Duration Of Ventricular Fibrillation Research Articles

Systematic review of swine models for ventricular fibrillation induction in evaluating cardiopulmonary resuscitation methods

Background and purpose: Ventricular fibrillation (VF) has been studied using a variety of swine models, historically balloon occlusion of the coronary artery and asphyxiation, and more recently, percutaneous electrical induction. These methods differ in face and construct validity, as well as requirement for expertise, cost, and duration. This study aimed to provide a systematic review these methods and their selection in research. Methods: Electronic searches were conducted in PubMed, Scopus, and Google Scholar. The Utstein-Style Guidelines for Uniform Reporting of Laboratory cardiopulmonary resuscitation (CPR) research were used to identify the extracted variables by two independent investigators. Discrepancy was resolved by discussion with the third investigator. Results: We included 236 studies published from 1990 to 2024. The most commonly used method was electrical induction using a pacing wire cannulated through the external jugular vein into the right ventricle (n = 112), followed by transthoracic electrical induction (n = 28), asphyxiation (n = 20), electrical induction via two subcutaneous needles (n = 15), and balloon occlusion (n = 10). The mean and standard deviation (SD) of the untreated VF duration were 6.9 and 5.0 minutes, respectively. Female and male pigs were used exclusively in 52 and 45 studies, respectively; both sexes were used in 31 studies; 106 studies not reporting the sex. The mean weight of the pigs was 30.2 ± 12.4 kg in 209 studies, and the number of pigs used in the studies ranged from 2 to 271 with a median of 20 (interquartile range: 15–30) pigs in 223 studies. The four most commonly used drugs for anesthesia/preparation were ketamine (n = 145), propofol (n = 76), isoflurane (n = 68), and pentobarbital (n = 61), either alone or in combination. Higher current and voltage were used for less invasive methods. Conclusions: The two most common electric method to induce VF were invasive pacing at the right ventricle and non-invasive transthoracic electrical induction. Asphyxiation was the most common ischemic VF induction. The choice of the VF induction method depends on cost, expertise, feasibility, and the nature of the CPR intervention to be tested.

Abstract 420: The Association Between Ventricular Fibrillation Duration and Successful Termination After the First Shock in Witnessed Out-of-Hospital Cardiac Arrest Patients

Introduction: In OHCA patients with an initial shockable rhythm, a longer time interval between onset of VF and the first shock decreases the likelihood of survival. The exact mechanism to explain this decrease is not clear. We investigated the time interval between delay to the first shock and outcomes VF termination, return of organized rhythm (ROOR), ROSC and survival. Methods: We studied witnessed OHCA patients with VF as an initial rhythm using the prospective ARREST registry. Patient- and resuscitation data, including time-synchronized AED and manual defibrillator data, were analysed to determine VF termination at 5 seconds after the first shock. Shock delay was defined as the time from initial emergency call till first shock by any defibrillator. Outcomes were rates of termination of VF, ROOR 5 seconds after the first shock, ROSC before transport, and survival to discharge, all in relation to the delay to the first shock. A logistic regression corrected for age, sex and basic life support before EMS arrival was used to analyse the association between VF duration and outcomes. Results: A total of 3676 cases were analysed. VF termination rates declined from 95% when the first shock was delivered <2 minutes after the call to 75% when delivered after >16 minutes (Figure 1). Rates of ROOR (49% to 23%), ROSC before transport (86% to 33%), and survival to discharge (79% to 23%) all declined significantly. Every additional minute in VF was associated with a 9% increased odds of failure to terminate VF (OR 1.09 [95% CI 1.07-1.12]), a 7% reduced odds of ROOR (OR 0.93 [95% CI 0.91-0.95]), a 12% reduced odds of acquiring ROSC before transport (OR 0.88 [95% CI 0.86-0.90]), and a 15% reduced odds of surviving to discharge (OR 0.85 [95% CI 0.83-0.87]). Conclusions: Every additional minute of delay to the first shock was associated with significant decreases in rates of VF termination, ROOR, and ROSC during transportation. This may explain the worse outcomes in patients with a long delay to defibrillation.

Effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/β-catenin/PPARγ pathway in arrhythmic rats

