Maintenance Of Ventricular Fibrillation Research Articles

Trigger and Substrate Mapping and Ablation for Ventricular Fibrillation in the Structurally Normal Heart.

Sudden cardiac death (SCD) represents approximately 50% of all cardiovascular mortality in the United States. The majority of SCD occurs in individuals with structural heart disease; however, around 5% of individuals have no identifiable cause on autopsy. This proportion is even higher in those <40 years old, where SCD is particularly devastating. Ventricular fibrillation (VF) is often the terminal rhythm leading to SCD. Catheter ablation for VF has emerged as an effective tool to alter the natural history of this disease among high-risk individuals. Important advances have been made in the identification of several mechanisms involved in the initiation and maintenance of VF. Targeting the triggers of VF as well as the underlying substrate that perpetuates these lethal arrhythmias has the potential to eliminate further episodes. Although important gaps remain in our understanding of VF, catheter ablation has become an important option for individuals with refractory arrhythmias. This review outlines a contemporary approach to the mapping and ablation of VF in the structurally normal heart, specifically focusing on the following major conditions: idiopathic ventricular fibrillation, short-coupled ventricular fibrillation, and the J-wave syndromes-Brugada syndrome and early-repolarization syndrome.

Electrophysiological characterization of a 19-years-old male marathon runner suffering a sudden cardiac death

1 in 50,000 of athletes suffers a cardiac student death (SCD) per year, more of them under 35 years of age. Around 25% of these patients had normal structure, implying that other electrical disorder cause these SCD. Determine the electrophysiological causes of a SCD of a young 19-years-old occurred during a marathon with any heart structural diseases. Pathologic left ventricle (PLV) (n = 1, male, 19-years-old) and control left ventricle (CLV) (n = 1, female, 56-years-old) were perfused and imaged using high resolution optical mapping and Di-4-ANEPPS like a dye. Endocardial and endocardial free wall and his bundle were paced to obtain activation time (AT), repolarization time (RT) and action-potential duration (APD). Purkinje-muscle junctions (PMJs) were determine like activation origins far from the his bundle pacing. Effective refractory period (ERP) was determined using S1S2S3S4 short-coupled pacing. The protocol was repeated after isoplenalie injection [500 nM] like β-adrenergic receptor agonist. His-ventricle activation at high frequency pacing was higher in PLV (143ms) than in control (84ms) and decrease in both at similar levels under ISO (≈60ms). APD gradient increase was observed in PLV near PMJs under ISO (from 3ms/mm to 40ms/mm) and any gradient was observed in the control one. Ectopic episodes were observed in PLV under ISO and 82% of the origins had less that 4 mm of distance with the PMJs. In PLV, the ERP in His-pacing is always lower (320, 260, 250 ms) than endocardial (350, 315, 285 ms) pacing but in CLV, the His-pacing ERP was always higher (320, 260, 240 ms) that endocardial pacing (280, 240, 220 ms). Ventricular fibrillation (VF) was observed in PLV after his bundle pacing at high frequency (more than 330 ms) and any VF was observed in CLV. During this VF, 76% of the focal activities had less than 4 mm of distance with the PMJs. Conduction system (CS) of the PLV shows high sensitivity to high frequency pacing and to presence of ISO. Ectopic episodes and APD gradient near PMJs may show the role of Purkinje network like arrhythmic source. Indeed, the shorter ERP during His-pacing than in the endocardium, give the possibility to produce a macro-re-entry in the conduction system and maintain the arrhythmia with focal activities. CS abnormalities likely played a critical role in arrhythmogenicity and maintenance of VF in this patient during sudden cardiac death.

PO-05-035 FASCICULAR SUBSTRATE MODIFICATION TO TREAT HUMAN VENTRICULAR FIBRILLATION: A MULTICENTER STUDY

Purkinje fibers play an important role in initiation and maintenance of ventricular fibrillation (VF). Fascicular substrate modification approaches have been suggested to treat recurrent VF in isolated case reports and small case series. To investigate the outcomes of catheter-based fascicular substrate modification to treat recurrent VF. Out of 2,212 consecutive patients with ventricular arrhythmia undergoing catheter ablation at our centers, 18 (0.81%) underwent fascicular substrate modification by targeting with short (<20 s) RF lesions in the most distal segment of the Purkinje fibers as identified with high-density mapping during sinus rhythm. Demographic, clinical, and follow-up characteristics were prospectively collected in our institutional database. A total of 18 patients (mean age: 56±3.8 years, female: 4, 22%) were included in the study. Of those, 11 (61.1%) had idiopathic VF (normal heart VF), 3 (16.7%) had non-ischemic cardiomyopathy and 4 (22.2%) had mixed cardiomyopathy. Average LVEF was 42.5%. Patients had failed ≥2 antiarrhythmic drugs pre-ablation. At baseline, all patients had inducible VF and non-inducibility of VF at the end of the procedure was achieved in 16 (88.9%) patients. In select patients, remapping revealed elimination of the targeted Purkinje potentials. At the end of the procedure, no patient demonstrated new evidence of fascicular block or bundle branch block. VF initiation and final lesion sets are shown in figure 1. There were no procedure-related complications. After a median follow-up of 24 months, 16 (88.9%) patients were arrhythmia-free on- or off-drugs; 11/11 (100%) patients with normal heart VF vs 5/7 (71.4%) with underlying cardiomyopathy (p=0.06). Catheter ablation of human VF with distal fascicular substrate modification is feasible, safe and appears highly effective with high rates of acute VF non-inducibility and long-term freedom from recurrent VF.

