Induction Of Ventricular Fibrillation Research Articles

ECMO attenuates inflammation response and increases ATPase activity in brain of swine model with cardiac arrest compared with CCPR.

Extracorporeal membrane oxygenation (ECMO) could increase survival rate and neurological outcomes of cardiac arrest (CA) patients compared with conventional cardiopulmonary resuscitation (CCPR). Currently, the underlying mechanisms how ECMO improves neurological outcomes of CA patients compared with CCPR have not been revealed. A pig model of CA was established by ventricular fibrillation induction and then underwent CCPR or ECMO. Survival and hemodynamics during the 6 h after return of spontaneous circulation (ROSC) were compared. The levels of inflammatory cytokines and Ca2+-ATPase and NA+-K+-ATPase activities were detected. Brain tissues histology and ultra-microstructure in CCPR and ECMO groups were also examined. Results suggested that ECMO significantly improved the survival of pigs compared with CCPR. Heart rate (HR) decreased while cardiac output (CO) increased along with the time after ROSC in both ECMO and CCPR groups. At each time point, HR in ECMO groups was lower than that in CCPR group while CO and mean arterial pressure in ECMO group was higher than CCPR group. In ECMO group, lower levels of IL-1, IL-1β, IL-6, TNFα, and TGFβ, especially IL-1, IL-6, TNFα, and TGFβ, were found compared that in CCPR group while no difference of IL-10 between the two groups was observed. Similar with the results from enzyme-linked immunosorbent assay, decreased expressions of IL-6 and TGFβ were also identified by Western blotting. And Ca2+-ATPase and NA+-K+-ATPase activities were increased by ECMO compared with CCPR. Hematoxylin and eosin staining and ultra-microstructure examination also revealed an improved inflammation situation in ECMO group compared with CCPR group.

Dose-Dependent Effects of Ranolazine on Reentrant Ventricular Arrhythmias Induced After Subacute Myocardial Infarction in Rabbits.

Ranolazine has been found to prevent ventricular arrhythmias (VAs) during acute myocardial infarction (AMI). This study aimed to investigate its efficacy on VAs induced several days post-MI. For this purpose, 13 anesthetized rabbits underwent coronary artery ligation. Ten of these animals that survived AMI were reanesthetized 3 to 7 days later for electrophysiologic testing. An endocardial monophasic action potential combination catheter was placed in the right ventricle for simultaneous pacing and recording. Monophasic action potential duration, ventricular effective refractory period (VERP), and VAs induced by programmed stimulation were assessed. Measurements were performed during control pacing, and following an intravenous infusion of either a low-dose ranolazine (2.4 mg/kg, R1) or a higher dose ranolazine (4.8 mg/kg cumulative dose, R2). During control stimulation, 2 animals developed primary ventricular fibrillation (VF), 6 sustained ventricular tachycardia (sVT), and 2 nonsustained VT (nsVT). R1 did not prevent the appearance of VAs in any of the experiments; in contrast, it aggravated nsVT into sVT and complicated sVT termination in 2 of 6 animals. Sustained ventricular tachycardia cycle length and VERP were only slightly decreased after R1 (112 ± 5 vs 110 ± 6 ms and 101 ± 11 vs 98 ± 10 ms, respectively). R2 suppressed inducibility of control nsVT, VF, and sVT in 2 animals. In 4 animals with still inducible sVT, R2 significantly prolonged VT cycle length by 150 ± 23 ms (P < .01), and VERP by 120 ± 7 ms (P < .001) versus control. In conclusion, R2 exerted antiarrhythmic efficacy against subacute-MI VAs, whereas R1 rather aggravated than prevented these arrhythmias. Ventricular effective refractory period prolongation could partially explain the antiarrhythmic action of R2 in this rabbit model.

