Duration Of Ventricular Tachycardia Research Articles

Inhalation exposure to flavored electronic nicotine delivery systems (vaping) negatively impacts cardiac electrophysiology

Abstract Background Electronic nicotine delivery systems (ENDS) heat "e-liquids" to generate "e-vapor", an inhalable aerosol. E-liquids contain nicotine and flavors in a solvent of 70% vegetable glycerin, 30% propylene glycol (70VG/30PG). Flavored ENDS are very popular among teens vapers, however, the possible cardiac electrophysiological harm of inhalation exposure to flavored ENDS are not fully understood. Purpose To test if inhalation exposure to e-liquids or their constituents compromises mitochondrial integrity, increases oxidative stress, and leads to cardiac electrophysiological toxicity. Methods Gas chromatography mass spectrometry (GC/MS), and flow cytometry, in-vivo programmed electrical stimulation (PES), and transmission electron microscopy (TEM) were used in atrial like HL-1 myocytes and in mice overexpressing the antioxidant mitochondrial catalase (MCAT) which underwent inhalation exposure to e-vapor. Results We compared the toxicity of e-vapor exposure to 30 differently flavored e-liquids (70VG/30PG, with 6 mg/ml nicotine) in HL-1 cells using annexinV flow cytometry. Most e-liquids were toxic. We then quantified the concentrations of major flavoring carbonyls (cinnamaldehyde, vanillin, ethyl-vanillin, maltol, and ethyl-maltol) in the 30 e-liquids using GC/MS. Toxicity of the e-liquids in HL-1 cells correlated with their flavoring carbonyls concentration. We assessed oxidative stress (OS) via CellROX flow cytometry in HL-1 cells exposed to vanilla flavored e-vapor. OS increased in exposed cells but this was blunted by N-acetylcycteine pretreatment. In-vivo inhalation exposure to e-vapor of vanilla flavored e-liquid with 6 mg/ml nicotine increased inducible ventricular tachycardia duration in WT but not in MCAT mice versus control. In TEM, mitochondrial perimeter was unaffected, but cristae thickness decreased in exposed WT, but not in exposed MCAT hearts versus controls. We then investigated whether adverse cardiac effects of vaping are due only to nicotine. Mice were exposed to the e-vapor of 70VG/30PG base alone or base plus vanillin WITHOUT nicotine. In telemetric ECG analysis of heart rate variability, exposure to base plus vanillin decreased parasympathetic indices more than exposure to base alone. In PES, the effective refractory periods of base alone and base plus vanillin groups tended to be shortened vs air controls. While exposure to base alone and to base plus vanillin significantly increased inducible ventricular tachycardia duration compared to air controls, the increase in the base plus vanillin group was more significant compared to that of base alone. Conclusions Inhalation exposure to flavored ENDS or to their NON-NICOTINE constituents negatively affects ventricular electrophysiology, possibly via adverse mitochondrial remodeling, and increased oxidative stress.

Vasovagal Responses to Human Monomorphic Ventricular Tachycardia: Hemodynamic Implications From Sinus Rate Analysis

BackgroundFactors determining hemodynamic stability during human ventricular tachycardia (VT) are incompletely understood. ObjectivesThe purposes of this study were to characterize sinus rate (SR) responses during monomorphic VT in association with hemodynamic stability and to prospectively assess the effects of vagolytic therapy on VT tolerance. MethodsThis is a retrospective analysis of patients undergoing scar-related VT ablation. Vasovagal responses were evaluated by analyzing sinus cycle length before VT induction and during VT. SR responses were classified into 3 groups: increasing (≥5 beats/min, sympathetic), decreasing (≥5 beats/min, vagal), and unchanged, with the latter 2 categorized as inappropriate SR. In a prospective cohort (n = 30) that exhibited a failure to increase SR, atropine was administered to improve hemodynamic tolerance to VT. ResultsIn 150 patients, 261 VT episodes were analyzed (29% untolerated, 71% tolerated) with median VT duration 1.6 minutes. A total of 52% of VT episodes were associated with a sympathetic response, 31% had unchanged SR, and 17% of VTs exhibited a vagal response. A significantly higher prevalence of inappropriate SR responses was observed during untolerated VT (sustained VT requiring cardioversion within 150 seconds) compared with tolerated VT (84% vs 34%; P < 0.001). Untolerated VT was significantly different between groups: 9% (sympathetic), 82% (vagal), and 32% (unchanged) (P < 0.001). Atropine administration improved hemodynamic tolerance to VT in 70%. ConclusionsNearly one-half of VT episodes are associated with failure to augment SR, indicative of an under-recognized pathophysiological vasovagal response to VT. Inappropriate SR responses were more predictive of hemodynamic instability than VT rate and ejection fraction. Vagolytic therapy may be a novel method to augment blood pressure during VT.