This paper aimed to investigate the effect of total flavonoids of buckwheat flower and leaf on myocardial cell apoptosis and Wnt/β-catenin/peroxisome proliferator-activated receptor γ(PPARγ) pathway in arrhythmic rats. SD rats were randomly divided into a control group, a model group, a low-dose(20 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a medium-dose(40 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a high-dose(80 mg·kg~(-1)) group of total flavonoids of buckwheat flower and leaf, a propranolol hydrochloride(2 mg·kg~(-1)) group, with 12 rats in each group. Except the control group, rats in other groups were prepared as models of arrhythmia by sublingual injection of 1 mL·kg~(-1) of 0.002% aconitine. After grouping and intervention with drugs, the arrhythmia, myocardial cells apoptosis, myocardial tissue glutathione peroxidase(GSH-Px), catalase(CAT), malondialdehyde(MDA), serum interleukin-6(IL-6), prostaglandin E2(PGE2) levels, myocardial tissue apoptosis, and Wnt/β-catenin/PPARγ pathway-related protein expression of rats in each group were measured. As compared with the control group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA levels in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels increased significantly in the model group, whereas the GSH-Px and CAT levels, and Bcl-2 and PPARγ protein expression levels in myocardial tissues reduced significantly. As compared with the model group, the arrhythmia score, the number of ventricular premature beats, ventricular fibrillation duration, myocardial cell apoptosis rate, MDA leve in myocardial tissues, serum IL-6 and PGE2 levels, Bax in myocardial tissues, and Wnt1 and β-catenin protein expression levels reduced in the drug intervention groups, whereas the GSH-Px and CAT levels and Bcl-2 and PPARγ protein expression levels in myocardial tissues increased. The groups of total flavonoids of buckwheat flower and leaf were in a dose-dependent manner. There was no significant difference in the levels of each index in rats between the propranolol hydrochloride group and the high-dose group of total flavonoids of buckwheat flower and leaf. The total flavonoids of buckwheat flower and leaf inhibit the activation of Wnt/β-catenin pathway, up-regulate the expression of PPARγ, reduce oxidative stress and inflammatory damage in myocardial tissues of arrhythmic rats, reduce myocardial cell apoptosis, and improve the symptoms of arrhythmia in rats.

Abstract 13766: Delays in Care and Outcomes in Out-of-Hospital Cardiac Arrest With Shockable Rhythm

Introduction: Longer duration of ventricular fibrillation (VF) and pulseless ventricular tachycardia (pVT) is associated with worse outcomes among cardiac arrest patients. The ROC-ALPS trial randomized adults with shock-refractory VF or pVT to receive amiodarone, lidocaine, or placebo and found no difference in outcomes with either amiodarone or lidocaine. We sought to quantify the delay in drug administration and its effect on outcomes. Methods: We performed a retrospective analysis of the ROC-ALPS trial dataset. We included all patients who achieved return of spontaneous circulation (ROSC), had documented time to first shock, and time to trial drug administration. A logistic regression model was created with the time to drug administration after first shock, time to first shock, time to ROSC, study randomization arm, and other covariates, as a predictor of survival and neurologic disability (Modified Rankin Scale >=4) at hospital discharge. Results: A total of 1439 patients (1116 male, mean age 63.5 [SD 13.9] years) were included, with 1043 (72.5%) of arrests witnessed. The median (IQR) time to first shock was 9.5 (7.8 - 11.6) minutes, and patients received a median of 4 (3 - 7) shocks. The median time from first shock to study drug administration was 6.9 (4.4 - 10.5) minutes. Three hundred and nine (21.5%) patients received the trial drug within 4 minutes of first shock, 540 (37.5%) had delay of 4 - 8 minutes, 309 (21.5%) had delay of 8 - 12 minutes, and 281 (19.5%) had delay of > 12 minutes. Delay in trial drug administration of greater than 12 minutes from first shock was associated with worse survival and neurologic function at hospital discharge ( Table ). This effect was not modified by drug randomization group. Conclusion: Among out-of-hospital cardiac arrest patients with shock-refractory VF or pVT who achieved ROSC, there was an association between delayed medication administration, a measurable surrogate for overall delays in care, and worse outcomes.

Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias

BackgroundAbnormal myocardial Nav1.5 expression and function cause lethal ventricular arrhythmias during myocardial ischemia–reperfusion (I/R). Protein inhibitor of activated STAT Y (PIASy)-mediated caveolin-3 (Cav-3) SUMO modification affects Cav-3 binding to the voltage-gated sodium channel 1.5 (Nav1.5). PIASy activity is increased after myocardial I/R, but it is unclear whether this is attributable to plasma membrane Nav1.5 downregulation and ventricular arrhythmias.MethodsUsing recombinant adeno-associated virus subtype 9 (AAV9), rat cardiac PIASy was silenced using intraventricular injection of PIASy short hairpin RNA (shRNA). After two weeks, rat hearts were subjected to I/R and electrocardiography was performed to assess malignant arrhythmias. Tissues from peri-infarct areas of the left ventricle were collected for molecular biological measurements.ResultsPIASy was upregulated by I/R (P < 0.01), with increased SUMO2/3 modification of Cav-3 and reduced membrane Nav1.5 density (P < 0.01). AAV9-PIASy shRNA intraventricular injection into the rat heart downregulated PIASy after I/R, at both mRNA and protein levels (P < 0.05 vs. Scramble-shRNA + I/R group), decreased SUMO-modified Cav-3 levels, enhanced Cav-3 binding to Nav1.5, and prevented I/R-induced decrease of Nav1.5 and Cav-3 co-localization in the intercalated disc and lateral membrane. PIASy silencing in rat hearts reduced I/R-induced fatal arrhythmias, which was reflected by a modest decrease in the duration of ventricular fibrillation (VF; P < 0.05 vs. Scramble-shRNA + I/R group) and a significantly reduced arrhythmia score (P < 0.01 vs. Scramble-shRNA + I/R group). The anti-arrhythmic effects of PIASy silencing were also evidenced by decreased episodes of ventricular tachycardia (VT), sustained VT and VF, especially at the time 5–10 min after ischemia (P < 0.05 vs. Scramble-shRNA + IR group). Using in vitro human embryonic kidney 293 T (HEK293T) cells and isolated adult rat cardiomyocyte models exposed to hypoxia/reoxygenation (H/R), we confirmed that increased PIASy promoted Cav-3 modification by SUMO2/3 and Nav1.5/Cav-3 dissociation after H/R. Mutation of SUMO consensus lysine sites in Cav-3 (K38R or K144R) altered the membrane expression levels of Nav1.5 and Cav-3 before and after H/R in HEK293T cells.ConclusionsI/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Nav1.5-related ventricular arrhythmias. Cardiac-targeted PIASy silencing mediated Cav-3 deSUMOylation and partially prevented I/R-induced Nav1.5 downregulation in the plasma membrane of cardiomyocytes, and subsequent ventricular arrhythmias in rats. PIASy was identified as a potential therapeutic target for life-threatening arrhythmias in patients with ischemic heart diseases.