Catheter Ablation of Ventricular Fibrillation.

Ventricular fibrillation (VF) is a common cause of sudden cardiac death (SCD) and is unfortunately without a cure. Current therapies focus on prevention of SCD, such as implantable cardioverter-defibrillator (ICD) implantation and anti-arrhythmic agents. Significant progress has been made in improving our understanding and ability to target the triggers of VF, via advanced mapping and ablation techniques, as well as with autonomic modulation. However, the critical substrate for VF maintenance remains incompletely defined. In this review, we discuss the evidence behind the basic mechanisms of VF and review the current role of catheter ablation in patients with VF.

Novel insights into the substrate involved in maintenance of ventricular fibrillation: results from continuous multipolar mapping in a canine model.

While the triggers for ventricular fibrillation (VF) are well-known, the substrate required for its maintenance remains elusive. We have previously demonstrated dynamic spatiotemporal changes across VF from electrical induction of VF to asystole. Those data suggested that VF drivers seemed to reside in the distal RV and LV. However, signals from these areas were not recorded continuously. The aim of this study was to map these regions of significance with stationary basket electrodes from induction to asystole to provide further insights into the critical substrate for VF rhythm sustenance in canines. In six healthy canines, three multipolar basket catheters were positioned in the distal right ventricle (RV), RV outflow tract, and distal left ventricle (LV), and remained in place throughout the study. VF was induced via direct current application from an electrophysiologic catheter. Surface and intracardiac electrograms were recorded simultaneously and continuously from baseline, throughout VF, and until asystole, in order to get a complete electrophysiologic analysis of VF. Focused data analysis was also performed via two defined stages of VF: early VF (immediately after induction of VF to 10min) and late VF (after 10min up to VF termination and asystole). VF was continuously mapped for a mean duration of 54 ± 9min (range 42-70min). Immediately after initiation of VF in the early phase, the distal LV region appeared to drive the maintenance of VF. Towards the terminal stage of VF, the distal RV region appeared to be responsible for VF persistence. In all canines, we noted local termination of VF in the LV, while VF on surface ECG continued; conversely, subsequent spontaneous termination of VF in the RV was associated with termination of VF on surface ECG into a ventricular escape rhythm. Continuous mapping of VF showed trends towards an increase in peak-to-peak ventricular electrogram cycle length (p = 0.06) and a decrease in the ventricular electrogram amplitude (p = 0.06) after 40min. Once we could no longer discern surface QRS activity, we demonstrated local ventricular myocardial capture in both the RV and LV but could not reinitiate sustained VF despite aggressive ventricular burst pacing. This study describes the evolution of VF from electrical initiation to spontaneous VF termination without hemodynamic support in healthy canines. These data are hypothesis-generating and suggest that critical substrate for VF maintenance may reside in both the distal RV and LV depending on stage of VF. Further studies are needed to replicate these findings with hemodynamic support and to translate such findings into clinical practice. Ventricular fibrillation maintenance may be dependent on critical structures in the distal RV. ECG: electrocardiogram; LV: left ventricle; RV: right ventricle; RVOT: right ventricular outflow tract; VF: ventricular fibrillation.

A case study: High resolution optical mapping of a 19 year old male victim of sudden cardiac death during a marathon