Increased in vivo perpetuation of whole-heart ventricular arrhythmia in heterozygous Na+/Ca2+ exchanger knockout mice

Na+/Ca2+ exchanger (NCX) upregulation in cardiac diseases like heart failure promotes as an independent proarrhythmic factor early and delayed afterdepolarizations (EADs/DADs) on the single cell level. Consequently, NCX inhibition protects against EADs and DADs in isolated cardiomyocytes. We here investigate, whether these promising cellular in vitro findings likewise apply to an in vivo setup. Programmed ventricular stimulation (PVS) and isoproterenol were applied to a murine heterozygous NCX-knockout model (KO) to investigate ventricular arrhythmia initiation and perpetuation compared to wild-type (WT). KO displayed a reduced susceptibility towards isoproterenol-induced premature ventricular complexes. During PVS, initiation of single or double ectopic beats was similar between KO and WT. But strikingly, perpetuation of ventricular tachycardia (VT) was significantly increased in KO (animals with VT - KO: 82%; WT: 47%; p=0.0122 / median number of VTs - KO: 4.5 (1.0, 6.25); WT: 0.0 (0.0, 4.0); p=0.0039). The median VT duration was prolonged in KO (in s; KO: 0.38 (0.19, 0.96); WT: 0.0 (0.0, 0.60); p=0.0239). The ventricular refractory period (VRP) was shortened in KO (in ms; KO: 15.1±0.7; WT: 18.7±0.7; p=0.0013). Not the initiation, but the perpetuation of provoked whole-heart in vivo ventricular arrhythmia was increased in KO. As a potential mechanism, we found a significantly reduced VRP, which may promote perpetuation of reentrant ventricular arrhythmia. On a translational perspective, the antiarrhythmic concept of therapeutic NCX inhibition seems to be ambivalent by protecting from initiating afterdepolarizations but favoring arrhythmia perpetuation in vivo at least in a murine model.

The Effects of Lipopolysaccharide Derivatives in Rodent Models of Cardiac Arrhythmia.

Several previous studies have suggested that sublethal doses of Escherichia coli lipopolysaccharide (endotoxin) and monophosphoryl lipid A Re595, a nonpyrogenic derivative of Salmonella minnesota lipopolysaccharide, exhibit antiarrhythmic effects in the rat model of ischemia-reperfusion arrhythmias. In this study, the protective effect of lipopolysaccharide derivatives was also further investigated in drug (aconitine or ouabain)-induced arrhythmia models, and conclusions were drawn with particular emphasis on the molecular characteristics of different types of lipopolysaccharide. The importance of the molecular structure for the antiarrhythmic effect of monophosphoryl lipid A and E. coli lipopolysaccharide was tested in the ischemia-reperfusion arrhythmia model. In contrast to monophosphoryl lipid A from Salmonella typhimurium SL 684 which has only monophosphoryl residue in its structure, monophosphoryl lipid A Re595, obtained from S. minnesota, and E. coli lipopolysaccharide which have both mono and diphosphoryl residue reduced the duration of ventricular tachycardia (e.g., during reperfusion: vehicle: 176 ± 22.8; monophosphoryl lipid A Re595: 132.83 ± 12.1, as second, n=8-10, P < .05) and the incidence of ventricular fibrillation. The antiarrhythmic effects of E. coli lipopolysaccharide and monophosphoryl lipid A Re595 in ischemia-reperfusion arrhythmia model were absent in either aconitine- (e.g., onset time for ventricular ectopic beats: saline 25.3 5.0, E. coli lipopolysaccharide 24.3 ± 7.1; vehicle: 24.0 ± 4.5, monophosphoryl lipid A SL684 23.8 ± 4.3, as second, n=6, P > .05) or ouabain-induced arrhythmia models in mice. Therefore, we conclude that lipopolysaccharide derivatives exhibit antiarrhythmic effect only in ischemia-reperfusion arrhythmias, and lipopolysaccharide should possess diphosphoryl groups in its subcomponent composition for this antiarrhythmic effect.

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

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

Investigation of the effect of 8 weeks of high-intensity interval training and berberine supplementation on some echocardiography and electrocardiogram indices following myocardial ischemia-reperfusion in rats.