MRI Safety for Patients Implanted With the MRI Ready ICD System

A prospective, multicenter study was performed to assess the safety and efficacy of the Durata and Optisure HV leads and the Ellipse VR implantable cardioverter-defibrillator (ICD) (St. Jude Medical, Sylmar, California) in a 1.5-T magnetic resonance imaging (MRI) environment. The primary safety objective was >90% freedom from MRI scan-related complications. The primary efficacy objectives were absence of change in capture threshold and absence of decrease of sensing amplitude from pre-MRI examination to 1 month after MRI. MRI scanning of patients has been shown to be safe in patients with magnetic resonance-conditional implantable cardioverter-defibrillators (ICD) systems. Patients with a previously implanted magnetic resonance-conditional system underwent a nondiagnostic MRI scan. After the scan, a questionnaire was given to investigators and patients who returned for 1-month follow-up examination. A subset of patients underwent ventricular tachyarrhythmia or ventricular fibrillation (VT/VF) induction testing after the MRI to evaluate defibrillation function. There were 220 patients (81% male; 62.1 ± 11.2 years of age) enrolled who received an MRI scans from 29centers. All primary safety and efficacy endpoints were met (p<0.0001). No significant detection delays were found in 34 patients who had VT/VF episodes after the MRI scan was performed. Most physicians reported easy and acceptable programming and ease of MRI scheduling. The MRI Ready MRI-conditional ICD system is safe, and electrical performance was not affected in patients receiving a 1.5-T whole-body MRI scan. Investigators reported favorable collaboration between cardiologists and radiologists in the MRI Ready IDE clinical trial. (A Clinical Evaluation of the Durata or Optisure High Voltage Leads and Ellipse VR ICD Undergoing MRI, an IDE Study [MRI Ready IDE]; NCT02787291).

Optical imaging of voltage and calcium in isolated hearts: Linking spatiotemporal heterogeneities and ventricular fibrillation initiation.

BackgroundAlternans have been associated with the development of ventricular fibrillation and its control has been proposed as antiarrhythmic strategy. However, cardiac arrhythmias are a spatiotemporal phenomenon in which multiple factors are involved (e.g. calcium and voltage spatial alternans or heterogeneous conduction velocity) and how an antiarrhythmic drug modifies these factors is poorly understood.ObjectiveThe objective of the present study is to evaluate the relation between spatial electrophysiological properties (i.e. spatial discordant alternans and conduction velocity) and the induction of ventricular fibrillation (VF) when a calcium blocker is applied.MethodsThe mechanisms of initiation of VF were studied by simultaneous epicardial voltage and calcium optical mapping in isolated rabbit hearts using an incremental fast pacing protocol. The additional value of analyzing spatial phenomena in the generation of unidirectional blocks and reentries as precursors of VF was depicted. Specifically, the role of action potential duration (APD), calcium transients (CaT), spatial alternans and conduction velocity in the initiation of VF was evaluated during basal conditions and after the administration of verapamil.ResultsOur results enhance the relation between (1) calcium spatial alternans and (2) slow conduction velocities with the dynamic creation of unidirectional blocks that allowed the induction of VF. In fact, the administration of verapamil demonstrated that calcium and not voltage spatial alternans were the main responsible for VF induction.ConclusionsVF induction at high activation rates was linked with the concurrence of a low conduction velocity and high magnitude of calcium alternans, but not necessarily related with increases of APD. Verapamil can postpone the development of cardiac alternans and the apparition of ventricular arrhythmias.

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome

BackgroundInformation on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited. ObjectivesThe purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence. MethodsA total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31). ResultsPatients’ median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents. ConclusionsYoung BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered.

Quantification of Electromechanical Coupling to Prevent Inappropriate Implantable Cardioverter-Defibrillator Shocks.

ObjectivesThis study sought to test specialized processing of laser Doppler signals for discriminating ventricular fibrillation (VF) from common causes of inappropriate therapies.BackgroundInappropriate implantable cardioverter-defibrillator (ICD) therapies remain a clinically important problem associated with morbidity and mortality. Tissue perfusion biomarkers, implemented to assist automated diagnosis of VF, sometimes mistake artifacts and random noise for perfusion, which could lead to shocks being inappropriately withheld.MethodsThe study tested a novel processing algorithm that combines electrogram data and laser Doppler perfusion monitoring as a method for assessing circulatory status. Fifty patients undergoing VF induction during ICD implantation were recruited. Noninvasive laser Doppler and continuous electrograms were recorded during both sinus rhythm and VF. Two additional scenarios that might have led to inappropriate shocks were simulated for each patient: ventricular lead fracture and T-wave oversensing. The laser Doppler was analyzed using 3 methods for reducing noise: 1) running mean; 2) oscillatory height; and 3) a novel quantification of electromechanical coupling which gates laser Doppler relative to electrograms. In addition, the algorithm was tested during exercise-induced sinus tachycardia.ResultsOnly the electromechanical coupling algorithm found a clear perfusion cut off between sinus rhythm and VF (sensitivity and specificity of 100%). Sensitivity and specificity remained at 100% during simulated lead fracture and electrogram oversensing. (Area under the curve running mean: 0.91; oscillatory height: 0.86; electromechanical coupling: 1.00). Sinus tachycardia did not cause false positive results.ConclusionsQuantifying the coupling between electrical and perfusion signals increases reliability of discrimination between VF and artifacts that ICDs may interpret as VF. Incorporating such methods into future ICDs may safely permit reductions of inappropriate shocks.