Sodium-Glucose cotransporter 2 inhibitor empagliflozin decreases ventricular arrhythmia susceptibility by alleviating electrophysiological remodeling post-myocardial-infarction in mice.

Background: Recent clinical trials indicate that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in myocardial infarction (MI) patients, but the underlying mechanisms remain unknown. As arrhythmia often occurs during myocardial infarction, it is the main cause of death. Objective: The purpose of this study was to investigate the influence of empagliflozin (EMPA), an SGLT2 inhibitor, on cardiac electrophysiological remodeling and arrhythmia susceptibility of myocardial infarction mice. Methods: ECG was obtained from mice 1 week after MI to determine the QT interval. In an electrophysiological study and optical mapping was performed to evaluate the function of EMPA and underlying mechanisms of post-myocardial-infarction in mice. Results: EMPA treatment significantly reduced the QT interval of MI mice (MI + EMPA 50.24 ms vs. MI 64.68 ms). The membrane potential and intracellular Ca [Cai] were mapped from 13 MI hearts and five normal hearts using an optical mapping technique. A dynamic pacing protocol was used to determine action potential duration and [Cai] at baseline and after EMPA (10 umol/L) infusion. EMPA perfusion did not change the APD80 and CaT80 in normal ventricles while shortening them in an infarct zone, bordering zone, and remote zone of MI hearts at 200 ms, 150 ms, 120 ms, and 100 ms pacing cycle length. The conduction velocity of infarcted ventricles was 0.278 m/s and 0.533 m/s in normal ventricles at baseline (p < 0.05). After EMPA administration, the conduction velocity of infarcted ventricles increased to 0.363 m/s, whereas no significant changes were observed in normal ventricles. The action potential rise time, CaT rise time, and CaT tau time were improved after EMPA perfusion in infarcted ventricles, whereas no significant changes were observed in normal ventricles. EMPA decreases early afterdepolarizations premature ventricular beats, and ventricular fibrillation (VF) in infarcted ventricles. The number of phase singularities (baseline versus EMPA, 6.26 versus 3.25), dominant frequency (20.52 versus 10.675 Hz), and ventricular fibrillation duration (1.072 versus 0.361 s) during ventricular fibrillation in infarcted ventricles were all significantly decreased by EMPA. Conclusion: Treatment with EMPA improved post-MI electrophysiological remodeling and decreased substrate for VF of MI mice. The inhibitors of SGLT2 may be a new class of agents for the prevention of ventricle arrhythmia after chronic MI.

Cardioprotective effects of sinomenine in myocardial ischemia/reperfusion injury in a rat model

BackgroundIschemia reperfusion (I/R) play an imperative role in the expansion of cardiovascular disease. Sinomenine (SM) has been exhibited to possess antioxidant, anticancer, anti-inflammatory, antiviral and anticarcinogenic properties. The aim of the study was scrutinized the cardioprotective effect of SM against I/R injury in rat. MethodsRat were randomly divided into normal control (NC), I/R control and I/R + SM (5, 10 and 20 mg/kg), respectively. Ventricular arrhythmias, body weight and heart weight were estimated. Antioxidant, inflammatory cytokines, inflammatory mediators and plasmin system indicator were accessed. ResultsPre-treated SM group rats exhibited the reduction in the duration and incidence of ventricular fibrillation, ventricular ectopic beat (VEB) and ventricular tachycardia along with suppression of arrhythmia score during the ischemia (30 and 120 min). SM treated rats significantly (P < 0.001) altered the level of antioxidant parameters. SM treatment significantly (P < 0.001) repressed the level of creatine kinase MB (CK-MB), creatine kinase (CK) and troponin I (Tnl). SM treated rats significantly (P < 0.001) repressed the tissue factor (TF), thromboxane B2 (TXB2), plasminogen activator inhibitor 1 (PAI-1) and plasma fibrinogen (Fbg) and inflammatory cytokines and inflammatory mediators. ConclusionOur result clearly indicated that SM plays anti-arrhythmia effect in I/R injury in the rats via alteration of oxidative stress and inflammatory reaction.