Myocardial ischemia leads to left ventricular (LV) dysfunction and cardiac arrhythmia. The present research was conducted with the aim to explore echocardiography changes and electrocardiogram parameters of the hearts of rats with ischemia-reperfusion injury (IRI). The study subjects included 50 male Wistar rats) 8-10 weeks), which were divided into 5 groups (1: trained, 2: supplemented, 3: combined (training and supplementation), 4: sham, and 5: control). High-intensity interval training ý(HIIT) was performed for 8 weeks, 5 sessions per week. Rats belonging to groups 2 and 3 received 10 mg/kg berberine. Finally, after 48 hours, electrocardiogram and echocardiography were performed on all rats. Moreover, myocardial ischemia was performed by descending coronary artery ligation for 30 minutes. There were significant differences between the 5 groups in terms of the volumes and dimensions of LV end-systolic dimension (LVSD), LV end-diastolic dimension (LVDD)ý, fractional shortening cardiac output, ejection fraction (EF), stroke volume (SV), ventricular tachycardia (VT), and ventricular ectopic beats (VEBs) episodes, duration of VTs, and ECG parameters (P ≤ 0.05). Berberine supplementation and HIIT, as preconditioning agents, can possibly prevent the elevation of EF and fractional shortening, the reduction of cardiac output and SV, and arrhythmia improvement after myocardial IRI. Finally, these changes result in increased LV function and decreased mortality in rats with myocardial IRI.

Predictors of Long-Term Survival after Cardiopulmonary Resuscitation

Introduction: Survival after cardiac arrest is one of the most important issues related to the safety and quality of patient care, and unexpected events such as failure to follow guidelines can endanger the patient's safety. Objective: This study aimed to determine the long-term survival after cardiopulmonary resuscitation and its predictors in patients with cardiac arrest. Materials and Methods: In this retrospective study, individual, disease-related, and 3-day follow-up-related factors were monitored after the cardiopulmonary resuscitation (CPR) in all patients with long-term survival after cardiac arrest (CA) who were discharged from the hospital between 2016 and 2019. Patients' survival or death after CPR was followed up by telephone interviews. The patient's survival time after discharge was calculated until the interview day. The obtained data were analyzed by the Kaplan-Meier and Cox regression tests. Results: Out of 1565 CPR cases (both In-Hospital Cardiac Arrest [IHCA] and Out-of-Hospital Cardiac Arrest [OHCA]), 667 were successful, of which 156 patients had long-term survival. The mean ±SD of the survival time for patients was 30.98 ±1.78 months. Significant variables in associations with long-term survival were old age (&gt;60 y) (HR=1.811, 95%CI;1.019-3.218, P=0.043), initial asystole rhythm (HR=4.199; 95%CI:2.129-8.282; P=0.001), ventricular tachycardia (VT) (HR=2.315; 95%CI:1.171-4.576; P=0.016), connection to mechanical ventilator (HR=1.992; 95%CI:1.229-3.229; P=0.005), cardiovascular disease (HR=1.795; 95%CI:1.111-2.901; P=0.017), and abnormal SpO2 (HR=2.447; 95%CI:1.507-3.972; P=0.001). Multivariate analysis also showed that asystole rhythm (P=0.001), VT (P=0.052), and prolonged duration of CPR (&gt;20 min) (P=0.043) significantly increase the risk of death. Conclusions: The major predictors in this study were age, initial rhythm, connection to a mechanical ventilator, CPR duration, cardiovascular disease, and SpO2 monitoring. Therefore, introducing post-resuscitation care protocols and conducting training programs and further studies are warranted.

Influence of ST2 level on the development of acute arrhythmias in NSTEMI

Abstract Funding Acknowledgements Type of funding sources: None. Purpose To determine the structure and relationship of cardiac arrhythmias in NSTEMI patients based on plasma ST2 level. Methods We studied 90 patients with NSTEMI aged from 35 to 79 years (mean 60.7 ± 0.8, median - 61, interquartile range 54 and 69). Plasma ST2 level was determined and analyzed in the NSTEMI patients group, the gradations of the ST2 level and the correlation with cardiac arrhythmias. All of the research corresponds to the principles of the Declaration of Helsinki of the World Medical Association. Results. Using the variation statistics method, the ST2 level gradations group were selected. Thus, the relatively low (RL) corresponded to less than 25, and the relatively high (RH) level of ST2 to more than 75 persons in the group, respectively. For patients in the main group, these levels were &amp;lt;26 and&amp;gt; 56 ng / ml, respectively. Instead, the relatively moderate (or intermediate) ST2 level (RM) for these patients was 26-56 ng / ml. It has been determined that the most frequent rhythm disturbances were observed in the RM and RH risk groups, and more often in the RM risk group, probably due to a larger number of observations (Tab. 1). At that time, the total duration of ventricular tachycardia (VT) episodes, regardless of the number of patients, was at RH risk group. The same was observed with episodes of ST-depression. Conclusions. Despite the number of observations, the risk of VT and ST-depression is significantly higher in patients at RH risk group. This should be taken into account when predicting the risk of complications in patients with NSTEMI. Abstract Figure. Tab. 1

The role of nitric oxide on the antiarrhythmic effects of ketamine/xylazine in a rat model of acute cardiac ischemia-reperfusion.