Phase-controlled intermittent intratracheal insufflation of oxygen during chest compression-active decompression mCPR improves coronary perfusion pressure over continuous insufflation

PurposeIt has previously been shown that continuous intratracheal insufflation of oxygen (CIO) is superior to intermittent positive pressure ventilation (IPPV) regarding gas exchange and haemodynamics. The purpose of this study was to investigate gas exchange and haemodynamics with a new technique of phase-controlled intermittent insufflation of oxygen (PIIO) compared to CIO. MethodTwenty (20) pigs were used, stratified into two groups (CIO, PIIO), with 10 animals each. Upon induction of ventricular fibrillation, standard ventilator support was replaced by either of CIO or PIIO ventilation. Chest compressions were delivered by the LUCAS I mCPR device. Following 20 min of CPR in normothermia, defibrillation was attempted. ResultsReturn of spontaneous circulation (ROSC) occurrence was not significantly higher (P < 0.16) in the PIIO (9/10) than in the CIO (6/10) group. During the decompression phase the PIIO group showed significant increases in mean (P < 0.01), maximal (P < 0.02) and end-decompression (P < 0.01) coronary perfusion pressure (CPP), compared to the CIO group. PIIO resulted in increased compression phase aortic pressure (P < 0.03). Intratracheal pressure was 5–30 cmH2O within both groups during mCPR, with a significantly lower (P < 0.02) mean for the PIIO group. Arterial and venous blood gas analysis showed comparable results between the groups, when taking base line values into account. An exception was that PIIO resulted in significantly higher (P < 0.05) oxygen partial pressure during mCPR, and lower (P < 0.05) arterial lactate following ROSC. ConclusionPIIO results in significantly higher CPP and compression phase aortic pressure during mCPR in a porcine population. Further studies are needed to validate these findings in humans.Study protocol conforming with ethic approval M174-15, issued by the Malmö/Lunds regionala djurförsöksetiska nämnd (REB).

ECG PATTERNS OF INITIATION OF VENTRICULAR FIBRILLATION: ANALYSIS OF 100 ELECTROPHYSIOLOGY STUDIES

The first beats of ventricular fibrillation (VF) usually demonstrates some organization before deteriorating in a nonspecific, chaotic rhythm. We sought to discern specific ECG patterns leading to the initiation of VF. 100 consecutive electrophysiology studies with induction of VF during programmed

Point-of-care laboratory analyses of intraosseous, arterial and central venous samples during experimental cardiopulmonary resuscitation

IntroductionScreening and correcting reversible causes of cardiac arrest (CA) are an essential part of cardiopulmonary resuscitation (CPR). Point-of-care (POC) laboratory analyses are used for screening pre-arrest pathologies, such as electrolyte disorders and acid–base balance disturbances. The aims of this study were to compare the intraosseous (IO), arterial and central venous POC values during CA and CPR and to see how the CPR values reflect the pre-arrest state. MethodsWe performed an experimental study on 23 anaesthetised pigs. After induction of ventricular fibrillation (VF), we obtained POC samples from the IO space, artery and central vein simultaneously at three consecutive time points. We observed the development of the values during CA and CPR and compared the CPR values to the pre-arrest values. ResultsThe IO, arterial and venous values changed differently from one another during the course of CA and CPR. Base excess and pH decreased in the venous and IO samples during untreated VF, but in the arterial samples, this only occurred after the onset of CPR. The IO, arterial and venous potassium values were higher during CPR compared to the pre-arrest arterial values (mean elevations 4.4 mmol/l (SD 0.72), 3.3 mmol/l (0.78) and 2.8 mmol/l (0.94), respectively). ConclusionsA dynamic change occurs in the common laboratory values during CA and CPR. POC analyses of lactate, pH, sodium and calcium within IO samples are not different from analyses of arterial or venous blood. Potassium values in IO, arterial and venous samples during CPR are higher than the pre-arrest arterial values.

