Inducible Tachyarrhythmias Research Articles

Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.

Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.

Low-dose dexmedetomidine sedation in patients undergoing electrophysiological study and ablation of supraventricular tachycardias in a same day setting

Abstract Background Catheter ablation for supraventricular tachycardias (SVT) can frequently cause patient discomfort, anxiety or pain. Through the years different drugs have been employed to provide an optimal sedation without interfere with inducibility of tachyarrhythmia. Moreover, the increasing number of patients with this clinical condition and the growing demand of catheter ablation, makes same day discharge mandatory. For this purpose, drugs that guarantee minimal sedation and reduce adverse events should be used. Dexedetomidine (DEX) is a selective alpha-2 agonist with analgesic and sedating effect without significant respiratory depression. Its electrophysiological effects include the sinus node and atrioventricular (AV) node depression and an increased atrial refractoriness. Albeit there is a reduction of side effects of most commonly used sedation drugs, data on the efficacy and safety profile of DEX during SVT ablation of adult patients are unclear and conflicting. Purpose The aim of this study was to assess whether optimal sedation and patient’s comfort can be achieved with a low-dose DEX without interfering with electrophysiological parameters during catheter ablation of SVT in adult population. Methods This is a single-center prospective study. Study population consisted of patients undergoing mapping and catheter ablation of SVT from January to September 2023 divided into DEX group (periprocedural infusion of Dexedetomidine 0.07-0.11 mcg/kg/h without loading dose) and non-DEX group (midazolam 1-2 mg periprocedural). Clinical and procedural data were recorded for all patients, as well as all measurements taken during electrophysiological study. Results The study population was predominantly female (60%) with a mean age of 56 ± 13.7 years. Hypotension occurred in only one patient, in the DEX group. No cases of desaturation were observed in both groups. Most of the induced tachyarrhythmias were the slow-fast type of atrioventricular nodal reentrant tachycardia (75%), whereas atrioventricular reentrant tachycardia and atrial tachycardia were less common (7.1% and 7.1%). No significant differences were recorded in relation to AV node refractoriness, atrial refractoriness, anterograde and retrograde conduction. (Table 1) Isoproterenol was required to induce tachyarrhythmia in both groups. Arrhythmia inducibility and aberrancy in tachycardia was not significantly influenced by DEX. The jump phenomenon was recorded more frequently in the DEX group (86.4% vs. 46.7%; p=0.004). The mean duration of the procedure did not differ between the two groups. All patients were discharged on the same day after 3 hours of observation. Conclusions The use of low-dose Dexedetomidine was succesful in improving periprocedural patient comfort, without reducing tachyarrhythmia inducibility or major electrophysiological parameters.

Machine-learning guided differentiation between photoplethysmography waveforms of supraventricular and ventricular origin

Abstract Aims To test, whether a neural network-based classifier could aid in distinguishing photoplethysmographic (PPG) pulse waveforms of ventricular from those of supraventricular origin. Methods Thirty patients undergoing invasive electrophysiological studies for documented narrow complex tachycardias between May and December 2021 at a university medical centre were included in the trial. PPG waveforms were recorded using a PPG wristband (Empatica E4) in parallel to 12-lead surface electrograms (ECGs) and intracardiac electrograms from diagnostic catheters. Pulse waves were then annotated to either supraventricular (sinus rhythm, atrial pacing) or ventricular origin (ventricular pacing) based on invasive electrogram recordings, ECGs and stimulation protocols. 21147 data sets were split into test, training and validation data sets and used to develop, train and validate a convolutional neural network (CNN) for classifying PPG waveforms according to their origin into sinus rhythm, atrial or ventricular pacing. Results Datasets were complete for 27 patients. 74% were female and median age was 53 (range 18, 78) years, median BMI was 27±5, 19% had arterial hypertension, 11% had diabetes and 15% had coronary artery disease. During the electrophysiological study, typical AV-nodal re-entrant tachycardias could be induced in 63% of patients, 15% had inducible atrial tachycardias and the other patients had no inducible tachyarrhythmias. Our CNN-based classifier was able to correctly predict the origins of pulse waves in 95±1% for sinus rhythm, 96±1% for atrial paced rhythms and 95±1% for ventricular rhythms. Conclusion A neural network-based classifier trained on ground truth PPG data obtained by using invasive EP measurements for annotation could accurately predict atrial or ventricular origin from PPG waveforms alone.Graphical abstract

Alcohol and caffeine synergistically induce spontaneous ventricular tachyarrhythmias: ameliorated with dantrolene treatment.

Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase cardiac arrhythmia risk. However, it is unknown whether alcohol and caffeine co-consumption can synergistically enhance cardiac arrhythmogenesis. The study sought to investigate whether caffeine and binge drinking synergistically affect cardiac arrhythmogenesis. A binge drinking rat model (alcohol 2 g/kg, intraperitoneal, every other day for 3 times) was used. Rats (4 months old, both sexes) were randomized into the following 4 groups: binge alcohol-only group (A) (n = 8), nonalcohol, caffeine-only (60 mg/kg, intraperitoneal) group (C) (n = 8), binge alcohol plus caffeine group (A+C) (n = 8), and binge alcohol + caffeine + dantrolene group (A+D) (n = 7, treated with dantrolene 10 mg/kg before each alcohol injection). We also investigated whether alcohol induces Ca2+ sparks and dantrolene treatment attenuates alcohol-induced Ca2+ leak in ventricular myocytes. No arrhythmia was induced with caffeine alone (group C, n = 0 of 8) or alcohol alone (group A, n = 0 of 8). However, alcohol + caffeine induced spontaneous ventricular tachyarrhythmias in all rats (group A+C, n = 8 of 8; P < .001 vs group C or A). Dantrolene prevented ventricular tachyarrhythmia induction in all 7 rats (group A+D, n = 0 of 7; P < .001 vs group A+C). In isolated ventricular myocytes, alcohol significantly increased Ca2+ sparks and dantrolene treatment reduced alcohol-induced Ca2+ sparks. Co-consumption of caffeine and binge drinking synergistically promote spontaneous ventricular tachyarrhythmias in rats. Dantrolene treatment can decrease alcohol-enhanced Ca2+ sparks invitro and prevented alcohol and caffeine induced ventricular tachyarrhythmias invivo.

PO-01-101 INDUCIBILITY AND MAINTENANCE OF PEDIATRIC & ADULT CONGENITAL ARRHYTHMIAS USING A MODIFIED INHALATIONAL ANESTHETIC STRATEGY

Controversy exists regarding the most appropriate anesthetic strategy to maximize the possibility of arrhythmia induction/maintenance in those individuals requiring general anesthesia for the ablation of arrhythmia substrates. The anesthetic regimen used at our facility consists of a light combined inhalational (sevoflurane) and intravenous (midazolam/fentanyl) general anesthesia (GA), hypercarbia, normothermia (37.0 C), and mostly spontaneous breathing. We investigated the rate of arrhythmia inducibility with this anesthesia strategy. To study the rate of inducibility and maintainence of arrhythmias with the anesthetic regimen used at our facility. A single center retrospective study was performed. Data from subjects 2-44 years undergoing elective electrophysiology study (EPS) for evaluation of supraventricular tachycardia, ectopic atrial tachycardia, premature ventricular contractions (PVC)/ventricular tachycardia (VT) or WPW (Wolff-Parkinson-White) from 2020 to 2022 were included. The primary outcome was positive EPS, defined as successful induction of clinical tachyarrhythmias. 134 subjects were evaluated: 57% male; mean age 14.5+/-6.3 years, 10% adult (age above 18 years). EPS conducted for documented arrythmia of SVT 46%, atrial tachycardia 4%, atrial flutter 7%, PVC 3%, VT 5%, A fib 1%, and WPW 32%. A positive EPS occurred in 74% of cases overall. Arrhythmia was induced in 85% of adult subjects versus 73% of children (p=0.37), and in 70% male versus 79% of female subjects (p=0.23). When arrhythmias were documented, they were inducible in 94.4% of cases; when there was no antecedent history of arrhythmias (such as asymptomatic WPW), they were still induced 36.9% (p<0.001). Overall, a positive EPS occurred in 52% of WPW cases. PVCs and VT remained present after anesthesia (or were inducible by pharmacologic/pacing maneuvers) in 100% of cases. Selected assessment of refractory periods during post-ablation protocols suggests that hypercarbia may be one of the key components of the strategy, with a lowering of AV nodal refractory periods of as much as 40 msec. Our data suggests that an inhalational anesthetic strategy is extremely effective at maintaining arrhythmia inducibility when combined with other strategies that preserve cardiac excitability and refractory periods. Additionally, this strategy may be more effective for the induction and maintenance of arrhythmias in PVC/VT cases.

Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats.