The prevalence of ventricular arrhythmias during general anesthesia is about 70%. In experimental studies on the antiarrhythmic effects of different agents, using anesthetic drugs that do not have any protective properties are preferable. The present study was conducted to investigate molecular mechanisms involved in the antiarrhythmic effects of ketamine/xylazine (K/X).Sixty male rats were assigned to eight groups: K/X, L -NAME (25–35 mg/kg) with thiopental (TP), L-NAME (25–35 mg/kg) with ketamine/xylazine, L arginine (100 mg/kg) with thiopental, L-arginine (100 mg/kg) with ketamine/xylazine. After anesthetic induction using TP or K/X, the animals were subjected to 30 min of ischemia. Hemodynamic parameters, ventricular arrhythmias during ischemia, the incidence of ventricular tachycardia (VT), and ventricular fibrillation (VF) were measured. Additionally, in order to assess nitrite/nitrate ratio and LDH after ischemia, serum samples were collected and used.Our results showed that in the K/X group, the number of VT and VF, duration of VT (p = 0.006), the severity of arrhythmias (p = 0.0179). There was no VF incidence in this group.These protective effects were faded by administration of L-NAME with K/X. The combination of L- Arginine in the TP group decreased the number and duration of VT (p < 0.001, p = 0.0013) with no incidence of VF in comparison with TP. L-arginine with K/X groups increased the number and duration of VT (p < 0.0001, p < 0.001) compared to K/X and VF was seen (100%). However, there was no significant difference between TP and K/X groups in terms of this nitrite/nitrate ratio. These findings suggest that the antiarrhythmic effects of ketamine/xylazine might be partially relative to the nitric oxide synthesis pathway.

Structure and function of the ventricular tachycardia isthmus.

Catheter ablation of postinfarction reentrant ventricular tachycardia (VT) has received renewed interest owing to the increased availability of high-resolution electroanatomic mapping systems that can describe the VT circuits in greater detail, and the emergence and need to target noninvasive external beam radioablation. These recent advancements provide optimism for improving the clinical outcome of VT ablation in patients with postinfarction and potentially other scar-related VTs. The combination of analyses gleaned from studies in swine and canine models of postinfarction reentrant VT, and in human studies, suggests the existence of common electroanatomic properties for reentrant VT circuits. Characterizing these properties may be useful for increasing the specificity of substrate mapping techniques and for noninvasive identification to guide ablation. Herein, we describe properties of reentrant VT circuits that may assist in elucidating the mechanisms of onset and maintenance, as well as a means to localize and delineate optimal catheter ablation targets.

Abstract 11402: Targeting RyR2 to Suppress Ventricular Arrhythmias and Improve Left Ventricular Function in Chronic Ischemic Heart Disease