Alpha-lipoic acid potentiates the anti-arrhythmic effects of ischemic postconditioning in the setting of cardiac ischemia/reperfusion injury in diabetic rats.

Prevention of lethal ventricular arrhythmias induced by myocardial ischemia/reperfusion (I/R) in diabetic patients is the major goal of cardioprotective strategies. Here, we aimed to examine the anti-arrhythmic effect of ischemic postconditioning (IPostC) and alpha-lipoic acid (ALA) in myocardial I/R injury of type-II diabetic rats, focusing on the involvement of connexin-43 and nitric oxide (NO) in this context. Diabetes (duration of 12weeks) was induced by high-fat diet and low dose of streptozotocin in thirty male Wistar rats (12weeks old, 200-250g). After mounting the hearts on the Langendorff apparatus, I/R was induced by the ligation of left anterior descending coronary artery for 35min, and reperfusion for 60min. ALA (100mg/kg/day) was administered orally in diabetic rats for five weeks before I/R. IPostC was applied immediately at early reperfusion. The arrhythmias were evaluated according to the Lambeth convention. Connexin-43 expression and NO levels were assessed by western blotting and Griess calorimetric method, respectively. IPostC could not significantly decrease the number, duration, and incidence of premature ventricular contraction, ventricular tachycardia, and ventricular fibrillation, also the severity of arrhythmias in diabetic hearts. However, IPostC in combination with ALA-preconditioning significantly decreased the above mentioned parameters compared with untreated or monotherapies-received diabetic rats (P < 0.05 to P < 0.001). Furthermore, this combination therapy significantly increased connexin-43 expression and NO levels, compared with untreated diabetic rats (P < 0.01). Preconditioning with ALA restored anti-arrhythmic effect of IPostC in diabetic hearts. Increased connexin-43 expression and NO levels may be the key players in this cardioprotection.

Pinocembrin ameliorates arrhythmias in rats with chronic ischaemic heart failure

Objective Ventricular arrhythmias (VAs) are a common complication of chronic ischaemic heart failure (CIHF). The purpose of this study is to investigate the efficacy of pinocembrin in a rat model of VAs induced by CIHF and further examine the possible mechanism. Methods Rats were subjected to ligation of left anterior descending coronary artery to mimic CIHF and then received pinocembrin treatment daily for 2 months. The vivo electrophysiology were performed to determine the effect of pinocembrin on ventricular electrical activity. The expression of Cav1.2, Kv4.2, and NGF was determined by Western blot. The structural change of ventricle was tested by the Echocardiography, Masson staining, and HE staining. The effect of pinocembrin on sympathetic nerve-related markers was detected by the immunostaining and the ELISA was used to test for biomarkers associated with heart failure. Results Pinocembrin increased the expression of ion channel protein Cav1.2 and Kv4.3, ameliorated the shortening of action potential duration (APD) and reduced the incidence and duration of ventricular fibrillation (VF). Pinocembrin also reduced the expression of nerve growth factor (NGF) and improved the autonomic nerve remodelling. In addition, pinocembrin reduced the area of infarct area and myocardial fibrosis, accompanied by increasing the expression of connexin protein 43 (CX43). Conclusion We demonstrate that pinocembrin reduces cardiac nerve remodelling and protects against Vas induced by CIHF. The findings suggest that pinocembrin can be a promising candidate for the treatment of VAs.

Predictive Utility of End-Tidal Carbon Dioxide on Defibrillation Success in Out-of-Hospital Cardiac Arrest

Introduction The likelihood of survival from ventricular fibrillation (VF) declines 7%-10% per minute until successful defibrillation. When VF duration is prolonged, immediate defibrillation of the ischemic myocardium is less likely to result in ROSC, and repeated unsuccessful defibrillations are associated with post-resuscitation myocardial dysfunction. Thus, the timing of defibrillation should be based upon the probability of shock success—a function of VF duration. Unfortunately, VF duration is often unknown in out-of-hospital cardiac arrest (OHCA) and a better predictor of shock success is needed. Objective To assess the ability of end-tidal carbon dioxide (EtCO2) to predict successful defibrillation in OHCA. Methods This retrospective study included adult patients among four EMS systems who experienced non-traumatic OHCA from August, 2015-July, 2017 and received one or more defibrillations. First and succedent shocks were analyzed separately. First shocks represented EMS-attempted defibrillation of patients who had not received a prior AED shock, whereas succedent shocks included all shocks subsequent to the first. Logistic regression provided odds ratios (OR) for first shocks resulting in ROSC, while a generalized estimating equation was used to analyze succedent shocks. Results Among 324 patients, 869 shocks were delivered by EMS (153 first and 716 succedent shocks). Layperson CPR was performed in 48.1% of cases and 21.6% received an AED shock before EMS arrival. First defibrillation ROSC was more likely with layperson CPR (OR = 4.41;p = 0.01) and increasing EtCO2 (OR = 1.03/mmHg;p = 0.01). No other variables were statistically significant. Notably, only one patient with EtCO2 < 20 mmHg was successfully defibrillated on the first shock. The probability of ROSC was higher with increasing values of EtCO2 when layperson CPR was provided, yet remained relatively unchanged across all values of EtCO2 ≥ 20 mmHg without layperson CPR. The optimal threshold first shock EtCO2 was 27 and 32 mmHg for those with/without layperson CPR, respectively. EtCO2 was not a predictor of ROSC for succedent shocks. Conclusions An optimal defibrillation threshold EtCO2 of 27 and 32 mmHg was observed for patients with and without layperson CPR, respectively. Further studies are warranted to verify these results and to evaluate the clinical effect of delaying defibrillation in favor of chest compressions until these values are attained.