Recent studies have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT2-i) reduce the risk of atrial fibrillation (AF) in patients with diabetes mellitus (DM), in which oxidative stress due to increased reactive oxygen species (ROS) contributes to the pathogenesis of AF. We aimed to further investigate this, and examine whether the SGLT2-i empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis. A high-fat diet and low-dose streptozotocin treatment were used to induce type-2 DM (T2DM) in Sprague-Dawley rats. The rats were randomly divided into three groups: control, DM, and DM treated with empagliflozin (30 mg/kg/day) for 8 weeks. The mitochondrial respiratory capacity and ROS generation in the atrial myocardium were measured using a high-resolution respirometer. Oxidative stress markers and protein expression related to mitochondrial biogenesis and dynamics as well as the mitochondrial morphology were examined in the atrial tissue. Additionally, mitochondrial function was examined in H9c2 cardiomyoblasts. Atrial tachyarrhythmia (ATA) inducibility, interatrial conduction time (IACT), and fibrosis were also measured. Inducibility of ATA, fibrosis, and IACT were increased in rats with DM when compared to controls, all of which were restored by empagliflozin treatment. In addition, the rats with DM had increased mitochondrial-ROS with an impaired complex I-linked oxidative phosphorylation capacity. Importantly, empagliflozin seemed to ameliorate these impairments in mitochondrial function. Furthermore, empagliflozin reversed the decrease in phosphorylated AMPK expression and altered protein levels related to mitochondrial biogenesis and dynamics, and increased mitochondrial content. Empagliflozin also improved mitochondrial function in H9c2 cells cultured with high glucose medium. These data suggest that empagliflozin has a cardioprotective effect, at least in part, by reducing mitochondrial ROS generation through AMPK signaling pathways in the atrium of diabetic rats. This suggests that empagliflozin might suppress the development of AF in T2DM.

Postnatal recurrence and transesophageal inducibility of prenatally treated fetal supraventricular tachycardia.

Antiarrhythmic treatment of fetal supraventricular tachycardia (SVT) is used to prevent morbidity and mortality. The postnatal management of survivors is often arbitrary and varied. The purpose of this study was to examine the utility of a risk-based postnatal management strategy. Sixty-six prenatally treated newborns with fetal long or short ventriculoatrial tachycardia were reviewed. Postnatal diagnoses included atrioventricular reentrant tachycardia, atrial ectopic tachycardia, and permanent junctional reciprocating tachycardia. Unless SVT persisted to birth, early neonatal observation without treatment was recommended. For newborns without spontaneous arrhythmia after ≥2 days of observation, inducibility was tested by transesophageal pacing study (TEPS). Postnatal therapy was advised for spontaneous or inducible SVT. Characteristics associated with these outcomes were analyzed. Twenty-eight patients (42%) experienced SVT at or early after birth, which was associated with fetal long ventriculoatrial tachycardia (odds ratio [OR] 6.8; 95% confidence interval [CI] 1.88-24.57; P = .0029); delayed in utero cardioversion with treatment (median 11 days vs 5.5 days; P < .0001); prenatal treatment with multiple antiarrhythmics (OR 4.42; 95% CI 1.56-12.55; P = .0059); and postnatal atrial ectopic tachycardia/permanent junctional reciprocating (OR 18.0; 95% CI 2.11-153.9; P = .0013). Of the 38 neonates undergoing TEPS, 19 (50%) had inducible tachyarrhythmias. Recurrence of SVT during infancy or childhood was documented in 4 of 6 patients with SVT at birth (66%), 8 of 22 patients with early neonatal SVT (36%), 4 of 19 patients with inducible SVT (21%), and 0 of 19 untreated patients without inducible SVT (0%) (P= .0032). The postnatal risk of SVT is related to the arrhythmia mechanism and prenatal treatment response. In newborns without spontaneous SVT, TEPS may be useful to guide the need for postnatal treatment on the basis of SVT inducibility.

Neuronal nitric oxide synthase inhibition exacerbates atrial electrical remodeling via small-conductance Ca2+-activated K+ channel activation