Three-dimensional cardiac fibre disorganization as a novel parameter for ventricular arrhythmia stratification after myocardial infarction.

AimsMyocardial infarction (MI) alters cardiac fibre organization with unknown consequences on ventricular arrhythmia. We used diffusion tensor imaging (DTI) of three-dimensional (3D) cardiac fibres and scar reconstructions to identify the main parameters associated with ventricular arrhythmia inducibility and ventricular tachycardia (VT) features after MI.Methods and resultsTwelve pigs with established MI and three controls underwent invasive electrophysiological characterization of ventricular arrhythmia inducibility and VT features. Animal-specific 3D scar and myocardial fibre distribution were obtained from ex vivo high-resolution contrast-enhanced T1 mapping and DTI sequences. Diffusion tensor imaging-derived parameters significantly different between healthy and scarring myocardium, scar volumes, and left ventricular ejection fraction (LVEF) were included for arrhythmia risk stratification and correlation analyses with VT features. Ventricular fibrillation (VF) was the only inducible arrhythmia in 4 out of 12 infarcted pigs and all controls. Ventricular tachycardia was also inducible in the remaining eight pigs during programmed ventricular stimulation. A DTI-based 3D fibre disorganization index (FDI) showed higher disorganization within dense scar regions of VF-only inducible pigs compared with VT inducible animals (FDI: 0.36; 0.36–0.37 vs. 0.32; 0.26–0.33, respectively, P = 0.0485). Ventricular fibrillation induction required lower programmed stimulation aggressiveness in VF-only inducible pigs than VT inducible and control animals. Neither LVEF nor scar volumes differentiated between VF and VT inducible animals. Re-entrant VT circuits were localized within areas of highly disorganized fibres. Moreover, the FDI within heterogeneous scar regions was associated with the median VT cycle length per animal (R2 = 0.5320).ConclusionThe amount of scar-related cardiac fibre disorganization in DTI sequences is a promising approach for ventricular arrhythmia stratification after MI.

Abstract 296: Early Mitochondrial Gene Regulation in Pediatric Cardiac Arrest

Introduction: Cerebral mitochondrial dysfunction is thought to play a role in the post-cardiac arrest syndrome, propagating secondary morbidity and mortality after return of spontaneous circulation (ROSC). Hypothesis: Based on our previous studies showing a persistent decrease in oxidative phosphorylation (particularly Complex I) and increased mitochondrial fission in a swine model of in-hospital cardiac arrest, we hypothesized that nuclear and mitochondrial genes related to respiratory function would be downregulated and genes promoting mitochondrial fission would be upregulated four hours post-ROSC. Methods: One-month old piglets were subjected to sham anesthesia (n=5) or asphyxial cardiac arrest (n=6; 7 minutes of asphyxia followed by induction of ventricular fibrillation) and treated with 10-20 minutes of AHA guideline-based CPR followed by four hours of standardized post-arrest management and humane euthanasia. RNA was extracted from flash-frozen sections of cerebral cortex using a QIAsymphony robot and sequenced on an Illumina HiSeq. Reads were aligned to the reference (SusScrofa11.1 and NC_012095) using STAR and quantified using subreads. Normalization and differential expression analysis were performed using DESeq2 with RNA quality, intra-arrest and post-ROSC physiologic variables as covariates. All p values were adjusted for multiple comparisons (Benjamini-Hochberg) with a significance cutoff of 0.05. Results: Compared to sham, cardiac arrest animals demonstrated reduced expression of multiple components of the respiratory chain, including NDUFA5 (2.4-fold, p&lt;0.001) and NDUFC1 (2.0-fold, p=0.02), key components of Complex I. Components of Complex III (UQCRB, UQCRH) and Complex IV (COX1, COX7C, COX7A2, COX7B) were also downregulated. Dynamin-2 (DNM2), which increases mitochondrial fission, was upregulated (2.3-fold, p=0.005). There was also differential expression of inner membrane solute channel expression (SLC44A1, SLC25A48 and SLC25A16). Conclusions: Multiple components of the mitochondrial respiratory chain are downregulated 4 hours post-ROSC in the brain, including key components of Complex I with concurrent upregulation of the mitochondrial fission protein dynamin-2.