Fifty thousand athletes suffer sudden cardiac death every year due to ventricular fibrillation (VF). Most sudden cardiac deaths of young patients have unexplained origin due to the absence of structural or electrical disease. Purkinje network is essential for a normal heart function, however, its role during electrical pathologies remains unclear. A case study to investigate the electrophysiological properties and the Purkinje network role in a 19 years old male after suffering a fatal sudden cardiac arrest during a marathon event. A coronary-perfused left ventricular preparation was imaged using high resolution optical mapping of epicardial and endocardial surfaces using a voltage-sensitive dye, Di-4-ANEPPS. Activation time, repolarization time and action potential duration were assessed during paced activity through the His bundle and endocardial and epicardial surfaces. Conduction system activation origins were identified as distant endocardial origins during His bundle pacing. Short-coupled S1S2S3S4 pacing was used to determine effective refractory period (ERP). Pacing protocols were repeated in the presence of isoprenaline (ISO) at 100 nM, 500 nM and 1 μM to mimic stress conditions. No changes in total activation time are observed during myocardial pacing cycle lengths of 667ms in control (63ms) and under ISO (up to 64ms). In contrary, His-ventricle delay during conduction system pacing was shorted from 61ms in control to 42ms, 44ms and 16ms under 100 nM, 500 nM and 1 μM of ISO respectively. Under His pacing, local APD gradients are observed near Purkinje-muscle junctions under ISO (from 3ms/mm and 3 ms/mm to 40ms/mm and 41ms/mm). ERP under His pacing was 55ms shorter than endocardial pacing. 82% of the ectopy origins observed have less than 4 mm distance from the PMJs. Repeated focal activations were observed during VF and 76% of them had less than 4 mm distance from PMJs. No structural abnormalities were identified under 9.4 T MRI. Conduction system electrical abnormalities play a role in arrhythmogenicity and maintenance of VF in this patient during sudden cardiac death.

Role of Purkinje-muscle junction in early ventricular fibrillation in a porcine model: Beyond the trigger concept.

The role of the Purkinje network in triggering ventricular fibrillation (VF) has been studied; however, its involvement after onset and in early maintenance of VF is controversial. We studied the role of the Purkinje-muscle junctions (PMJ) on epicardial-endocardial activation gradients during early VF. In a healthy, porcine, beating-heart Langendorff model [control, n = 5; ablation, n = 5], simultaneous epicardial-endocardial dominant frequent mapping was used (224 unipolar electrograms) to calculate activation rate gradients during the onset and early phase of VF. Selective Purkinje ablation was performed using Lugol's solution, followed by VF re-induction and mapping and finally, histological evaluation. Epicardial activation rates were faster than endocardial rates for both onset and early VF. After PMJ ablation, activation rates decreased epicardially and endocardially for both onset and early VF [Epi: 9.7 ± 0.2 to 8.3 ± 0.2 Hz (p <.0001) and 10.9 ± 0.4 to 8.8 ± 0.3 Hz (p < .0001), respectively; Endo: 8.2 ± 0.3 Hz to 7.4 ± 0.2 Hz (p < .0001) and 7.0 ± 0.4 Hz to 6.6 ± 0.3 Hz (p = .0002), respectively]. In controls, epicardial-endocardial activation rate gradients during onset and early VF were 1.7 ± 0.3 Hz and 4.5 ± 0.4 Hz (p < .001), respectively. After endocardial ablation of PMJs, these gradients were reduced to 0.9 ± 0.3 Hz (onset VF, p < .001) and to 2.2 ± 0.3Hz (early VF, p <.001). Endocardial-epicardial Purkinje fiber arborization and selective Purkinje fiber extinction after only endocardial ablation (not with epicardial ablation) was confirmed on histological analysis. Beyond the trigger paradigm, PMJs determine activation rate gradients during onset and during early maintenance of VF.

Endurance training increases ventricular refractoriness and wavelength of the cardiac impulse without participation of parasympathetic postganglionic neurons. A study in isolated rabbit heart

Abstract Background Endurance physical training plays a protective role in against ventricular fibrillation (VF), but the exact underlying mechanisms are not completely understood. It is well-known that modifications in myocardial ventricular properties such as refractoriness, conduction velocity and wavelength are key in the initiation and maintenance of VF; furthermore, vagus nerve stimulation has prophylactic effects on malignant arrhythmias and VF. On the other hand, parasympathetic nervous system activity is increased in trained individuals, which in turn affects different ventricular electrophysiological properties. We hypothesized that physical training increases conduction velocity and wavelength, and that these changes are mediated by myocardial cholinergic neurons. Methods To test this hypothesis, ten rabbits were submitted to a six-week endurance training protocol and twenty controls were not trained (divided in control group, n=10 and sham group n=10). After training, rabbits were euthanized and their hearts excised, isolated and perfused in a Langendorff system. A pacing electrode and a plaque with 240 recoding electrodes acquiring at 1 KHz were positioned on the left ventricle (LV). Extraestimulus test using four different pacing cycle lengths (90% basal cycle length, 250, 200 and 150 ms) was performed before and after atropine (1μM, control and trained groups) or vehicle (tyrode, sham group) infusion. We studied 1) LV effective refractory period (ERP), 2) LV functional refractory period (FRP), 3) LV conduction velocity (CV), and 4) LV wavelength, determined as LV FRP x CV. Factorial ANOVA (mixed model) was used for statistical analysis (p&amp;lt;0.05). Results Before parasympathetic blockade, LV FRP increased in trained animals (Figure, B) whereas no difference was found in LV CV between trained and control animals at any pacing cycle length (Figure, A). In consequence, LV wavelength increased in trained animals (Figure, C). There were no changes in LV ERP, FRP, CV and wavelength when comparisons were made within groups before and after atropine infusion. In sham animals, vehicle infusion or time-course of the experiment did not modify LV FRP, ERP, CV and wavelength. Conclusion Physical training increases LV wavelength, which can be one electrophysiological mechanism by which endurance training could protect against VF. Since modifications of ventricular refractoriness and wavelength do not seem dependent of intrinsic parasympathetic nervous system activity, other intrinsic mechanisms could be implied and warrant further research. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Generalitat Valenciana