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): The Japan Society for the Promotion of Science KAKENHI Background The presence of atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF itself. Small conductance Ca2+-activated K+ (SK) channels; K+-selective and voltage-independent ion channels are key factors in the atrial electrical remodeling (2, 3). However, the mechanism of its activation remains unclear. A recent study showed that neuronal nitric oxide synthase (nNOS) expression and activity are reduced in AF patients and that nNOS depletion causes the abbreviation of action potential duration (APD), leading to increased AF inducibility in animal experiments (4). Decreased NO production, especially driven by nNOS inhibition, might play a key role in the atrial electrical remodeling, and the downstream alteration of SK channels might result from this process. Purpose We aimed to evaluate the potential of SK channel blocking to mitigate abnormal electrophysiological properties and the inducibility of atrial tachyarrhythmia (ATA) which was induced by nNOS depletion, and to describe the related mechanism. Methods Atrial tachyarrhythmia induction and optical mapping were performed in perfused rat hearts. nNOS was pharmacologically inhibited by S-methylthiocitrulline (SMTC, 100 nM). The influence of the SK channel was examined by a specific channel inhibitor, apamin (100 nM). APD, conduction velocity, and calcium transient (CaT) parameters (CaTD, rise time, time to 50% decay, and tau) were evaluated by voltage and calcium dual optical mapping. Dominant frequency was evaluated to analyze the wave dynamics of AF. Results SMTC increased the inducibility of ATA and apamin mitigated the nNOS inhibition-induced arrhythmogenicity (0% [0/7] vs 62% [8/13] vs 15% [2/13] in control, SMTC and SMTC + apamin). SMTC caused the abbreviation and enhanced spatial dispersion of APD, which were reversed by apamin. In contrast, conduction velocity was not affected by SMTC or apamin. Moreover, apamin reduced the dominant frequency of SMTC-induced ATA. In voltage and calcium optical mapping, STMC and apamin did not alter the parameters associated with CaT, however, SMTC caused the abbreviation of APD, which was reversed by apamin (APD80: 48.4 ± 2.7 msec in control group, 30.8 ± 1.5 msec in SMTC group, p &amp;lt;0.0001 vs. control, 41.8 ± 1.5 msec in SMTC + apamin, p = 0.01 vs. SMTC by One-way ANOVA and Tukey’s multiple-comparison test) (Figure A-C). Conclusion Acute nNOS inhibition abbreviated APD via activating SK channels. A specific SK channel blocker mitigated APD abbreviation without the alteration of CaT, implying an underlying mechanism of post translational modification of SK channels.

PO-630-05 A NOVEL MECHANISM OF SMALL-CONDUCTANCE CA2+-ACTIVATED K+ CHANNEL ACTIVATION VIA NEURONAL NITRIC OXIDE SYNTHASE INHIBITION IN RAT ATRIA

The presence of atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF itself. Small-conductance Ca2+-activated K+ (SK) channel is a key factor in the atrial electrical remodeling. However, the mechanism of its activation is unclear. A recent study showed that neuronal nitric oxide synthase (nNOS) expression and activity are reduced in AF patients and that nNOS depletion causes the abbreviation of APD, leading to increased AF vulnerability in animals. Decreased NO production, especially driven by nNOS inhibition, might play a key role in the atrial electrical remodeling, and the downstream alteration of SK channels might result from this process. We aimed to evaluate the potential of SK channel blocking to mitigate abnormal electrophysiological properties and the inducibility of atrial tachyarrhythmia which was induced by neuronal nitric oxide synthase (nNOS) depletion, and to describe the related mechanism. Atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS was pharmacologically inhibited by S-methylthiocitrulline (SMTC, 100nM). The influence of the SK channel was examined by a specific channel inhibitor, apamin (100nM). Action potential duration (APD), conduction velocity, and calcium transient (CaT) parameters (CaTD, Rise time, T 1/2, Tau) were evaluated by voltage and calcium optical mapping. Dominant frequency was examined in the analysis of AF dynamics. SMTC increased the inducibility of ATA and apamin mitigated the nNOS inhibition-induced arrhythmogenicity. SMTC caused the abbreviation and enhanced spatial dispersion of APD, which was reversed by apamin. In contrast, conduction velocity was not affected by SMTC or apamin. Moreover, apamin reduced the dominant frequency of SMTC-induced ATA. In voltage and calcium optical mapping, STMC and apamin does not altered parameters associated with CaT, however, SMTC caused abbreviation APD, which was reversed by apamin. Acute nNOS inhibition abbreviated APD via activating SK channels. A specific SK channel blocker mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of post translational modification of SK channels.

Electrophysiological Study Prognostic Value and Long-Term Outcome in Drug-InducedType1Brugada Syndrome: The IBRYD Study.

This study aimed to retrospectively assess long-term outcome and the prognostic role of electrophysiological study (EPS) for risk stratification of drug-induced type 1 Brugada syndrome (BrS) patients. BrS is a hereditary cardiac disease, predisposing to sudden cardiac death. Few real-world data are available on long-term outcomes of drug-induced type 1 BrS patients, and questions about risk stratification still remain unanswered. The IBRYD (Italian Brugada Syndrome) study is a multicenter observational retrospective study. A total of 226 drug-induced type 1 BrS patients were enrolled from 9 Italian tertiary referral institutions. Primary endpoint was a composite of appropriate implantable cardioverter-defibrillator (ICD) therapy and sudden cardiac death. The authors further assessed clinical predictors to ICD implantation, as well as for arrhythmia induction at EPS, along with EPS as potential risk factor for the outcomes of interest. 142 patients (62.8%) received an ICD due to syncope and/or inducible ventricular tachyarrhythmias at EPS. During a median follow-up of 106months, 11 patients (4.9%) experienced primary outcome events. The ICD therapy median annual incidence over 8 years was 0.38% (interquartile range: 0% to 1.47%). Ventricular tachyarrhythmia inducibility during EPS was not predictive of arrhythmic events in ICD recipients versus non-ICD patients and in symptomatic versus asymptomatic subgroups, showing a low positive predictive value (9.6% and 8.9%, respectively) versus a high negative predictive value (96.6% and 95%, respectively). The authors reported 29 ICD-related complications and 4.9% inappropriate shocks. Drug-induced type 1 BrS patients have a very low arrhythmic risk. Clinical decision for implantation is supported by syncope and/or EPS positivity, though they fail to stratify high-risk patients. A better risk-to-benefit ratio should be pursued, considering both arrhythmic risk and ICD-related complications.

