Transesophageal Pacing Research Articles

Stress Echocardiography by the ABCDE Protocol ln the Assessment of Prognosis of Stable Coronary Heart Disease.

To assess the role of clinical indicators and parameters of stress echocardiography performed according to an extended protocol as predictors for the occurrence of a composite cardiovascular endpoint (CCVEP) in IHD. The study included 186 patients (60.2% men, mean age 60.6±9.9 years) with an established (n=73; 39.2%) and suspected (60.8%) diagnosis of IHD. Stress EchoCG with adenosine triphosphate (38.2%), transesophageal pacing (15.1%), dobutamine (2.6%), and bicycle ergometry on a recumbent ergometer (44.1%) was performed. The stress EchoCG protocol included assessment of regional wall motion abnormalities (WMA), B-lines, LV contractile reserve (CTR), coronary reserve (CR), and heart rate reserve. The median follow-up period was 13 [9; 20] months. The composite CCVEP included death from cardiovascular diseases and their complications, acute coronary syndrome, and revascularization and was defined at the first of these events. Statistical analysis was performed with the Statistica 16.0 and SPSS Statistics 23.0 software packages. Differences were considered statistically significant at p<0.05. Invasive or noninvasive coronary angiography was performed in 90.3% of patients; obstructive coronary disease (stenosis ≥50%) was detected in 67.9% of cases. During the follow-up period, 58 (31.2%) patients had cardiovascular complications. The risk of developing CCVEP was associated with the pretest probability (PTP) of ischemic heart disease (odds ratio, OR, 1.05; 95% confidence interval, CI, 1.02-1.08), dyslipidemia (DLP) (OR 0.40; 95% CI 0.20-0.82), carotid atherosclerosis (OR 0.39; 95% CI 0.18-0.86), LV ejection fraction (OR 0.96; 95% CI 0.93-0.99), appearance at peak stress of new significant (2 LV segments or more) regional WMAs (OR 0.32; 95% CI 0.18-6.55), decreased LV CTR (OR 0.46; 95% CI 0.27-0.79) and CR (OR 0.33; 95% CI 0.18-0.61); p<0.05 for all. In a multivariate analysis with Cox regression, the model with clinical indicators included PTP of IHD (OR 1.04; 95% CI 1.01-1.07; p=0.01) and DLP (OR 0.14; 95% CI 0.02-1.01; p=0.05) as predictors. The model with stress EchoCG parameters included the appearance of new significant WMAs (OR 0.33, 95% CI 0.16-0.65; p=0.001) and reduced <2.0 CR (OR 0.44; 95% CI 0.24-0.82; p=0.01). A comparative analysis of Kaplan-Meier curves confirmed statistically significant differences in the dynamics of the CCVEP occurrence depending on the absence or presence of hemodynamically significant WMAs and/or reduced CR during stress EchoCG (p<0.01). Reduced LV CR and WMA during stress EchoCG in patients with suspected or confirmed IHD are significant independent predictors for the CCVEP occurrence. Among clinical indicators, PTP of IHD and DLP are of the greatest importance for prognosis.

An inflammation resolution-promoting intervention prevents atrial fibrillation caused by left ventricular dysfunction.