B-PO03-206 TERMINATION OF VENTRICULAR FIBRILLATION DURING CATHETER ABLATION

Catheter ablation (CA) targeting Purkinje triggers is an established technique for treating ventricular fibrillation (VF). However, the mechanism of human VF maintenance is not well understood. While 2 previous cases of spontaneous termination of VF after CA have been reported, none have occurred during radiofrequency (RF) application. N/A N/A A 50 year-old man presented to an outside hospital with a STEMI and underwent PCI to the RCA. He developed VF refractory to IV amiodarone, lidocaine and over 10 defibrillation attempts. He was placed on full circulatory support and transferred to our institution. Procainamide and then PO quinidine were also ineffective with persistent VF storm. The VF appeared to be initiated by a PVC with indeterminate V1 morphology with superior axis and dominant S wave, suggestive of moderator band (MB) or left posterior fascicle PVC (Panel A). He was brought to the EP lab, where the same PVC initiated VF, requiring defibrillation. An ablation catheter was positioned at the MB (Panels B, C). 85 s into an episode of VF, RF energy was delivered and in 3.8 s terminated VF to monomorphic VT (MMVT) (Panel D). The MMVT was then mapped to an exit site lateral to the posteromedial papillary muscle. The signal was 65 ms pre-QRS at this site and ablation terminated VT to SR. VF and VT did not recur and circulatory support was weaned. To our knowledge, this case is the first reporting direct termination of VF during delivery of RF energy. Though it is well known that abnormal Purkinje potentials and resultant PVCs may serve as initiators of VF, this case presents direct evidence that the triggering focus may in fact be critical to VF maintenance.

Ventricular fibrillation mechanism and global fibrillatory organization are determined by gap junction coupling and fibrosis pattern.

AimsConflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganized multiple-wavelet activation to organized rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism.Methods and resultsOptical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact fibrosis (CF), diffuse fibrosis (DiF), and patchy fibrosis (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum. Enhanced GJ coupling with rotigaptide (n = 10) progressively organized fibrillation in a concentration-dependent manner; increasing FDI (0 nM: 0.53 ± 0.04, 80 nM: 0.78 ± 0.03, P < 0.001), increasing RA-sustained VF time (0 nM: 44 ± 6%, 80 nM: 94 ± 2%, P < 0.001), and stabilized RAs (maximum rotations for an RA; 0 nM: 5.4 ± 0.5, 80 nM: 48.2 ± 12.3, P < 0.001). GJ uncoupling with carbenoxolone progressively disorganized VF; the FDI decreased (0 µM: 0.60 ± 0.05, 50 µM: 0.17 ± 0.03, P < 0.001) and RA-sustained VF time decreased (0 µM: 61 ± 9%, 50 µM: 3 ± 2%, P < 0.001). In CF, VF activity was disorganized and the RA-sustained VF time was the lowest (CF: 27 ± 7% vs. PF: 75 ± 5%, P < 0.001). Global fibrillatory organization measured by FDI was highest in PF (PF: 0.67 ± 0.05 vs. CF: 0.33 ± 0.03, P < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411 ± 266 ms vs. compact: 354 ± 38 ms, P < 0.001). DiF (n = 11) exhibited an intermediately organized VF pattern, sustained by a combination of multiple-wavelets and short-lived RAs.ConclusionThe degree of GJ coupling and pattern of fibrosis influences the mechanism sustaining VF. There is a continuous spectrum of organization in VF, ranging between globally organized fibrillation sustained by stable RAs and disorganized, possibly multiple-wavelet driven fibrillation with no RAs.

4969Enhanced gap junction coupling organised and terminated acute ventricular fibrillation in ex-vivo perfused hearts