Introduction: Sarcoplasmic reticulum Ca +2 leak from RyR2 is a common finding in chronic ischemic heart disease (CIHD) and may be a key driver for ventricular arrhythmias and reduced excitation-contraction coupling in failingm myocytes. Here, we test the hypothesis that targeting Ca +2 leak using the non-selective RyR inhibitor, Dantrolene, suppresses ventricular arrhythmias and improves left ventricular contractile function in CIDH. Methods: CHID was induced in 24 C57BL/6J mice by left coronary artery ligation. Four weeks after myocardial infarction (MI), subcutaneous osmotic pumps were placed to deliver continuous dantrolene (20 mg/kg/day) or vehicle (0.9% Saline). Left ventricular (LV) function was assessed by echocardiogram at 4-, 7- and 10-weeks post-MI. Peripheral muscle strength was assessed by provoked electromyogram at 6 weeks. Inducibility of ventricular tachycardia (VT) was assessed by rapid transesophageal pacing with isoproterenol at 10 weeks. Results: Dantrolene reduced the peripheral muscle strength in mice (0.014±0.001 vs 0.010±0.001 N, P&lt;0.05), but had no adverse effects on weight loss or mortality. Dantrolene increased fractional shortening (18.7±1.3% vs 22.1±1.6%, P&lt;0.001) and mean velocity fiber shortening (mVcfc 1.37±0.09 vs 1.74±0.1 circ/sec, P&lt;0.002) in non-infarcted regions at 10 weeks. This prevented the progression in LV ejection fraction reduction from 4 to 10 weeks (Saline: 35.6±3.4% to 30.6%±3.4%; Dantrolene 34.6±2.4% to 38.1±1.9% vs, P&lt;0.01). Dantrolene reduced VT frequency per animal (0.083±0.04 vs 0.028±0.02 VT/pacing train, P&lt;0.02) and the total duration of inducible VT per animal (59.2±24 secs vs 1.2±0.6 sec, P&lt;0.04). Dantrolene significantly prolonged the ventricular effective refractory period (VERP) (35.1±1.6 msec vs 42.0±0.9 msec, P&lt;0.005). Conclusion: Dantrolene suppression of RyR2 diastolic Ca +2 leak in chronic ischemic heart failure improves the systolic function of surviving myocardium and reduces VT burden by prolonging the VERP, preventing the re-entry circuit for VT in this model. RyR2 inhibition may represent a new therapeutic target for the treatment of CIDH with ventricular arrhythmias.

Up-regulation of chemokine receptor type 4 expression in the ischemic reperfused heart by alcoholic extract of Cichorium intybus rescue the heart from ischemia injury in male rat.

Cichorium intybus is used in traditional medicine for various diseases including heart disease. This study aimed at evaluating the chemokine receptor type 4 up-regulation and cardioprotective effects of hydroalcoholic extract of C. intybus in a rat model of ischemic reperfusion. Animals in four groups of eight rats each received vehicle or one of three doses of C. intybus (50, 100 or 200 mg/kg/d) for 14 days. Then they were subjected to 30 min of ischemia followed by 7 days of reperfusion. At the end of the experiment, blood specimens were prepared for serum assays. The level of myocardium chemokine receptor type 4 was also measured using RT-PCR. Cichorium intybus (CI-50) improved infarct size, episodes of the ventricular ectopic beat, ventricular tachycardia, and duration of ventricular tachycardia, QTc shortening. It also stabilized the ST segment changes and increased heart rate during ischemia. The blood pressure decreased in CI-50 group in comparison to the control and CI-200 group. C. intybus increased serum superoxide dismutase and reduced lactate dehydrogenase activity, Cardiac Troponin I and malondialdehyde levels. C. intybus led to an increase in the expression of chemokine receptor type 4. These findings suggest that C. intybus administration before ischemia is able to induce cardioprotective effect against ischemic reperfusion injury, probably through chemokine receptor type 4 over-expression and antioxidant activity.

Angiotensin receptor-neprilysin inhibitior (thiorphan/irbesartan) decreased ischemia-reperfusion induced ventricular arrhythmias in rat; in vivo study

Ventricular arrhythmias are considered as a major risk of sudden cardiac death. This study was designed to investigate the potential effects of angiotensin receptor neprilysin inhibitor; thiorphan/irbesartan (TH/IRB) combination therapy on myocardial ischemic-reperfusion (I/R)-induced arrhythmia. Fifty male Wistar rats were divided into 5 groups; (I, II): Sham, I/R both received DMSO intraperitoneally before the procedure. (III, IV, V): TH/IRB + IR (0.1/5 mg/kg, 0.1/10 mg/kg and 0.1/15 mg/kg). The drugs were injected intraperitoneally 15 min before I/R induction. Electrocardiograms changes, mean arterial blood pressure, incidence of ventricular tachycardia (VT), incidence of ventricular fibrillation (VF) and arrhythmia score were assessed. Cardiac levels of creatinine kinase–MB (CK-MB), Malondialdehyde (MDA), superoxide dismutase (SOD), endothelin-1 (ET-1), ATP content, and Na+/K+-ATPase pump activity were measured. TH (0.1 mg/kg) in combination with IRB (5, 10 and 15 mg/kg) produced significant decrease in QTc interval duration, ST height, incidence of VT and VF, duration of VT + VF, and arrhythmia score compared to I/R group. All treated groups showed significant decrease in the cardiac levels of: CK-MB, MDA and ET-1 and significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to I/R. TH/IRB + IR (0.1/10 mg/kg) group produced significant decrease in CK-MB, MDA and ET-1 and a significant increase in SOD, ATP content, and Na+/K+-ATPase pump activity compared to other treated groups. In conclusion, angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) decreased arrhythmia score and decreased cardiac damage. These could be explained in part by its ability to decrease oxidative stress and ET-1, increase ATP, and Na+/K+-ATPase pump activity in this rat model of I/R-induced arrhythmia.