Recent studies suggest that bioactive mediators called resolvins promote an active resolution of inflammation. Inflammatory signalling is involved in the development of the substrate for atrial fibrillation (AF). The aim of this study is to evaluate the effects of resolvin-D1 on atrial arrhythmogenic remodelling resulting from left ventricular (LV) dysfunction induced by myocardial infarction (MI) in rats. MI was produced by left anterior descending coronary artery ligation. Intervention groups received daily intraperitoneal resolvin-D1, beginning before MI surgery (early-RvD1) or Day 7 post-MI (late-RvD1) and continued until Day 21 post-MI. AF vulnerability was evaluated by performing an electrophysiological study. Atrial conduction was analysed by using optical mapping. Fibrosis was quantified by Masson's trichrome staining and gene expression by quantitative polymerase chain reaction and RNA sequencing. Investigators were blinded to group identity. Early-RvD1 significantly reduced MI size (17 ± 6%, vs. 39 ± 6% in vehicle-MI) and preserved LV ejection fraction; these were unaffected by late-RvD1. Transoesophageal pacing induced atrial tachyarrhythmia in 2/18 (11%) sham-operated rats, vs. 18/18 (100%) MI-only rats, in 5/18 (28%, P < 0.001 vs. MI) early-RvD1 MI rats, and in 7/12 (58%, P < 0.01) late-RvD1 MI rats. Atrial conduction velocity significantly decreased post-MI, an effect suppressed by RvD1 treatment. Both early-RvD1 and late-RvD1 limited MI-induced atrial fibrosis and prevented MI-induced increases in the atrial expression of inflammation-related and fibrosis-related biomarkers and pathways. RvD1 suppressed MI-related atrial arrhythmogenic remodelling. Early-RvD1 had MI sparing and atrial remodelling suppressant effects, whereas late-RvD1 attenuated atrial remodelling and AF promotion without ventricular protection, revealing atrial-protective actions unrelated to ventricular function changes. These results point to inflammation resolution-promoting compounds as novel cardio-protective interventions with a particular interest in attenuating AF substrate development.

Transesophageal pacing studies reduce readmission but prolong initial admission in infants with supraventricular tachycardia: A cost-comparison analysis.

Supraventricular tachycardia (SVT) is a common arrhythmia. Infants with SVT are often admitted to initiate antiarrhythmics. Transesophageal pacing (TEP) studies can be used to guide therapy prior to discharge. The objective of this study was to investigate the impact of TEP studies on length of stay (LOS), readmission, and cost in infants with SVT. This was a 2-site retrospective review of infants with SVT. One site (Center TEPS) utilized TEP studies in all patients. The other (Center NOTEP) did not. Patients with structural heart disease, patients with gestational age <34 weeks, and patients diagnosed after 6 months were excluded. At Center TEPS, repeat TEP studies were performed after titration of medication until SVT was not inducible. Primary endpoints were LOS and readmission for breakthrough SVT within 31 days of discharge. Hospital reimbursement data were utilized for cost-effectiveness analysis. The cohort included 131 patients, 59 in Center TEPS and 72 in Center NOTEP. One patient was readmitted in Center TEPS vs 17 in Center NOTEP (1.6% vs 23.6%; P ≤ .001). Median LOS was longer for Center TEPS at 118.0 (interquartile range [IQR] 74.0-189.5) hours vs Center NOTEP at 66.9 (IQR 45.5-118.3) hours (P = .001). Twenty-one patients had multiple TEP studies. Median length of readmission for Center NOTEP was 65 (IQR 41-101) hours. Including readmission costs, utilization of TEP studies resulted in a probability-weighted cost of $45,531 per patient compared with $31,087 per patient without TEP studies. Utilization of TEP studies was associated with decreased readmission rates but longer LOS and greater cost compared with SVT management without TEP studies.

Cardiac Arrhythmias Requiring Electric Countershock during the Neonatal Period-A Systematic Review.

In neonates, cardiac arrhythmias are rare. Electric countershock therapy is an effective alternative to drug therapy for neonatal arrhythmias. There are no randomized controlled studies investigating electric countershock therapy in neonates. To identify all studies and publications describing electric countershock therapy (including defibrillation, cardioversion, and pacing) in newborn infants within 28 days after birth, and to provide a comprehensive review of this treatment modality and associated outcomes. For this systematic review we searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Cumulative Index to Nursing and Allied Health Literature (CINAHL). All articles reporting electric countershock therapy in newborn infants within 28 days after birth were included. In terms of figures, 113 neonates who received electric countershock due to arrhythmias were reported. Atrial flutter (76.1%) was the most common arrhythmia, followed by supraventricular tachycardia (13.3%). Others were ventricular tachycardia (9.7%) and torsade de pointes (0.9%). The main type of electric countershock therapy was synchronized cardioversion (79.6%). Transesophageal pacing was used in twenty neonates (17.7%), and defibrillation was used in five neonates (4.4%). Electric countershock therapy is an effective treatment option in the neonatal period. In atrial flutter especially, excellent outcomes are reported with direct synchronized electric cardioversion.