Abstract Background The underlying mechanism of ventricular fibrillation (VF) remains unclear. There are both experimental and clinical data to support the existence of rotational drivers (RDs), though other opposing studies suggest that VF is the result of disorganized myocardial activation. Abnormal electrical coupling between cardiomyocytes through gap junctions (GJ) has been considered an important factor in the genesis and maintenance of VF and pre-treatment with GJ couplers, rotigaptide (RTG), has been shown to reduce VF inducibility. Purpose We hypothesized that the degree of GJ coupling determines the underlying mechanism of VF, and that changes in GJ coupling can shift or modify the predominant mechanism of fibrillation along the spectrum between disorganised activity and organised drivers. We proposed that increased organisation of VF is critical to its termination. Methods Thirty Sprague-Dawley rat hearts were explanted, perfused ex-vivo and acute VF was induced with burst pacing and 30μM pinacidil. Optical mapping of transmembrane potential was performed at baseline and the effects of GJ coupling on VF dynamics were studied in an acute VF model by perfusing with increasing concentrations of a GJ uncoupler; carbenoxolone (0–50μM, CBX, n=10) or a GJ coupling-enhancer; RTG (0–80nM, n=10). A chronic diffuse fibrosis model (n=10) was generated with 4 weeks of in-vivo angiotensin infusion (500nm/kg/min). Fibrillation dynamics were quantified using phase analysis, phase singularity (PS) tracking and our novel method of global fibrillation organisation quantification, frequency dominance index (FDI), which is a power ratio of highest amplitude dominant frequency in the frequency spectrum. Results RTG increased average rotations per RD (Baseline: 2.86±0.10 vs 80nM: 5.66±0.43, p&lt;0.001) whilst CBX caused a reduction (Baseline: 3.77±0.39 vs 50μM: 0.26±0.26, p&lt;0.001). Maximum rotations for a RD increased with RTG (5.4±0.45 vs 48.20±12.32, p&lt;0.001) and decreased with CBX (8.0±1.3 vs 0.3±0.3, p&lt;0.001). Proportion of time PSs were detected in VF increased with RTG (0.44±0.06 vs 0.93±0.02, p&lt;0.001) and decreased with CBX (0.61±0.9 vs 0.03±0.02, p&lt;0.001). RTG reduced meander of longest duration RD (20.6±1.68 vs 11.51±0.77 pixels, p&lt;0.001) for PS &gt;5 rotations. FDI increased with RTG (0.53±0.04 vs 0.78±0.3, p&lt;0.001) and decreased with CBX (0.60±0.05 vs 0.17±0.03, p&lt;0.001). In the diffuse fibrosis group, in comparison to baseline RTG 80nM increased FDI (0.35 vs 0.65, p&lt;0.001) and terminated VF in 40% of hearts. Conclusion The degree of GJ coupling is a key determinant of the underlying mechanism of VF. RTG organised fibrillation and stabilised RDs in a concentration-dependent manner whilst CBX disorganised VF. Enhancing GJ coupling with RTG in diseased hearts with fibrosis can terminate VF and may be a potential therapeutic target in acute VF. Acknowledgement/Funding BHF Programme Grant PG/16/17/32069

P1594Ventricular fibrosis spatial distribution and quantity is a key mechanistic determinant of ventricular fibrillation mechanisms

Abstract Background Ventricular fibrosis is known to play a critical role in initiation and maintenance of ventricular fibrillation (VF). Post myocardial infarction the quantity of fibrosis negatively correlates with survival. There is a lack of data on how the quantity and degree of fibrosis influences the mechanisms of VF itself. VF mechanisms remain debated, there are data to support both critical areas sustaining rotational drivers (RDs) and the contrary hypothesis of disorganized myocardial activation driving VF. Purpose We hypothesized that the underlying mechanism of VF is influenced by the spatial distribution and quantity of ventricular fibrosis. Methods Thirty-five Sprague-Dawley rats underwent permanent left anterior descending (LAD) ligation (n=11), 20mins LAD territory ischaemia-reperfusion (n=13) or in-vivo angiotensin infusion (500ng/kg/min, n=11) to generate compact (CF), patchy (PF) and diffuse fibrosis (DF) models respectively. After a 4-week maturation period, the hearts were explanted, Langendorff perfused and VF induced with burst pacing and 30μM pinacidil. Fibrillation dynamics were quantified using phase analysis, phase singularity (PS) tracking and our novel method of global fibrillation organisation quantification, frequency dominance index (FDI), which is a power ratio of highest amplitude dominant frequency in the frequency spectrum. Results Ventricular fibrosis for each group was characterized and quantified (CF: 22.3±3.2%, PF: 18.4±4.2%, DF: 5.8±1.3%, p=0.046). VF was driven predominantly by disorganised activity in CF, PSs were detected 26±7% of time comparative to 51.2±4% in DF and 69.5±8% in PF group (p=0.001). PF stabilised RDs, average maximum rotations for a single RD in PF were 31.6±7.1 comparative to 12.5±1.7 in DF and 6.4±1.1 in CF, p&lt;0.001. The average maximum duration for a single RDs was significantly longer in PF (PF: 1231±365ms, DF: 568±68ms, CF: 363±41ms, p=0.014). Similarly, average rotations per RD were greater in the PF group (PF: 4.5±0.7, DF: 3.3±0.2, CF: 2.41±0.3 rotations, p=0.013). Total number of RDs/second were much greater with PF (PF: 12.4±2.0, DF: 5.4±0.8, CF: 3.1±1.1, p&lt;0.001). VF organisation measured by FDI was higher in PF (PF: 0.61±0.07, DF: 0.47±0.04, CF: 0.33±0.03, p=0.004). RDs in DF showed a greater degree of meander comparative to PF (DF: 12.6±1.4 vs PF: 9.3±0.8 pixels, p=0.024). Conclusion VF mechanisms occur along a spectrum between organised activity sustained by discrete drivers and disorganised myocardial activation. The underlying VF mechanism can differ significantly dependent on the quantity and pattern of fibrosis. Patchy fibrosis stabilises RDs with localization to discrete areas and sustains an organised form of VF comparative to CF where VF is largely disorganised. Characterising the degree and pattern of fibrosis in patient groups vulnerable to VF might be beneficial in identifying patients with suitable targets for ablation. Acknowledgement/Funding BHF Programme Grant PG/16/17/32069