Abstract 311: Selection of Optimal Predictor and Critical Thresholds for Return of Spontaneous Circulation Using Non-Invasive Frequency-Domain Diffuse Optical Spectroscopy During Cardiopulmonary Resuscitation

Introduction: We have shown that during CPR, novel non-invasive monitoring of cerebral tissue oxygenation (StO 2 , %) and total hemoglobin concentration (THC, μmol/L) by frequency-domain diffuse optical spectroscopy (FD-DOS) is associated with ROSC in a swine model of pediatric cardiac arrest. Our objective is to find the optimal non-invasive predictor for ROSC and assess feasibility of a stable critical threshold over time in early CPR. Hypothesis: Stable critical thresholds with high sensitivity or specificity for ROSC may be established in early CPR (&lt;10 min) from non-invasive cerebral StO 2 and THC measurements initiated at CPR start. Methods: One-month-old swine (n=31) underwent 7 minutes of asphyxia, induction of ventricular fibrillation, and up to 20 minutes of CPR till ROSC or death (no ROSC). Absolute StO 2 and THC and absolute and relative change from 1 minute into CPR (time for chest molding and FD-DOS placement) were evaluated as ROSC predictors over time. For each variable, an ROC curve and two critical thresholds, maximizing specificity (=1) or sensitivity (=1), were determined at 1-min intervals from 2-10 minutes of CPR using univariate logistic regression. Optimal predictor was selected by highest mean AUC. A stable specificity or sensitivity threshold was feasible if the mean threshold had a specificity or sensitivity &gt;0.9 over all intervals, respectively. Results: Absolute change in StO 2 (ΔStO 2 ) had the highest mean (SD) AUC of 0.90 (0.07). Consistently &gt;0.8, the AUC exceeded 0.9 after 7 minutes of CPR ( see Fig. ). The mean specificity threshold (ΔStO 2 = +5.1%) and sensitivity threshold (ΔStO 2 = +1.4%) achieved an overall specificity of 0.93 and sensitivity of 0.98, respectively. Conclusions: Non-invasive monitoring of absolute change in StO 2 was most predictive of ROSC and stable critical thresholds with high specificity or sensitivity were established in early CPR. Future work will independently validate this promising tool for CPR optimization.

Abstract 149: Role of Pre and Intra-Arrest Hemodynamics in Evolution of the Ventricular Fibrillation Electrocardiogram Waveform

Purpose: Quantitative waveform measures (QWM) of the ventricular fibrillation (VF) waveform have been shown in laboratory and clinical studies to be predictive of return of spontaneous circulation (ROSC) and survival to hospital discharge. During resuscitation, QWM are responsive to hemodynamic changes resulting from CPR. It is not known whether the trajectory of QWM are affected by pre-arrest hemodynamics or intra-arrest arterio-venous pressure equilibration. We sought to investigate the role of hemodynamics on the evolution of VF before and during prolonged VF. Methods: We pooled data from six previous porcine experiments. Each modeled prolonged VF and included electrical induction of VF which was left untreated for up to 10 minutes, followed by attempted resuscitation. All animals were instrumented with pressure transducers (Millar, MikroTip) placed via femoral cutdown in the aorta and right atrium, as well as Lead II surface ECG. Signals were recorded continuously at 1000Hz with a data acquisition unit (PowerLab, ADInstruments). Mean baseline central arterial (CAP) and central venous pressure (CVP) were calculated from 1- minute of immediate pre-VF pressure traces. Coronary perfusion pressure (CPP) during untreated VF was calculated as the continuous difference between the CAP and CVP channels. Median slope (MS), a QWM, was calculated in 1-second windows and interpolated to the full length of the intra-arrest ECG. For trajectory analysis, CPP and MS traces were normalized on a 0-1 scale and grouped by morphological similarity. Pearson’s Correlation coefficient was calculated between corresponding CPP and MS traces. Results: A total of 141 experiments were included in the analysis. Overall mean (SD) correlation between CPP and MS was 0.56 (0.29). CPP-MS correlation strength did not correlate with baseline pressures. However, trajectory analysis revealed multiple patterns of hemodynamic and QWM evolution through untreated VF, with the most well-defined (mean coeff. = 0.58) indicating a shared bimodality temporally offset between CPP and MS. Conclusions: Hemodynamics during untreated VF show some correlation with the trajectory of QWM of the VF signal. More work is needed to understand the mechanism of this relationship.

