing may have the theoretical advantage of more accurately mimicking the clinical reality of atrial fibrillation and thus may serve to better assess accessory pathway function. This cross-sectional study included 25 consecutive patients, aged≤18years, undergoing electrophysiology study for WPW. The longest S1S2, S2S3, S3S4 coupling intervals at which the antegrade AP refractoriness occurred, SPERRI, and SPPCL were recorded. Induction of atrial fibrillation was attempted in all patients and induced in 8 (32%, 4 SPERRIbaseline (265ms±61ms), 4 SPERRIIsuprel (258ms±41ms)). At baseline, the lower value of the S3ERP or S4ERP (274ms±52ms) was lower than the SPPCL (296ms±54ms, p<0.0001) and APERP (296ms±41ms, p<0.0001). More patients had S3ERP or S4ERP≤250ms (12/25, 48%) compared to those with APERP≤250ms (2/25 8%), p=0.0016), SPPCL 5/24, 20%), p=0.008 or either (6/25, 24%), p=0.0143). With Isuprel, the lower value of the S3ERP or S4ERP (221ms±36ms) trended to be lower than the APERP (252ms±36ms, p=0.0001) and the SPPCL (266ms±57ms, p=0.001). With Isuprel, there was no statistical difference in the proportion of patients with S3ERP or S4ERP<250ms (12/16, 75%) compared to those with APERP≤250ms ((9/16, 56%), p=0.08), SPPCL≤250ms ((9/16, 56%), p=0.08), or either ((10/16, 63%), p=0.16). Multi-extrastimulus pacing protocols demonstrate that accessory pathways are less refractory than as defined by single extrastimulus pacing and straight decremental pacing.

P321Subthreshold delayed afterdepolarizations form a substrate for conduction block in the infarcted heart

Abstract Funding Acknowledgements National Institute for Health Research; British Heart Foundation; and The Wellcome Trust and Engineering and Physical Sciences Research Council. Background Delayed afterdepolarizations (DADs) due to spontaneous calcium (Ca) release (SCR) events from the sarcoplasmic reticulum have been implicated with a variety of arrhythmias. Such SCR events have also been reported in cells that survive in the infarct border zone (BZ). While the potential of Ca-mediated DADs to become suprathreshold and propagate in the form of ectopic beats has been well characterized, the role of subthreshold DADs in arrhythmia formation in the infarcted heart remains to be elucidated. Purpose To use computational modelling to investigate whether subthreshold Ca-mediated DADs may form a substrate for conduction block and reentry in the BZ. Our hypothesis is that subthreshold DADs can hinder local tissue excitability in critical infarct BZ regions by inactivating the fast sodium current (INa), leading to temporary unidirectional conduction block providing a trigger for arrhythmogenesis. Methods We developed an idealized infarct model of the left ventricle. The infarct region consisted of a non-conducting scar transcended by an isthmus of cells that survived myocardial infarction (border zone). These cells were made prone to Ca-mediated DADs described by a phenomenological model of SCR events. The model was pre-paced at the apex followed by a 1500ms-pacing pause to see whether DADs would emerge. An extra beat with a longer coupling interval (CI) was then applied. The following electrophysiological changes resulting from remodeling processes in the isthmus were simulated to assess their contribution to the arrhythmogenic potential of subthreshold DADs: INa loss-of-function due to a (2.5mV and 5mV) negative-shift in the steady-state channel inactivation; 50% reduction in tissue conductivity; and increased levels of fibrosis (up to 50%). Results On average, Ca-mediated DADs reached their maximum value 1065ms after the last paced beat (Fig. A). Despite this, in the default electrophysiological setup, simulations with extra beats with 1000ms &amp;gt; CI &amp;gt; 1100ms did not result in conduction block in any of the experiments. When repeated with combined changes of reduced tissue conductivity and fibrosis, subthreshold DADs were still unable to create a substrate for block. However, when combined with a 5mV-shift in INa inactivation, block at isthmus’ mouth proximal to the stimulus site was detected for extra beats 1010 ms ≥ CI ≥ 1070ms (see Fig. B). The cause of block was due to a subthreshold DAD occurring just prior to the arrival of the extra beat. All blocked beats degenerated into reentry. Conclusions Under most physiological conditions, subthreshold DADs are unlikely to provide a substrate for unidirectional block. However, under conditions of decreased excitability, subthreshold DADs can hinder tissue excitability in the infarcted region leading to conduction block and reentry. Abstract Figure. DAD-mediated conduction block in the BZ