Elimination of Purkinje Fibers by Electroporation Reduces Ventricular Fibrillation Vulnerability.

BackgroundThe Purkinje network appears to play a pivotal role in the triggering as well as maintenance of ventricular fibrillation. Irreversible electroporation (IRE) using direct current has shown promise as a nonthermal ablation modality in the heart, but its ability to target and ablate the Purkinje tissue is undefined. Our aim was to investigate the potential for selective ablation of Purkinje/fascicular fibers using IRE.Methods and ResultsIn an ex vivo Langendorff model of canine heart (n=8), direct current was delivered in a unipolar manner at various dosages from 750 to 2500 V, in 10 pulses with a 90‐μs duration at a frequency of 1 Hz. The window of ventricular fibrillation vulnerability was assessed before and after delivery of electroporation energy using a shock on T‐wave method. IRE consistently eradicated all Purkinje potentials at voltages between 750 and 2500 V (minimum field strength of 250–833 V/cm). The ventricular electrogram amplitude was only minimally reduced by ablation: 0.6±2.3 mV (P=0.03). In 4 hearts after IRE delivery, ventricular fibrillation could not be reinduced. At baseline, the lower limit of vulnerability to ventricular fibrillation was 1.8±0.4 J, and the upper limit of vulnerability was 19.5±3.0 J. The window of vulnerability was 17.8±2.9 J. Delivery of electroporation energy significantly reduced the window of vulnerability to 5.7±2.9 J (P=0.0003), with a postablation lower limit of vulnerability=7.3±2.63 J, and the upper limit of vulnerability=18.8±5.2 J.ConclusionsOur study highlights that Purkinje tissue can be ablated with IRE without any evidence of underlying myocardial damage.

Intramural conduction system gradients and electrogram regularity during ventricular fibrillation

IntroductionThe His-Purkinje system has been shown to harbor triggers for ventricular fibrillation (VF) initiation. However, the substrate responsible for VF maintenance remains elusive. We hypothesized that standard, electrode-based, point-to-point mapping would yield meaningful insight into site-specific patterns and organization which may shed light on the critical substrate for maintenance of VF. MethodsVF was induced under general anesthesia by direct current (DC) application to the right ventricle in 7 acute canines. A standard EPT Blazer mapping catheter (Boston Scientific, Natuck, MA) was used for mapping in conjunction with a Prucka recording system. We collected 30 consecutive electrograms at 24 distinct sites, confirmed by fluoroscopy and intracardiac echo. These sites included both endocardial and epicardial locations throughout the ventricles and conduction system. ResultsA total of 5040 individual data points were collected in 7 separate canine studies. During VF mapping, a transmural disparity was found between the epicardium (average cycle length [CL] of 1136 m s) and the endocardium (average CL of 123 m s) with a p value of <0.01. An additional, intramural gradient was found when comparing the proximal, insulated conduction system to the distal, non-insulated conduction system (average CL 218 versus 111 m s [p = 0.03]). ConclusionOur data are supportive of a novel observation of intramural difference between insulated and non-insulated regions of the His-Purkinje network in canines. In addition, certain areas exhibited periods of regular electrogram characteristics; this was despite the heart remaining in terminal VF. These early canine data merit further study to investigate if specific ablation of the distal conduction system can perturb or extinguish VF.

Effects of combination of sotalol and verapamil on initiation, maintenance, and termination of ventricular fibrillation in swine hearts.