Critical Volume of Human Myocardium Necessary to Maintain Ventricular Fibrillation.

Abnormal QT intervals, long QT or short QT, have been epidemiologically linked with sudden cardiac death because of ventricular fibrillation (VF). Consequently, Food and Drug Administration recommends testing all pharmacological agents for QT toxicity as a risk factor for cardiac toxicity. Such tests assess QT/QTc interval, which represents ventricular depolarization and repolarization. However, the current QT toxicity analysis does not account for the well-known anisotropy in cardiac tissue conductivity. Mines demonstrated in 1913 that cardiac wavelength (λ) determines inducibility of reentrant arrhythmia, where both repolarization time or action potential duration and conduction velocity determine λ=action potential duration×conduction velocity. We aimed to determine the role of anisotropic wavelength in inducibility of VF in explanted human left ventricular preparations. We tested the hypothesis that 3-dimensional cardiac wavelength, which takes into account anisotropic cardiac tissue conductivity, can accurately predict VF sustainability. We conducted panoramic optical mapping of coronary perfused human left ventricular wedge preparations subjected to pharmacologically induced shortening and prolongation of action potential duration, by IK,ATP agonist pinacidil and antagonist glybenclamide, respectively. This measured action potential duration, conduction velocity, and thus determined pacing cycle length-dependent wavelengths in longitudinal (λL), transverse (λTV), and transmural (λTM) directions using S1S1 pacing protocol, from which wavelength volume (Vλ) was determined, as Vλ=λL×λTV×λTM, and compared with tissue volume. We tested a hypothesis that tissue volume/Vλ ratio can predict VF sustainability. At baseline, at pacing rate of 240 beats per minute, the wavelengths were λL=9.6±0.6 cm, λTV=4.2±0.3 cm, and λTM=5.8±0.2 cm, respectively (n=7), and thus Vλ=246.4±42.1 cm3. Administration of pinacidil at escalating concentrations progressively decreased Vλ, and VF became sustained, when tissue volume/Vλ was above safety factor κ=4.4±0.6 (n=9) during rapid pacing. Treatment with glybenclamide decreased VT/Vλ below κ at any pacing rate and prevented VF sustainability. Sustained VF was only sustained in ventricular volume exceeding critical Vλ=λL×λTV×λTM.

Prognostic value of noninvasive programmed stimulation in patients with implantable cardioverter defibrillator.

Implantable cardioverter defibrillator (ICD) offers an opportunity to examine vulnerability to ventricular tachycardia (VT) or ventricular fibrillation (VF) by performing noninvasive programmed ventricular stimulation (NIPS). Whether NIPS can predict VT/VF recurrences has not yet been established. To examine the predictive value of NIPS for identification of patients with VT/VF recurrences. The study group consisted of consecutive 105 ICD recipients included in the prospective NIPS-ICD study (ClinicalTrials ID: NCT02373306) (88 males, age 65±11years). The patientsunderwent NIPS using the protocol up to three premature extrastimuli at 600-500- and 400-ms drive cycle lengths. The endpoint of NIPS was induction of sustained VT or VF or completion of the protocol. VT/VF was induced in 29 (27.6%) patients. During a 12-month follow-up NIPS-inducible patients had significantly more frequently appropriate ICD therapy than noninducible patients (17%vs 4%, P=0.023). NIPS-induced VT/VF had a sensitivity of 63%, specificity of 75%, positive predictive value of 17%, and negative predictive value of 96% for identification of patients with future VT/VF. Apart from NIPS, age ≥65years, QRS duration, treatment with angiotensin-converting enzyme, history of coronary artery bypass grafting, history of VT/VF prior to NIPS, and prior appropriate ICD therapy were also associated with VT/VF recurrences. Multivariate analysis showed that, together with QRS duration, NIPS result was an independent predictor of future VT/VF. Predictive value of NIPS was significantly higher in ischemic than nonischemic patients. NIPS result is associated with future VT/VF. Noninducibility at NIPS identifies those patients with high accuracy who will have uneventful follow-up.

DOES SGLT2 INHIBITION ALTER CARDIAC ELECTROPHYSIOLOGY IN RABBIT MODEL?