Pralidoxime-Induced Potentiation of the Pressor Effect of Adrenaline and Hastened Successful Resuscitation by Pralidoxime in a Porcine Cardiac Arrest Model.

Pralidoxime potentiated the pressor effect of adrenaline and facilitated restoration of spontaneous circulation (ROSC) after prolonged cardiac arrest. In this study, we hypothesised that pralidoxime would hasten ROSC in a model with a short duration of untreated ventricular fibrillation (VF). We also hypothesised that potentiation of the pressor effect of adrenaline by pralidoxime would not be accompanied by worsening of the adverse effects of adrenaline. After 5min of VF, 20 pigs randomly received either pralidoxime (40mg/kg) or saline, in combination with adrenaline, during cardiopulmonary resuscitation (CPR). Coronary perfusion pressure (CPP) during CPR, and ease of resuscitation were compared between the groups. Additionally, haemodynamic data, severity of ventricular arrhythmias, and cerebral microcirculation were measured during the 1-h post-resuscitation period. Cerebral microcirculatory blood flow and brain tissue oxygen tension (PbtO2) were measured on parietal cortices exposed through burr holes. All animals achieved ROSC. The pralidoxime group had higher CPP during CPR (P = 0.014) and required a shorter duration of CPR (P = 0.024) and smaller number of adrenaline doses (P = 0.024). During the post-resuscitation period, heart rate increased over time in the control group, and decreased steadily in the pralidoxime group. No inter-group differences were observed in the incidences of ventricular arrhythmias, cerebral microcirculatory blood flow, and PbtO2. Pralidoxime improved CPP and hastened ROSC in a model with a short duration of untreated VF. The potentiation of the pressor effect of adrenaline was not accompanied by the worsening of the adverse effects of adrenaline.

Anti-arrhythmogenic effects of quercetin postconditioning in myocardial ischemia/reperfusion injury in a rat model

The prevention of myocardial damage occurring from ischemia/reperfusion (IR) is a major issue in ischemic heart disease in civilized worldwide. The object of recent study was based on investigating the anti-arrhythmogenic effect of quercetin postconditioning (QPC) in IR injury in rats, aiming at the involvement of nitric oxide (NO) system and mitochondrial K-ATP (mitoKATP) channels activities. Upon separation of the hearts of 64 male Wistar rats, they were randomly assigned to eight groups (n = 8/group). Except for the sham group, ischemia has exerted by inducing interruption of the aortic supply for 30 min ischemic condition, then 55 min reperfusion. Each experiment lasted 100 min in total with 15 min as stabilization period. The levels of LDH in coronary effluent were estimated colorimetrically. Overall the experiment lambeth convention-based used to assess arrhythmias, which were classified as number and severity of premature ventricular complexes (PVC), number and duration of ventricular fibrillation (VF), and ventricular tachycardia (VT). The arrhythmias induced by IR, LDH and number and duration VF significantly enhanced in control group (P < 0.05 vs. control). The Que group could reduce the LDH level, number of PVC, number and duration of VT, VF and severity of arrhythmias (P < 0.05 compared with control). The effects of Que were abrogated by the concurrent administration of L-NAME (L-nitro-arginine methyl ester) or 5-HD (5-hydroxydecanoate) as selective antagonists of NO system and mitoKATP channel, respectively. Accumulating evidence indicates that the cardioprotective effect of QPC highlights the importance of in anti-arrhythmogenic during IR, thereby opening a new direction for treatment in patients with myocardial infarction (MI).

Vildagliptin reduces myocardial ischemia-induced arrhythmogenesis via modulating inflammatory responses and promoting expression of genes regulating mitochondrial biogenesis in rats with type-II diabetes.