Sotalol and verapamil alone reduce reentry incidence during ventricular fibrillation (VF). We tested whether the combination of these two drugs had a synergistic effect on initiation, maintenance, and termination of VF. Six open-chest pigs received intravenous sotalol (1.5mg/kg) followed by verapamil (0.136mg/kg). VF threshold (VFT) was determined by a burst pacing protocol. Two 20seconds episodes of VF were recorded from a 21×24 unipolar electrode plaque on the lateral posterior left ventricular epicardium before and after each drug. VF activation patterns were quantified. The duration of long duration VF (LDVF) maintenance was compared to our previously published data. Sotalol alone and combined with verapamil significantly increased the VFT from 12.3±4.1 to 20.3±7.1 and 26.7±8.6mA compared with baseline (P<.05). Sotalol decreased the number of wavefronts by 20%, VF activation rate by 17% and conduction velocity 11%, while the addition of verapamil neutralized these effects. Addition of verapamil to sotalol further decreased the fractionation incidence from 14% to 29% and multiplicity from 24% to 31% compared with baseline. The combination of the two drugs increased the VF cycle length, decreased synchronicity, increased regularity index and shortened the duration of LDVF maintenance compared with our previous data of verapamil alone or no drug. Synchronicity index was lower and regularity index was higher in animals in which VF spontaneously terminated earlier than 10minutes than in animals in which VF terminated longer than 10minutes. The combination of sotalol and verapamil increased VFT but accelerated LDVF termination.

Spatiotemporal Progression of Early Human Ventricular Fibrillation.

The objective of this study was to evaluate the spatio-temporal organization and progression of human ventricular fibrillation (VF) in the left (LV) and right (RV) ventricles. Studies suggest that localized sources contribute to VF maintenance, but the evolution of VF episodes has not been quantified. Synchrony between electrograms recorded from 25 patients with induced VF is computed and used to define the Asynchronous Index (ASI), indicating regions which are out-of-step with surrounding tissue. Computer simulations show that ASI can identify the location of VF-maintaining sources, where larger values of ASImax correlate with more stable sources. Automated synchrony analysis shows elevated values of ASI in a majority of self-terminating episodes (LV: 8/9, RV: 7/8) and sustained episodes (LV: 11/11, RV: 12/12). The locations of ASImax in sustained episodes co-localize with rotor cores when rotational activity is simultaneously present in phase maps (LV: 8/8, RV: 5/7, p<.05). The distribution of ASImax differentiates self-terminating from sustained episodes (mean ASImax = 0.60±0.14 and 0.70±0.16, respectively; p=0.01). Across sustained episodes the LV exhibits an increase in ASImax with time. Quantitative analysis identifies localized asynchronous regions that correlate with sources in VF, with sustained episodes evolving to exhibit more stable activation in the LV. This successive increase in stability indicates a stabilizing agent may be responsible for perpetuating fibrillation in a "migrate-and-capture" mechanism in the LV.

Rotor Stability Separates Sustained Ventricular Fibrillation From Self-Terminating Episodes in Humans

This study mapped human ventricular fibrillation (VF) to define mechanistic differences between episodes requiring defibrillation versus those that spontaneously terminate. VF is a leading cause of mortality; yet, episodes may also self-terminate. We hypothesized that the initial maintenance of human VF is dependent upon the formation and stability of VF rotors. We enrolled 26 consecutive patients (age 64 ± 10 years, n = 13 with left ventricular dysfunction) during ablation procedures for ventricular arrhythmias, using 64-electrode basket catheters in both ventricles to map VF prior to prompt defibrillation per the institutional review board-approved protocol. A total of 52 inductions were attempted, and 36 VF episodes were observed. Phase analysis was applied to identify biventricular rotors in the first 10 s or until VF terminated, whichever came first (11.4 ± 2.9 s to defibrillator charging). Rotors were present in 16 of 19 patients with VF and in all patients with sustained VF. Sustained, but not self-limiting VF, was characterized by greater rotor stability: 1) rotors were present in 68 ± 17% of cycles in sustained VF versus 11 ± 18% of cycles in self-limiting VF (p < 0.001); and 2) maximum continuous rotations were greater in sustained (17 ± 11, range 7 to 48) versus self-limiting VF (1.1 ± 1.4, range 0 to 4, p < 0.001). Additionally, biventricular rotor locations in sustained VF were conserved across multiple inductions (7 of 7 patients, p = 0.025). In patients with and without structural heart disease, the formation of stable rotors identifies individuals whose VF requires defibrillation from those in whom VF spontaneously self-terminates. Future work should define the mechanisms that stabilize rotors and evaluate whether rotor modulation may reduce subsequent VF risk.

Dominant frequency of ventricular fibrillation can be one of predictive values to discriminate high risk patients with Brugada syndrome