M2 muscarinic autoantibodies and thyroid hormone promote susceptibility to atrial fibrillation and sinus tachycardia in an autoimmune rabbit model.

What is the central question of this study? Do autoantibodies to the M2 muscarinic receptor (M2R-AAbs) have the potential to facilitate specific sustained tachyarrhythmias in the presence of thyroxine(T4 ) in rabbits? What is the main finding and its importance? The M2R-AAb and T4 jointly destabilized the electrophysiological properties, thus promoting the occurrence of atrial and sinus tachyarrhythmias in rabbits. These findings provide a practical basis for understanding the pathophysiological role of M2R-AAb alone and with T4 in arrhythmia induction and might provide an innovative option for treatment of Graves' disease with rhythm disturbance. Activating autoantibodies toward the β1/2 -adrenergic receptors (β1/2AR-AAbs) and M2 muscarinic receptor (M2R-AAbs) are present in a high proportion of patients with Graves' disease. We previously demonstrated that β1/2AR-AAbs with or without the presence of M2R-AAbs in combination with excessive thyroxine(T4 ) increased the induction of sustained tachyarrhythmias in an autoimmune rabbit model. However, the separate role of M2R-AAbs and their interaction with T4 are not clear. The aim of this study was to investigate the impact of M2R-AAbs and T4 on the induction of cardiac arrhythmias in a similar rabbit model. Ten New Zealand White rabbits were randomly divided into two groups. In groupA (n=6), the rabbits were immunized with the second extracellular loop peptide of M2R and subjected to 2weeks of T4 treatment. In groupB (n=4), the rabbits were treated only with T4 for 2weeks. After induction of general anaesthesia, rabbits were subjected to an electrophysiological study at 0 (pre-immune), 6 (post-immune) and 8weeks (post-immune+T4 treatment) in groupA and at 0 (baseline) and 8weeks (T4 treatment) in groupB. Each rabbit served as its own control. In groupA, high levels and activity of M2R-AAbs were detected in all immunized animals. Thyroxine in combination with immunization significantly increased induction of sustained sinus tachycardia and atrial fibrillation in comparison to the pre-immune state. In groupB, T4 predominantly induced sustained sinus tachycardia. This study demonstrated that M2R-AAbs and T4 jointly increased the susceptibility to both sinus and atrial tachyarrhythmias. The data supported the pathophysiological role of M2R-AAbs in hyperthyroidism-associated supraventricular tachyarrhythmias.

Presence of low voltage area predicts atrial tachyarrhythmia inducibility with atrial burst pacing after pulmonary vein isolation

Abstract Background Induction of atrial fibrillation (AF)/atrial tachycardia (AT) by atrial burst pacing following ablation procedure may reflect the presence of residual substrates in the atria that maintain AF. However, the relation between the inducibility and left atrial low voltage area (LVA) has not been established. Methods Fifty-nine patients (65 years old, 43 males) with persistent AF who underwent pulmonary vein isolation (PVI)-based ablation were studied. All patients underwent left atrial voltage mapping during sinus rhythm and atrial burst pacing after PVI. Atrial burst pacing was performed with 30-beat at an amplitude of 10V from the ostium of the coronary sinus; increasing from 240 to 320 ppm in steps of 20 ppm or failure to 1:1 atrial capture. Inducibility was defined as AF/AT lasting more than 5 minutes following burst pacing. Left atrial LVA and other co-variates were analyzed with regard to burst pacing positivity. Results AF/AT was induced by burst pacing in 23 patients (39%). Univariate analysis revealed that past history of stroke, CHADS2 score and presence of left atrial LVA were significantly associated with the inducibility of AF/AT. Multivariate analysis revealed that only the presence of LVA was associated with the inducibility (OR 1.5: per 10% increase; p=0.04). We focused on the relationship between the extent of LVA and burst positivity. AF/AT inducibility increased as low voltage area increased, and it was as high as 72.7% when low voltage area was more than 20% (P&amp;lt;0.05). Interestingly, induced arrhythmia type was AT rather than AF when low voltage area was more than 20%. Conclusions Presence of left atrial LVA is an independent predictor of atrial tachyarrhythmia inducibility after PVI in patients with persistent AF. A large amount of low voltage area is related to AT inducibility rather than AF. Extent of LVA and burst positivity Funding Acknowledgement Type of funding source: None

Reverse electromechanical modelling of diastolic dysfunction in spontaneous hypertensive rat after sacubitril/valsartan therapy.