Fatal arrhythmias are one of the main manifestations of ischemic heart disease in diabetic patients. Here, we investigated the effect of pretreatment with vildagliptin on myocardial arrhythmias, inflammatory responses, and expression of genes regulating mitochondrial biogenesis following cardiac ischemic injury in type II diabetic male Wistar rats. Chronic diabetes was modeled by a high-fat diet and low-dose streptozotocin method and lasted for 12weeks. Vildagliptin (6mg/dl) was orally administered during the last 4 weeks of the diabetic period. Then, rats' hearts (n = 8/each group) were immediately isolated and transferred to the Langendorff apparatus, in which left anterior descending coronary artery was tightened for 35min to induce regional ischemia. Electrocardiography was continuously recorded and myocardial arrhythmias were interpreted according to the Lambeth Convention. Inflammatory cytokines in left ventricular samples were measured using ELISA kits, and gene expression was assayed using real-time PCR. Diabetic groups showed increased incidence and duration of ventricular fibrillation (VF) than controls (P < 0.05). Pretreatment of diabetic rats with vildagliptin resulted in a significant decrease in number, duration, and severity of premature ventricular complexes (PVC), tachycardia (VT), and VF during ischemia, compared to non-treated diabetic group (P < 0.05). Additionally, vildagliptin significantly increased the expression of genes PGC-1α, SIRT-1, and NRF-2 and reduced the levels of myeloperoxidase, creatine kinase release, and myocardial content of TNF-α and IL-1β in nondiabetic and diabetic rats as compared to corresponding controls (P < 0.01-0.05). Vildagliptin preconditioning reduced the occurrence and severity of fatal ventricular arrhythmias induced by myocardial ischemia in type II diabetic rats through increased activity of mitochondrial biogenesis-regulating genes and reduction of inflammatory reactions.

Effect of flunarizine on defibrillation outcomes and early refibrillation in a canine model of prolonged ventricular fibrillation

New Findings What is the central question of this study? Can successful electrical shock in combination with a delayed after‐depolarization (DAD) blocker suppress early refibrillation episodes following long duration ventricular fibrillation (LDVF)? What is the main finding and its importance? Flunarizine significantly reduced the activation of LDVF and early ventricular fibrillation (VF) recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in prolonged VF. Thus, DAD inhibition can be used as an adjunctive therapy for electrical defibrillation to treat prolonged VF and suppress refibrillation following LDVF. This study attempts to detect changes in the defibrillation threshold (DFT) at different stages of ventricular fibrillation (VF) (short duration VF, SDVF; long duration VF, LDVF) and during early refibrillation following successful defibrillation of LDVF by giving flunarizine, a blocker of delayed after‐depolarizations (DADs). Twelve beagles were divided into two groups (the control group, n = 6; and the flunarizine group, n = 6). Two 64‐electrode basket catheters were deployed into the left and the right ventricles for global endocardium mapping. The DFTs of SDVF and LDVF were determined at 20 s and 7 min, respectively, after VF induction in each group. Any refibrillation episodes were recorded within 15 min after the first successful defibrillation of LDVF. In the flunarizine group, the SDVF‐DFT values before and after the drug were not significantly different. The 7 min LDVF‐DFTs were markedly reduced by 26% (P < 0.05, the control group) and 38% (P < 0.01, the flunarizine group) compared to the 20 s SDVF‐DFTs within each group. The difference between SDVF‐DFT and LDVF‐DFT after flunarizine was larger than that in the control group (213 ± 65 vs. 120 ± 84 V, P < 0.05). The number of refibrillation episodes per animal (1.3 ± 1.0) following successful defibrillation of LDVF after flunarizine was 48% of that in controls (2.7 ± 2.0, P < 0.05). The effect of flunarizine on SDVF‐DFT and LDVF‐DFT indicates that the role of DADs in the defibrillation mechanism may differ as VF continues. Flunarizine significantly reduced early VF recurrence following LDVF, suggesting that DADs potentially contribute to refibrillation in a canine model of prolonged VF.

P1705The association between pre-shock ventricular fibrillation duration and shock success during out-of-hospital cardiac arrest

Abstract Background After the first shock, most ventricular fibrillation (VF) out-of-hospital cardiac arrest (OHCA) patients require subsequent shocks before organized rhythm is restored. Currently, all those shocks are given after a fixed 2 or 3-minute chest compression interval, resulting in many unsuccessful shocks. However, recently new defibrillators have been developed that can recognize VF during chest compressions, and enable earlier shocks immediately upon detection of VF. This prompts the question whether VF of shorter duration is associated with higher shock success. Purpose To study the association between pre-shock VF-duration and shock success in all subsequent shocks during OHCA. Methods Detailed VF-study on a subset of our prospective, real-world cardiac arrest-registry, focusing on patients with ≥2 shocks for VF and available ECG-tracings. These were scrutinized to determine VF-duration (time from VF-onset until shock) and shock success (return of organized rhythm within 1 min. after the shock). All first shocks were excluded. Results We studied 397 shocks from 101 patients. Of these, 77% were male and median age was 64 (interquartile range [IQR] 54–76) years. Overall shock success was 51% and survival to discharge was 19%. Overall median pre-shock VF-duration was 221s (IQR 125–433). The median pre-shock VF-duration was shorter before a successful (171s [IQR 75–295]) than before an unsuccessful shock (334s [IQR 174–740]), p&lt;0.001. Shock success decreased from 75% in the quartile with the shortest to 21% in the quartile with the longest pre-shock VF-duration, p for trend&lt;0.001 (Figure 1). Figure 1 Conclusion In shocks following the first defibrillation attempt, VF of shorter duration is associated with higher proportions of shock success. In an era of defibrillators that are able to recognize VF during chest compressions, our findings prompt the question whether shock upon detection of VF may improve the dismal outcomes of VF cardiac arrest. Acknowledgement/Funding None