Purpose: Recent European and Japanese studies showed the induction of ventricular fibrillation (VF) during electrophysiological stimulation test (EPS) could not predict the sudden cardiac death in patients with Brugada syndrome (BrS). However, some recent studies indicated that the shortness of effective refractory period (ERP) or the mode of induction of VF might be good predictive value. Those indicated the exist of inherent electrical substrates in high risk patients with BrS. We accessed VF cycle length as the dominant frequency (DF) obtained by a fast Fourier transformation (FFT) analysis. Methods: The induced VF recorded from RV apex (RVA) and RV outflow tract (RVOT) was performed with a 4096 point-FFT analysis in 28 patients (all male, 51±14 years old) with BrS. DF was obtained by Fast Fourier transform from 4-s data (phase) and sequentially every 2 s before cardioversion. The average of DF from intracardiac electrograms were compared between the symptomatic group (n=15) and the asymptomatic group (n=13). EPS was performed during isoproterenol (ISP) and after propranolol (PRO) in selected patients. Results: The DF had a weak negative correlation to ERP. The relationship of DF between RVA and RVOT had a very good correlation in all phases. The DF significantly increased from phase 1 to 6 (p<0.003; 5.72±0.36 Hz to 6.19±0.49 Hz). The DFs were significantly higher in symptomatic group than in asymptomatic group (p=0.012). ISP significantly (p<0.05) shorten ERP of RV and prevented induction of VF in 20 of 25 patients (80%). During ISP, 5 patients experienced induction of VF. ISP significantly influenced DF transition compared with the control state. DF gradually increased but was unchanged after the middle phase. PRO induced VF in 5 (83.3%) of 6 patients who tested negative during ISP. DF after PRO was higher than that in the corresponding phase in the control state. ISP suppressed the induction of VF and the increase of DF with time. PRO aggravated VF and accelerated DF. Those pharmacological results were not inconsistent with the previous reports. Conclusions: Those data suggested that the DF of VF in patients with BrS was related to the ERP of RV and/or the maintenance of VF as an electrophysiological substrate of high risk patients. Higher DF of VF can be one of predictive values to discriminate the high risk Brugada patients.

And the beat goes on ... the beat goes on: organization and quasi-periodicity in ventricular fibrillation

This editorial refers to ‘KATP channel opening accelerates and stabilizes rotors in a swine heart model of ventricular fibrillation’ by J.G. Quintanilla et al ., pp. 576–585, this issue. Ventricular fibrillation (VF) is a remarkably complex and seemingly disorganized cardiac excitation, in which propagating electrical waves fail dismally to activate the ventricles synchronously, with the consequent loss of contractile function. Despite its declining incidence, VF is still a major cause of sudden cardiac death in industrialized nations, which accounts for nearly 300 000 annual fatalities in the USA alone.1,2 Clinically, VF can be observed on the electrocardiogram (ECG) as the sudden transition from the highly ordered and rhythmic pattern generated by sinuatrial activation into an irregular and aperiodic pattern, with undulating and variable morphology of the QRS complex. Traditionally, the highly aperiodic and irregular ECG traces associated with VF have been thought to be the result of a totally random excitation of the ventricles.3,4 However, over the last 20 years,5 numerous advances in high-resolution spatiotemporal imaging, computer simulations, molecular, and genetic techniques have led to the gradual emergence of a new concept of VF, which turns out to be much more organized than the ECG would first suggest.6,7 Such new advances have allowed investigation into the dynamics of fibrillatory behaviour and, just as important, the mechanisms underlying such dynamics in the structurally normal heart. Our technology has progressed to the point where we can now integrate multiple levels of organization, from the molecule to the organ level, as an aid to generate a cohesive understanding of the mechanisms that underlie the generation and maintenance of VF even in the structurally abnormal, diseased heart. With such efforts, we might be able to improve patient outcomes through the development of better designed and …

Apamin-Sensitive Potassium Current Modulates Action Potential Duration Restitution and Arrhythmogenesis of Failing Rabbit Ventricles

Apamin-sensitive K currents (I(KAS)) are upregulated in heart failure. We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and can reduce ventricular fibrillation duration in failing ventricles. We simultaneously mapped membrane potential and intracellular Ca (Ca(i)) in 7 rabbit hearts with pacing-induced heart failure and in 7 normal hearts. A dynamic pacing protocol was used to determine APDR at baseline and after apamin (100 nmol/L) infusion. Apamin did not change APD(80) in normal ventricles, but prolonged APD(80) in failing ventricles at either long (≥300 ms) or short (≤170 ms) pacing cycle length, but not at intermediate pacing cycle length. The maximal slope of APDR curve was 2.03 (95% confidence interval, 1.73-2.32) in failing ventricles and 1.26 (95% confidence interval, 1.13-1.40) in normal ventricles at baseline (P=0.002). After apamin administration, the maximal slope of APDR in failing ventricles decreased to 1.43 (95% confidence interval, 1.01-1.84; P=0.018), whereas no significant changes were observed in normal ventricles. During ventricular fibrillation in failing ventricles, the number of phase singularities (baseline versus apamin, 4.0 versus 2.5), dominant frequency (13.0 versus 10.0 Hz), and ventricular fibrillation duration (160 versus 80 s) were all significantly (P<0.05) decreased by apamin. Apamin prolongs APD at long and short, but not at intermediate pacing cycle length in failing ventricles. I(KAS) upregulation may be antiarrhythmic by preserving the repolarization reserve at slow heart rate, but is proarrhythmic by steepening the slope of APDR curve, which promotes the generation and maintenance of ventricular fibrillation.