AimsHypertension is a significant risk for the development of left ventricular hypertrophy, diastolic dysfunction, followed by heart failure and sudden cardiac death. While therapy with sacubitril/valsartan (SV) reduces the risk of sudden cardiac death in patients with heart failure and systolic dysfunction, the effect on those with diastolic dysfunction remains unclear. We hypothesized that, in the animal model of hypertensive heart disease, treatment with SV reduces the susceptibility to ventricular arrhythmia.Methods and resultsYoung adult female spontaneous hypertensive rats (SHRs) were randomly separated into three groups, which were SHRs, SHRs treated with valsartan, and SHRs treated with SV. In addition, the age‐matched and weight‐matched Wistar Kyoto rats were considered as controls, and there were 12 rats in each group. In vivo ventricular tachyarrhythmia induction and in vitro optical mapping were used to measure the inducibility of ventricular arrhythmias and to characterize the dynamic properties of electrical propagation. The level of small‐conductance Ca2+‐activated potassium channel type 2 (KCNN2) was analysed in cardiac tissue. Compared with SHR with left ventricular hypertrophy, treatment with SV significantly improved cardiac geometry (relative wall thickness, 0.68 ± 0.11 vs. 0.76 ± 0.13, P < 0.05) and diastolic dysfunction (isovolumetric relaxation time, 59.4 ± 3.2 vs. 70.5 ± 4.2 ms, P < 0.05; deceleration time of mitral E wave, 46 ± 4.8 vs. 42 ± 3.8, P < 0.05). The incidence of induced ventricular arrhythmia was significantly reduced in SHR treated with SV compared with SHR (ventricular tachycardia, 1.14 ± 0.32 vs. 2.91 ± 0.5 episodes per 10 stimuli, P < 0.001; ventricular fibrillation, 1.72 ± 0.31 vs. 5.81 ± 0.42 episodes per 10 stimuli, P < 0.001). The prolonged action potential duration (APD) and increase of the maximum slope of APD restitution were observed in SHR, while the treatment of SV improved the arrhythmogeneity (APD, 37.12 ± 6.18 vs. 92.41 ± 10.71 ms at 250 ms pacing cycle length, P < 0.001; max slope 0.29 ± 0.01 vs. 1.48 ± 0.04, P < 0.001). These effects were strongly associated with down‐regulation of KCNN2 (0.38 ± 0.07 vs. 0.74 ± 0.12 ng/ml, P < 0.001). The treatment of SV also decreased the level of N‐terminal pro‐B‐type natriuretic peptide, cardiac bridging integrator‐1, and intramyocardial fibrosis of SHR.ConclusionsIn conclusion, synergistic blockade of the neprilysin and the renin–angiotensin system by SV in SHRs results in KCNN2‐associated electrical remodelling in ventricle, which stabilizes electrical dynamics and attenuates arrhythmogenesis.

Exendin-4 inhibits atrial arrhythmogenesis in a model of myocardial infarction-induced heart failure via the GLP-1 receptor signaling pathway.

Glucagon-like peptide-1 receptor (GLP-1 receptor) agonists are considered to exert cardioprotective effects in models of acute and chronic heart disease. The present study aimed to investigate the role of exendin-4 (a GLP-1 receptor agonist) in atrial arrhythmogenesis in a model of myocardial infarction (MI)-induced heart failure and to elucidate the mechanisms underlying its effects. For this purpose, male Sprague-Dawley rats underwent sham surgery or left anterior descending artery ligation prior to being treated with saline/exendin-4/exendin-4 plus exendin9-39 (an antagonist of GLP-1 receptor) for 4 weeks. The effects of exendin-4 on atrial electrophysiology, atrial fibrosis and PI3K/AKT signaling were assessed. Rats with MI exhibited depressed left ventricular function, an enlarged left atrium volume, prolonged action potential duration, elevated atrial tachyarrhythmia inducibility, decreased conduction velocity and an increased total activation time, as well as total activation time dispersion and atrial fibrosis. However, these abnormalities were attenuated by treatment with the GLP-1 receptor agonist, exendin-4. Moreover, the expression levels of collagen I, collagen III, transforming growth factor-β1, phosphorylated PI3K and AKT levels in atrial tissues were upregulated in rats with MI. These changes were also attenuated by exendin-4. It was also found that these exedin-4-mediated attenutations were mitigated by the co-administration of exendin9-39 with exendin-4. Overall, the findings of the present study suggested that exendin-4 decreases susceptibility to atrial arrhythmogenesis, improves conduction properties and exerts antifibrotic effects via the GLP-1 receptor signaling pathway. These findings provide evidence for the potential use of GLP-1R in the treatment of atrial fibrillation.

Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model

BackgroundCoronary artery disease is the most common cause of heart failure (HF) in developed countries. The aim of this study was to elucidate the mechanisms of reduction of arrhythmias after sacubitril/valsartan (LCZ696) therapy in a myocardial infarction (MI)-HF rabbit model. Methods and ResultsChronic MI in rabbits with HF were divided into 3 groups: placebo control, valsartan 30 mg/day and LCZ696 60 mg/day. After 4 weeks of therapy, an electrophysiologic study and a dual voltage-calcium optical mapping study were performed. The LCZ696 group had significantly better left ventricular ejection fraction and lower ventricular tachyarrhythmia inducibility than the valsartan and placebo groups. The most common ventricular tachyarrhythmia pattern was 1 or 2 ectopic beats originating from the peri-infarct areas, followed by re-entrant beats surrounding phase singularity points. Compared to the valsartan and placebo groups, the LCZ696 group had significantly shorter action-potential duration, shorter intracellular calcium tau constant, faster conduction velocity, and shorter pacing cycle length to induce arrhythmogenic alternans. LCZ696 therapy reduced the phosphorylated calmodulin-dependent protein kinase II (CaMKII-p) expression. ConclusionsIn a rabbit model with chronic MI and HF, LCZ696 therapy ameliorated postinfarct heart function impairment and electrophysiologic remodeling and altered CaMKII-p expression, leading to reduced ventricular tachyarrhythmia inducibility.

Tongguan capsule derived-herb ameliorates remodeling at infarcted border zone and reduces ventricular arrhythmias in rats after myocardial infarction

ObjectiveTongguan Capsule, a traditional Chinese medicine, is safe to use and is efficient in treating ischemic heart diseases. The present study aimed to investigate whether Tongguan capsule derived-herb (TGD) can mitigate left ventricular remodeling and dysfunction in post myocardial infarction (MI) rats as well as reduce arrhythmias. Design and methodsMI was induced by a ligation of the left anterior descending coronary artery. TGD was administered to the post-MI rats over a period of 4 weeks. TGD treatment significantly attenuated tachyarrhythmia inducibility and cardiac dysfunction in post-MI heart. Echocardiogram showed that TGD significantly reduced the development of ventricular remodeling. Histological study revealed that TGD significantly reduced myocardial interstitial collagen deposition, myocyte area and α-smooth muscle actin (α-SMA) expression, and increased connexin 43 expression in the infarcted border zone (IBZ). Western blotting results revealed that TGD treatment significantly down-regulated the protein expression levels of type I and III collagen, α-SMA, and up-regulated connexin 43. RT-qPCR results showed that TGD decreased the levels of ANP and BNP. ConclusionsThese findings provided strong evidences that TGD intervention ameliorated interstitial fibrosis, myocyte hypertrophy and gap junction expression in the IBZ, attenuated left ventricular remodeling and dysfunction, and reduced vulnerability to tachyarrhythmia. TGD inhibited IBZ remodeling by its inhibition effect on myofibroblasts differentiation.

Danqi soft capsule prevents infarct border zone remodelling and reduces susceptibility to ventricular arrhythmias in post-myocardial infarction rats.

Danqi soft capsule (DQ) is a traditional Chinese medicine containing Salvia miltiorrhiza and Panax notoginseng; it is safe and efficient in treating ischaemic heart diseases. The purpose of the present study was to assess whether DQ could prevent infarct border zone (IBZ) remodelling and decrease ventricular arrhythmias occurrence in post‐myocardial infarction (MI) stage. MI was induced by a ligation of the left anterior descending coronary artery. DQ was administered to the post‐MI rats started from 1 week after MI surgery for 4 weeks. The results showed that DQ treatment significantly attenuated tachyarrhythmia induction rates and arrhythmia score in post‐MI rats. In echocardiography, DQ improved left ventricular (LV) systolic and diastolic function. Histological assessment revealed that DQ significantly reduced fibrotic areas and myocyte areas, and increased connexin (Cx) 43 positive areas in IBZ. Western blot revealed that DQ treatment significantly reduced the protein expression levels of type I and III collagens, α‐smooth muscle actin (α‐SMA), transforming growth factor‐β1 (TGF‐β1) and Smad3 phosphorylation, while increasing Cx43 amounts. Overall, these findings mainly indicated that DQ intervention regulates interstitial fibrosis, Cx43 expression and myocyte hypertrophy by TGF‐β1/Smad3 pathway in IBZ, inhibits LV remodelling and reduces vulnerability to tachyarrhythmias after MI. This study presents a proof of concept for novel antiarrhythmic strategies in preventing IBZ remodelling, modifying the healed arrhythmogenic substrate and thus reducing susceptibility to ventricular arrhythmias in the late post‐MI period.