Cardioplegia defibrillation of circulatory and metabolic phase ventricular fibrillation in a swine model

IntroductionWe previously found potassium cardioplegia followed by rapid calcium reversal (Kplegia) can achieve defibrillation in a swine model of electrical phase of ventricular fibrillation (VF) comparable to standard care. HypothesisExploring 3 possible potassium dose and timing protocols, we hypothesize Kplegia may benefit resuscitation of longer duration untreated VF. MethodsThree separate blinded randomized placebo-controlled trials were performed with electrically-induced VF untreated for durations of 6, 9, and 12min in a swine model. Experimental groups received infusion of 1 or 2 boluses of intravenous (IV) potassium followed by a single calcium reversal bolus. Potassium was replaced by saline in the control groups. Outcomes included: amplitude spectrum area (AMSA) during VF, resulting rhythms, number of defibrillations, return of spontaneous circulation (ROSC), and hemodynamics for 1h post ROSC. Binomial and interval data outcomes were compared with exact statistics. Serial interval data were assessed with mixed regression models. ResultsTwelve, 12, and 8 animals were included at 6, 9, and 12min VF durations for a total of 32. ROSC was achieved in: 4/6 Kplegia and 3/6 control animals in the 6min protocol, (p=1.00), 4/6 Kplegia and 2/6 control animals in the 9min protocol,(p=0.57), and 0/5 Kplegia and 1/3 control animals in the 12min protocol,(p=0.38). Two of 8 Kplegia animals achieved ROSC with chemical defibrillation alone. ConclusionsThe majority of animals achieved ROSC after up to 9min of untreated VF arrest using K plegia protocols. K plegia requires further optimization for both peripheral IV and intraosseous infusion, and to assess for superiority over standard care.Institutional Animal Care and Use Committee protocol #15127224.

Functional biological pacemaker generation by T-Box18 protein expression via stem cell and viral delivery approaches in a murine model of complete heart block

Despite recent advances in the treatment of cardiac arrhythmia, the available options are still limited and associated with some complications. Induction of biological pacemakers via Tbx18 gene insertion in the heart tissue has been suggested as a promising therapeutic strategy for cardiac arrhythmia. Following a previous in vitro study reporting the production of Tbx18-expressing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), we aimed to investigate the efficacy of these engineered cells to generate pacemaker rhythms in a murine model of complete heart block. We also attempted to generate a functional pacemaker by Tbx18 overexpression in native cardiac cells of rat heart. The hiPSC-derived pacemaker cells were produced by lentiviral delivery of Tbx18 gene to stem cells during a small molecule-based differentiation process. In the present study, 16 male albino Wistar rats were randomly assigned to Tbx18-lentivirus (n = 4) and Tbx18-pacemaker cells (n = 4) administered via injection into the left ventricular anterolateral wall. The control rats received GFP-lentiviruses (n = 4) and GFP-pacemaker cells (n = 4). Fourteen days after the injection, the rats were sacrificed and analyzed by electrocardiography (ECG) recording using a Langendorff-perfused heart model following complete heart block induced by hypokalemia and crashing. Immunofluorescence staining was used to investigate the expression of Tbx18, HCN4 and connexin 43 (Cx43) proteins in Tbx18-delivered cells of heart tissues. The heart rate was significantly reduced after complete heart block in all of the experimental rats (P < 0.05). Heart beating in the Tbx18-transduced hearts was slower compared with rats receiving Tbx18-pacemaker cells (P = 0.04). The duration of ventricular fibrillation (VF) was higher in the lentiviral Tbx18 group compared with the GFP-injected controls (P = 0.02) and the Tbx18-pacemaker cell group (P = 0.02). The ECG recording data showed spontaneous pacemaker rhythms in both intervention groups with signal propagation in Tbx18-transduced ventricles. Immunostaining results confirmed the overexpression of HCN4 and downregulation of Cx43 as a result of the expression of the Tbx18 gene and spontaneously contracting myocyte formation. We confirmed the formation of a functional pacemaker after introduction of Tbx18 via cell and gene therapy strategies. Although the pacemaker activity was better in gene-received hearts since there were longer VF duration and signal propagation from the injection site, more data should be gathered from the long-term activity of such pacemakers in different hosts.