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).

P1595Increased in vivo perpetuation of whole-heart ventricular arrhythmia in heterozygous Na+/Ca2+-exchanger knockout mice

Abstract Background Commonly, innovative antiarrhythmic strategies are derived from single cell studies that frequently yield promising in vitro findings. However, these results may differ on the whole-heart level, since multicellular electrophysiology is characterized by several emergent features. In previous cellular studies, we have identified the Na+/Ca2+-exchanger (NCX) as a promising target for an innovative antiarrhythmic strategy, as NCX upregulation is present in major cardiac diseases (e.g. heart failure) and promotes independently cellular early and late afterdepolarizations (EADs and DADs). Vice versa, we found that genetic and pharmacological NCX inhibition protects against EADs and DADs. To date, it is unknown, whether the concept of NCX inhibition indeed beneficially applies to the whole-heart level. Thus, we here investigate the in vivo inducibility and perpetuation of whole-heart arrhythmia using a heterozygous NCX-knockout mouse (KO) model that is protected against EADs and DADs on the cellular level. Methods/Results Programmed electrical right ventricular stimulation (PVS) and burst stimulation were performed in KO (n=22) and wild-type (n=34) mice by an octapolar mouse electrophysiological catheter introduced via the right jugular vein. Inducibility for ventricular tachycardia (VT) during PVS was similar in WT (73.5%) compared to KO (90.0%) (p=0.1707). With burst stimulation, VT inducibility was higher in KO (KO: 68.2%; WT: 32.4%; p=0.0134). During PVS, KO exhibited increased VT perpetuation as reflected in a significantly prolonged mean (in s; KO: 0.89±0.93; WT: 0.39±0.41; p=0.0097) and cumulative VT duration (in s; KO: 19.54±27.98; WT: 4.46±6.35; p=0.0019). Analysis of animals that were inducible for VT consistently yielded similar results. The ventricular refractory period (VRP) (in ms; KO: 15.1±3.5; WT: 18.7±4.1; p=0.0050) and the QTc interval were shortened in KO (in ms; KO: 46.5±5.8; WT: 53.2±5.9; p=0.0001). Conclusions As opposed to findings on the single cell level, KO mice exhibited an increased in vivo arrhythmia burden on the whole-heart level during PVS. This mainly resulted from increased perpetuation of artificially induced VTs, since the inducibility of VTs was not significantly increased in KO with PVS. As a mechanistic explanation of these surprising results, we found significantly reduced VRP and QTc durations in KO in line with the previously demonstrated action potential shortening in single KO cardiomyocytes, which promotes the perpetuation of VTs. We conclude that genetic NCX inhibition can protect from proarrhythmic cellular triggers like EADs and DADs that can initiate VT. However, VTs may perpetuate longer in KO most likely due to reduced refractory periods. This finding carries important translational limitations for the antiarrhythmic concept of NCX inhibition and demonstrates that the value of novel innovative strategies needs evaluation on both the cellular and the whole-heart level. Acknowledgement/Funding None

Abstract 16677: Protein Kinase G I Alpha Attenuates Inducible Ventricular Tachycardia and QRS/T Wave Alternans in the Type II Diabetic Heart