Empagliflozin (EMPA), an inhibitor of renal sodium-glucose cotransporter (SGLT) 2, is reported to reduce the risk of cardiovascular death in type 2 diabetic patients. The mechanisms underlying the benefit are unknown. Though SGLT2 expression on the heart is yet to be demonstrated, the off target effects of EMPA and its influence of cardiac electrophysiology have not been studied. To determine the effects of Empagliflozin on ventricular arrhythmia vulnerability, by studying ventricular fibrillation (VF) inducibility and calcium handling. Following 30 minutes of global ischemia, normal saline (n=5) or 1μM EMPA (n=4) was infused to Langendorff-perfused rabbit hearts. Each heart was electrically stimulated five times to assess VF inducibility. Left ventricular epicardial calcium mapping was performed at baseline, after ischemia, and after drug administration. Calcium alternans (CA) threshold (the lowest pacing rate that led to CA) was used to measure intracellular calcium dynamic. EMPA treated hearts had less successful induction of fibrillation episodes compared to controls (16% vs. 52%, p=0.002). Compared to baseline, CA threshold significantly decreased after ischemia both in EMPA treated hearts (5.88±0.23 vs. 5±0.17 Hz, p=0.03) and controls (6±0.13 vs. 5.1±0.05 Hz, p=0.01). Following drug intervention, CA threshold was significantly higher in EMPA treated hearts, compared to controls (5.38±0.25 vs. 4.7±0.23 Hz, p=0.02, Figure 1). Empagliflozin has cardiac electrophysiological effects in ex-vivo rabbit hearts. The mechanisms by which these effects are mediated need further evaluation.

EFFECT OF AZUMOLENE ON VENTRICULAR REFIBRLLATION IN LANGENDORFF-PERFUSED RABBIT HEARTS

During cardiopulmonary resuscitation, external shock-resistant ventricular fibrillation (VF) and re-fibrillation are common complicating factors. To determine the effects of azumolene, a modulator of ryanodine receptors (RyR), on VF, by studying re-fibrillation vulnerability and calcium transients. Following 15 minutes of global ischemia, normal saline (n=8) or 20μM azumolene (n=8) was infused during reperfusion of Langendorff-perfused rabbit hearts. To induce further stress, we induced long VF (120 seconds) twice in each heart. Those who did not stay in VF for 120 seconds were paced at 50Hz for the same duration. We then tested re-VF inducibility five times in each heart. Left ventricular (LV) epicardial calcium mapping was performed at baseline, after ischemia, after 1st and 2nd VF induction. Calcium dynamics and re-VF inducibility and organization were studied. Azumolene-treated hearts had less successful induction of re-fibrillation episodes compared to controls (32.5% vs. 67.5%, p<0.001). More calcium wavefronts (the surrogate for VF disorganization) were seen in the controls (2.88±0.05 vs. 2.14±0.13 waves per frame, p<0.01; calcium signals appeared more organized visually in azumolene-treated hearts (Panel A). Spontaneous diastolic calcium elevation (SCaE) was significantly increased in controls during post VF compared to baseline (0.117±0.029 vs. 0.052±0.010 AU, p<0.01) and SCaE was abrogated in azumolene-treated hearts (Panel B). RyR modulator, azumolene, reduces re-fibrillation vulnerability and improves calcium dynamics following VF. Dysfunctional RyR is a potential therapeutic target in VF.

Effects of long-term exercise on arrhythmogenesis in aged hypertensive rats

Chronic hypertension is a multifactorial disease that is highly associated with cardiovascular disorders. Physical activity, such as long-term exercise, is advocated as a treatment for hypertension, but the responses of different age groups to long-term exercise are unknown. We used aged spontaneous hypertensive rats (SHRs, 80 weeks old) to test the hypothesis that long-term exercise compensated for deficient autonomic control and reduced susceptibility to ventricular tachycardia (VT) and ventricular fibrillation (VF) in this animal model. The aged SHRs were divided into control and voluntary exercise groups. Ambulatory electrocardiography was recorded for the heart rate variability (HRV) analysis. Programmed stimulation was applied to exposed hearts to induce ventricular arrhythmia in situ. Then, the hearts were isolated for an optical mapping study. The results showed that increased HRV indices were broadly related to vagal dominance in the high-intensity exercise group. Exercise altered the electrical propagation dynamic properties, such as the action potential duration restitution (APDR). Furthermore, the VF inducibility decreased with increased exercise intensity. Taken together, our results suggest that long-term exercise reduces the risk of arrhythmogenesis in aged SHRs through enhanced vagal control and stabilized electrical dynamics.