Endogenous nociceptin/orphanin FQ affects the occurrence of arrhythmia in acute myocardial ischemia in rats through the regulation of connexin 43 protein

Objective Observing influence of various ventricular arrhythmias induced by acute myocardial ischemia and the change of connexin 43 (Cx43) protein content in myocardium in rats and effects of nociceptin/orphanin FQ (OFQ) receptor antagonist UFP-101 on the expression of arrhythmia and Cx43 protein. Methods Sixty-four male SD rats, weighing 200-250 g, were randomly divided into control group(group C, each group was divided into three subgroups, which named coronary artery occlusion 15 min, coronary artery occlusion 60 min and coronary artery occlusion 120 min, n=8), N/OFQ receptor antagonist group (group U, each group was divided into three subgroups, which named coronary artery occlusion 15 min, coronary artery occlusion 60 min and coronary artery occlusion 120 min, n=8), Sham operation group (group S, each group was divided into two subgroups, which named thread without ligation 15 min and thread without ligation 60 min, n=8). Group U was treated with OFQ antagonist compound UFP-101 in the dosage of 1 μl/g by caudal vein. Group C was treated with equal volume of saline. Group C and group U were administered 5 min before they were subjected to the coronary artery occlusion. Group S only was thread without ligation. Record data of electrocardiogram of group C and group U that from 10 min before the injection to 15, 60 min and 120 min after coronary artery occlusion, analyze data of all kinds of ventricular arrhythmia. Determination of expression levels of phosphorylated Cx43 (p-Cx43) protein and total Cx43 protein in all specimens by Western blot. Results At 15 min, numbers of ventricular premature contraction and ventricular bigeminy or trigeminy, the duration of ventricular tachycardia and ventricular fibrillation of group U were obviously lower than numbers in group C (P<0.05). At 60 min, numbers of ventricular premature contraction, ventricular bigeminy and trigeminy, ventricular tachycardia and ventricular fibrillation of group U were lower than those numbers in group C obviously (P<0.05). Expression of p-Cx43 protein at 15 min after coronary artery occlusion, the expression of p-Cx43 in group C were significantly lower than expression levels in group S (P<0.05), the expression of p-Cx43 in group U was significantly higher than that in group C (P<0.05). At 60 min after coronary artery occlusion, the expression of p-Cx43 in group C and group U were significantly lower than expression levels in group S (P<0.05). Conclusions Endogenous OFQ antagonist UFP-101 can reduce the occurrence of arrhythmia in acute myocardial ischemia by promoting phosphorylation of Cx43 protein in rats. Key words: Endogenous nociceptin/orphanin FQ; Protein Cx43; Phosphorylation; Arrhythmia

Ventricular fibrillation recorded and analysed within an area the size of a mobile phone: could it enable cardiac arrest recognition?

Recognition of out-of-hospital-cardiac arrests (OHCAs) at emergency medical communication centres is based on questions of OHCA symptoms, resulting in 50-80% accuracy rates. However, OHCAs might be recognized more promptly using 'rhythm-based' recognition, whereby a victim's cardiac rhythm is recorded with mobile phone technology that analyses and transmits recordings to emergency medical communication centres for further interpretation. To examine whether the quality of normal cardiac rhythm and the rhythm with the best prognosis in OHCA, ventricular fibrillation (VF), is sufficient for 'rhythm-based' OHCA recognition when recorded within a mobile phone-sized device. mid-sternum within an area the size of a mobile phone and analysed by automated external defibrillator (AED) software and two cardiologists. The rhythms were categorized as shockable or nonshockable. The cardiologists assessed the quality of the recordings. The AED software correctly analysed all normal rhythms and 15 of 22 VF rhythms. The VF duration was too short for automatic detection in seven cases. The cardiologists analysed all the normal rhythms and VF sequences correctly and graded them as high quality. The recordings of normal ECG rhythm and VF within an area the size of a mobile phone are of sufficient quality and could be used in 'rhythm-based' OHCA recognition. The VF period was too short for an accurate analysis by the AED software in some cases.

Abstract 334: Cardioplegia Defibrillation of Circulatory Phase Ventricular Fibrillation in a Swine Model: Three Randomized Controlled Trials

Introduction: We previously found potassium cardioplegia followed by rapid calcium reversal (K plegia) can achieve defibrillation in a swine model of electrical phase ventricular fibrillation (VF) comparable to standard care. Hypothesis: Exploring 3 possible potassium (K) dose and timing protocols, we hypothesize K plegia may benefit resuscitation of circulatory phase VF. Methods: Three separate blinded randomized placebo-controlled trials were performed with electrically-induced VF untreated for durations of 6,9, and 12 minutes in a swine model. All experimental groups received infusion of 1 or 2 boluses of intravenous (IV) K followed by a single calcium reversal bolus. Only K was replaced by saline in the control groups. All other treatments were the same. Outcomes included: amplitude spectrum area (AMSA) during VF, resulting rhythms, number of defibrillations, return of spontaneous circulation (ROSC), and hemodynamics for 1 hour post ROSC. Single nominal and interval outcomes were compared with Fisher’s Exact test and Mann-Whitney U, respectively. Results: Twelve, 12, and 8 animals were included at 6, 9 , and 12 minute VF durations for a total of 32. ROSC, average number of shocks, and post-ROSC norepinephrine requirement are listed below. 4/6 K plegia and 2/6 control animals achieved ROSC in the 9 minute protocol, (p=0.24). Two of 8 animals that achieved ROSC with K plegia did so without electrical defibrillation. Conclusions: The majority of animals achieved ROSC after up to 9 minutes of untreated VF arrest using K plegia protocols. K plegia requires further optimization for both peripheral IV and intraosseous infusion, and to assess for superiority over standard care.