Introduction: Diabetes increases ventricular tachycardia (VT) and sudden cardiac death risk in humans. We previously found the type I diabetic (DMI) heart displays: reduced responsiveness to parasympathetic stimulation; increased QRS/T Wave alternans (marker of proarrhythmic calcium dyshomeostasis); and hyperactive GSK3beta. Cardiac parasympathetic stimulation promotes production of intracellular cyclic GMP (cGMP). The effects of cGMP and its downstream effector PKG, on these indices of VT in type II diabetes (DMII) remain poorly understood. Hypothesis: PKGIa modulates inducibility of VT and QRS/TWA in the DMII heart and mediates the cGMP effect on VT through inhibition of myocardial GSK3beta. Methods: Using an established protocol of programmed ventricular stimulation we measured: VT incidence, duration, and QRS/T Wave alternans. We studied the following mice: wild type; Db/Db model of DMII; high fat high sucrose (HFHS) model of insulin resistance; and the PKGIa leucine zipper mutant (LZM) mouse, which has no DM but has PKGIa disrupting mutations. Mice were treated with or without the cGMP-augmenting phosphodiesterase inhibitor sildenafil 10 mg/kg, or the GSK3b inhibitor TWS119 20 mg/kg. Results: LVs of HFHS mice displayed 30 ± 8% reduction of cGMP compared with control (p&lt;0.05, n=3 per group), while myocardial cGMP in LZM mice did not differ from control. In failing LVs from humans, there was also a 46% reduction in myocardial cGMP in DM compared with nondiabetic (p= .058, n=3 per group). Db/Db and HFHS mice had increased inducible VT (0.25 +/- 0.1 s in Db/Db, 2.2 +/- 1 s HFHS, vs 0 s in WT control, p &lt;0.05), as well as TWA. Treatment with sildenafil reduced VT incidence, duration, and TWA in Db/Db and HFHS mice. LZM mice also had increased VT duration and TWA incidence (0 of 4 in WT vs 5 of 6 in LZM, p&lt;0.05). Inhibition of GSK3β rescued inducibility of VT in Db/Db, HFHS, and in LZM mice. Conclusions: These findings support that in the DMII heart reduced cGMP promotes VT, whereas pharmacological augmentation of cGMP inhibits VT. Inducible VT and TWA in the PKG LZM mouse provides direct support that PKGIa opposes VT in the DMII heart. These support that cGMP activation of PKG inhibits GSK3beta, leading to reduced incidence of inducible VT.

Abstract 16621: Holter Monitoring in Patients With Left Ventricular Noncompaction

Introduction: Multiple arrhythmias including ventricular tachycardia (VT) and atrial fibrillation (AF) have been reported in patients with left ventricular noncompaction (LVNC). We sought to determine the frequency of rhythm abnormalities on Holter monitoring, and their association with all-cause mortality, in patients with LVNC. Methods: Imaging databases from 2000-2016 were reviewed to identify patients with LVNC. On transthoracic echocardiography (TTE), LVNC was defined as: end systolic noncompacted: compacted (NC:C) ratio&gt;2 and end diastolic epicardium to trough: epicardium to peak trabeculation (X:Y) ratio&lt;0.5. Holter monitor reports from the medical record were evaluated. VT was defined as ≥3 consecutive beats of ventricular origin. All-cause mortality was obtained from a web-based research and location service (Accurint). We used a proportional hazards model to determine associations of Holter variables with all-cause mortality. Results: Among 340 LVNC patients, Holter reports were available for 177 patients (median age 45 years, interquartile range [IQR] 33-61; 45% females). On TTE, the median NC:C ratio was 2.7 (IQR 2.4-3.2) and X:Y ratio was 0.25 (IQR 0.20-0.28). The median ejection fraction (EF) was 48% (IQR 33-58). 48 patients (27%) had at least one episode of VT (median 4 episodes, IQR 2-4). The median longest duration of VT was 5 beats (IQR 4-9) and maximum rate was 148 beats per minute (IQR: 125-169). PVC burden &gt;5% and 20% was present in 13% and 5% of patients respectively. Patients with EF&lt;50% were more likely to have VT (43% vs 16%, p=0.0003) and PVC burden &gt;5% (19% vs 7%, p=0.03). AF was infrequent (N=5, all persistent). All-cause mortality was 12% over median 6.9 years of follow up (IQR: 3.6-11.3 years). Presence of VT and PVC burden on Holter monitoring were not associated with all-cause mortality (p&gt;0.05). Among patients with VT, the number, longest duration, and fastest rate of VT episodes were not associated with all-cause mortality. Conclusions: Ventricular tachycardia on Holter monitoring is common among patients with LVNC, especially those with a reduced EF. However, the clinical significance of this finding is uncertain, and presence of VT was not associated with long term all-cause mortality.

Selective ablation of the ligament of Marshall reduces ischemia and reperfusion-induced ventricular arrhythmias.