Efficacy of Endocardial Ablation of Drug-Resistant Ventricular Fibrillation in Brugada Syndrome: Long-Term Outcome.

Background Both endocardial trigger elimination and epicardial substrate modification are effective in treating ventricular fibrillation (VF) in Brugada syndrome. However, the primary approach and the characteristics of patients who respond to endocardial ablation remain unknown. Methods Among 123 symptomatic Brugada syndrome patients (VF, 63%; syncope, 37%), ablation was performed in 21 VF/electrical storm patients, the majority of whom were resistant to antiarrhythmic drugs. Results Careful endocardial mapping revealed that 81% of the patients had no specific findings, whereas 19% of the patients, who experienced the most frequent VF episodes with notching of the QRS in lead V1, had delayed low-voltage fractionated endocardial electrograms. Ablation of VF triggers followed by endocardial substrate modification was performed in the right ventricular outflow tract in 85% of the cases and in the right ventricle in 15%. VF triggers could not be completely eliminated in 1 patient and VF became noninducible in 14 (88%) patients among 16 patients who underwent VF induction with normalization of Brugada-type ECG in 3. During follow-up (56.14±36.95 months), VF recurrence was observed in 7 patients. Importantly, all patients who had nothing of QRS in lead V1 did not respond to endocardial ablation despite presence of VF-triggering ectopic beats during ablation. Conclusions With careful documentation of VF-triggering ectopic beats and detailed endocardial mapping, endocardial VF trigger elimination followed by endocardial substrate modification has an excellent long-term outcome, whereas presence of QRS notching in lead V1 was associated with high VF recurrence suggesting epicardial substrate ablation as effective initial approach.

Sex-specific activation of SK current by isoproterenol facilitates action potential triangulation and arrhythmogenesis in rabbit ventricles.

It is unknown if a sex difference exists in cardiac apamin-sensitive small conductance Ca2+ -activated K+ (SK) current (IKAS ). There is no sex difference in IKAS in the basal condition. However, there is larger IKAS in female rabbit ventricles than in male during isoproterenol infusion. IKAS activation by isoproterenol leads to action potential triangulation in females, indicating its abundant activation at early phases of repolarization. IKAS activation in females induces negative Ca2+ -voltage coupling and promotes electromechanically discordant phase 2 repolarization alternans. IKAS is important in the mechanisms of ventricular fibrillation in females during sympathetic stimulation. Sex has a large influence on cardiac electrophysiological properties. Whether sex differences exist in apamin-sensitive small conductance Ca2+ -activated K+ (SK) current (IKAS ) remains unknown. We performed optical mapping, transmembrane potential, patch clamp, western blot and immunostaining in 62 normal rabbit ventricles, including 32 females and 30 males. IKAS blockade by apamin only minimally prolonged action potential (AP) duration (APD) in the basal condition for both sexes, but significantly prolonged APD in the presence of isoproterenol in females. Apamin prolonged APD at the level of 25% repolarization (APD25 ) more prominently than APD at the level of 80% repolarization (APD80 ), consequently reversing isoproterenol-induced AP triangulation in females. In comparison, apamin prolonged APD to a significantly lesser extent in males and failed to restore the AP plateau during isoproterenol infusion. IKAS in males did not respond to the L-type calcium current agonist BayK8644, but was amplified by the casein kinase 2 (CK2) inhibitor 4,5,6,7-tetrabromobenzotriazole. In addition, whole-cell outward IKAS densities in ventricular cardiomyocytes were significantly larger in females than in males. SK channel subtype 2 (SK2) protein expression was higher and the CK2/SK2 ratio was lower in females than in males. IKAS activation in females induced negative intracellular Ca2+ -voltage coupling, promoted electromechanically discordant phase 2 repolarization alternans and facilitated ventricular fibrillation (VF). Apamin eliminated the negative Ca2+ -voltage coupling, attenuated alternans and reduced VF inducibility, phase singularities and dominant frequencies in females, but not in males. We conclude that β-adrenergic stimulation activates ventricular IKAS in females to a much greater extent than in males. IKAS activation plays an important role in ventricular arrhythmogenesis in females during sympathetic stimulation.