Epicardial ganglionated plexi ablation increases the inducibility of ventricular tachyarrhythmias in a canine postmyocardial infarction model.

Previous studies have shown that epicardial ganglionated plexi ablation (EGPA) could increase the risk of ventricular arrhythmias induced by acute myocardial ischemia. However, the long-term effect of EGPA in a canine postmyocardial infarction (MI) model is not well established. Twenty mongrel dogs were randomly divided into two groups: an MI group (n = 10) and an EGPA group (EGPA plus MI, n = 10). EGPA was achieved by ablation of four major ganglion plexi and the ligament of Marshall. The electrocardiograph (ECG) parameters, ventricular effective refractory period (ERP), inducibility of tachyarrhythmias, and ventricular fibrillation threshold (VFT) were measured at baseline and after 8 weeks. Tyrosine hydroxylase (TH) and nerve growth factor (NGF) expression levels in the peri-infarcted zone were also determined by immunohistochemistry in both groups at the end of the study. No significant differences were found in electrophysiological parameters at the baseline between the two groups. At the end of the 8-week follow-up, however, the EGPA group was associated with a longer QT interval, corrected QT (QTc) interval and ventricular ERP, larger dispersion of QT, QTc, and ERP, and higher inducibility of tachyarrhythmia and VFT when compared to the MI group. In addition, the density of TH and NGF in the peri-infarcted zone was also significantly increased in the EGPA group in comparison to the MI group. After the 8-week follow-up, EGPA increased the ventricular arrhythmia inducibility in the canine post-MI model, likely by increasing ventricular electrophysiological instability and promoting ventricular sympathetic remodeling.

Safety of Continuous Postextrasystolic Pacing in the Human

Continuous postextrasystolic pacing is a potential positive inotropic treatment for several depressed myocardial states. The safety of this pacing, however, has been questioned since the mid‐1960's because the pacing markedly raises the myocardial oxygen consumption, thereby increasing the potential for proarrhythmia. To understand the actual safety of continuous postextrasystolic pacing, six clinical studies and case reports were reviewed involving a wide range of cardiovascular maladies (atrial or ventricular septal defect, congestive cardiomyopathy, heart failure, mitral or pulmonary stenosis, mitral, tricuspid, or aortic regurgitation, patent ductus arteriosis, mitral valve prolapse, coronary arterial‐arteriosclerotic heart disease, and pulmonary arterial hypertension): Braunwald E., et al. Amer. J. Med. 37: 700–711, 1964. Meijler, F. L. and D. Durrer. Bull. N. Y. Acad. Med. 41: 575–591, 1965. Lister, J. W., et al. Am. Heart J. 73: 362–368, 1967. Resnekov, L. Med. Clin. N. Amer. 54: 247–259, 1970. Gerschwind, H., et al. J. Am. Coll. Cardiol. 4: 216–225, 1984. Freudenberger, R., et al. J. Cardiac Fail. 14: 35–40, 2008. Patients received paired or coupled atrial, ventricular, or dual‐chamber pacing. Continuous postextrasystolic pacing in 63 of 63 patients resulted in zero incidences of ventricular tachyarrhythmia induction, including in 7 with a compromised coronary circulation. Only when a seventh clinical study was reviewed, involving myocardial infarction‐associated cardiogenic shock, did any arrhythmia occur, and only in 1 of 5 cases: Gourgon, R., et al. Paired Pulse Stimulation of the Heart. Proceedings of the Second Conference on Paired Pulse Stimulation and Postextrasystolic Potentiation in the Heart. 1968. pp. 36–51. Hence, when coronary arterial blood flow and myocardial oxygen supply are not compromised, and in the vast majority of cases where it is, continuous postextrasystolic potentiation pacing is a safe positive inotropic technique.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Potent immunomodulation and angiogenic effects of mesenchymal stem cells versus cardiomyocytes derived from pluripotent stem cells for treatment of heart failure

BackgroundOptimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF.MethodsEight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 108 hESC-CMs (hESC-CM group), or 2 × 108 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation.ResultsAt 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors.ConclusionsOur results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.