Cardiac sympathetic tone overdrive is a key mechanism of arrhythmia. Cardiac sympathetic nerves denervation, such as LSG ablation or renal sympathetic denervation, suppressed both the prevalence of VAs and the incidence of SCD. Accumulating evidence demonstrates the ligament of Marshall (LOM) is a key component of the sympathetic conduit between the left stellate ganglion (LSG) and the ventricles. The present study aimed to investigate the roles of the distal segment of LOM (LOMLSPV) denervation in ischemia and reperfusion (IR)-induced VAs, and compared that LSG denervation. Thirty-three canines were randomly divided into group 1 (IR group, n = 11), group 2 (LOMLSPV Denervation + IR, n = 9), and group 3 (LSG Denervation + IR, n = 13). Hematoxylin-Eosin (HE) and Immunohistochemistry staining revealed that LOMLSPV contained bundles of sympathetic but not parasympathetic nerves. IR increased the cardiac sympathetic tone [serum concentrations of noradrenaline (NE) and epinephrine (E)] and induced the prevalence of VAs [ventricular premature beat (VPB), salvo of VPB, ventricular tachycardia (VT), VT duration (VTD) and ventricular fibrillation (VF)]. Both LOMLSPV denervation and LSG denervation could reduce the cardiac sympathetic tone in Baseline (BS) [heart rate variability (HRV)]. Compared with group 1, LOMLSPV denervation and LSG denervation similarly reduced sympathetic tone [NE (1.39±0.068 ng/ml in group 2, 1.29±0.081 ng/ml in group 3 vs 2.32±0.17 ng/ml in group 1, P<0.05) and E (114.64±9.22 pg/ml in group 2, 112.60±9.69 pg/ml in group 3 vs 166.18±15.78 pg/ml in group 1, P<0.05),] and VAs [VT (0±3.00 in group 2, 0±1.75 in group 3 vs 8.00±11.00 in group 1, P<0.05) and VTD (0 ± 4 s in group 2, 0±0.88s in group 3 vs 10.0 ± 22.00s in group 1, P<0.05)] after 2h reperfusion. These findings indicated LOMLSPV denervation reduced the prevalence of VT by suppressing SNS activity. These effects are comparable to those of LSG denervation. In myocardial IR, the anti-arrhythmic effects of LOMLSPV Denervation may be related to the inhibition of the expression of NE and E.

Effects of Postconditioning with Fructose on Arrhythmias and the Size of Infarct Caused by Global Ischemia and Reperfusion in Isolated Rat Heart.

Purpose: In the present study, postconditioning effect of fructose against ischemia/reperfusion (I/R)-induced arrhythmias and infarct size were investigated in isolated rat heart.Methods: The isolated hearts were divided into 7 groups, mounted on a Langendorff apparatus at constant pressure then subjected to 30 min zero flow global ischemia followed by 120 min reperfusion. In the control group, normal Krebs–Henseleit (K/H) solution was perfused into the hearts throughout the experiment. In two separate sets of experiments, the treatment groups received 12, 24 and 48 mM of fructose with/without normal glucose in K/H solution for 20 min at the beginning of reperfusion. Cardiac arrhythmias including number of ventricular tachycardia (VT), total ventricular ectopic beats, incidence and duration of VT, reversible and irreversible ventricular fibrillation were recorded and analyzed during the first 30 min of reperfusion. Computerized planimetry method was used to determine volume and percentage of infarct size.Results: Administration of fructose as a postconditioning agent clearly reduced volume and percentage of infarct size in the all treatment groups. The effect was statistically significant especially in the hearts that treated by fructose plus glucose (P<0.05). However, fructose alone or its co-administration with glucose had no significant inhibitory effect against reperfusion arrhythmias.Conclusion: The results showed that perfusion of high concentration of fructose alone or coincident with glucose in globally ischemic-reperfused isolated rat hearts can reduce infarct size without inhibitory effect against reperfusion arrhythmias. Probably, fructose by providing adequate ATP for cardiac functions may inhibit necrosis and death of cardiomyocytes during I/R.

Effects of preconditioned plasma collected during the late phase of remote ischaemic preconditioning on ventricular arrhythmias caused by myocardial ischaemia reperfusion in rats.

ObjectiveThe administration of preconditioned plasma collected during the late phase of preconditioning has been shown to reduce myocardial infarct size. This study aimed to investigate if preconditioned plasma could attenuate ventricular arrhythmias in a rat model in vivo.MethodsEighty rats were randomized to eight groups (10 rats/group). Two groups provided preconditioned or non-preconditioned plasma 48 h after transient limb ischaemia or the control protocol. Six groups of ischaemia-reperfusion (IR) rats received normal saline, non-preconditioned plasma, or preconditioned plasma, respectively, 1 h (groups A1, A2, A3) or 24 h (groups B1, B2, B3) before undergoing myocardial IR. Electrocardiograms were monitored using a BIOPAC system, and the incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analysed.ResultsNo significant differences existed in the incidence and duration of VT or VF among groups A1–A3 or in the incidence and duration of VT among groups B1–B3. However, there was a significantly lower incidence and shorter duration of VF in group B3 rats than in group B1 rats.ConclusionPreconditioned plasma collected during the late phase of preconditioning can reduce the incidence and duration of VF compared with normal saline, suggesting its anti-arrhythmic potential.