Abstract P3016: Role Of AMPK/Sirtuin3 Signaling In HFpEF-associated Atrial Myopathy

Background: Patients with heart failure with preserved ejection fraction (HFpEF) are uniquely predisposed to atrial fibrillation (AF), which significantly worsens clinical outcomes. Pathological atrial remodeling, i.e. atrial myopathy, usually precedes clinical AF and is deemed to be an underlying cause of AF. However, little is known about its molecular features, and no effective treatments have been identified. Method: Wild type C57Bl6 mice were fed a high fat diet (HFD) and received L-NAME via drinking water (5-8 weeks). Atrial morphology and function were assessed by echocardiography. AF was induced by transesophageal pacing. Results: We discovered that HFpEF mice manifest prominent sinoatrial node (SAN) dysfunction and are highly susceptible to pacing-induced AF, suggesting that this is an ideal model for studying HFpEF-associated atrial changes. Our findings revealed that atrial hypertrophy, contractile dysfunction, and conduction abnormalities are key features of HFpEF-associated atrial myopathy. Interestingly, we did not observe significant atrial fibrosis in this model, a prominent feature of other AF models. Importantly, we discovered impaired AMPK/Sirt3 signaling in the atria of HFpEF mice, and similar atrial defects were observed in mice with cardiomyocyte-specific loss of sirtuin3 (Sirt3) or AMPK, indicating a critical role of AMPK/Sirt3 signaling in HFpEF-associated atrial myopathy. Lastly, we found that metformin, a widely used clinical AMPK agonist, significantly attenuated AF inducibility and SAN dysfunction in HFpEF mice. Conclusion: Our “two-hit” HFpEF model successfully recapitulates HFpEF-associated atrial phenotypes. Using this model, we unveiled molecular features of a distinct atrial myopathy. We identified a critical role of AMPK/Sirt3 signaling in HFpEF-associated atrial remodeling and demonstrated the therapeutic effect of metformin. As next steps, confirming this benefit in a clinical trial is warranted.

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.

Successful transesophageal pacing in a very-low-birth-weight-infant with atrioventricular block.

A baby with complete atrioventricular block was born with a birth weight of 1403 g. Isoproterenol was ineffective and emergency pacing was required. Since transcutaneous pacing was ineffective and transvenous pacing was untenable due to small body size, transesophageal pacing was performed for 3.5 hours until permanent pacemaker implantation. There were no complications. This is the first report of continuous transesophageal pacing in a very-low-birth-weight infant.

Myl-4 mutation induces atrial inflammation and fibrosis associated with increased Atrial Fibrillation vulnerability

Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia. The genet mutation Myl4-pE11k affecting the atrial cardiomyocyte contractile machinery, via a myosin light chain abnormality, is associated with familial AF. The underlying pathophysiological mechanisms governing the through which the Myl-4 mutation causes AF remains poorly understood. To elucidate the arrhythmogenic atrial remodeling induced by the Myl4-p.E11 K mutation associated with AF in rats. A Knock-In (KI) model using male Wistar rats was generated to study the impact of the Myl-4 mutation on atrial structure and function. Different age groups (embryo, neonate, 15 days, 1 month, 3 months, and 6 months) were used to identify whether the mutation is associated with age-dependant arrhythmogenic remodeling. The functional consequences of this mutation were assessed by electrocardiogram, transoesophageal pacing and optical mapping. Morphometric and histologic aspects of Myl4-mutation-induced atrial changes were determined by immunohistochemistry. Atrial expression levels of genes and proteins involved in fibrosis, inflammation and cellular necrosis were studied by qPCR, Western blot and Multiplex assays. Compared to control rats, a significant decrease in P-wave amplitude and duration was reported in transgenic rats. In vivo transoesophageal tachypacing induced AF and/or atrial flutter in 80% KI rats compared to control animals. The mutation was associated with early development of atrial fibrosis (observed from embryonic ages) and increased expression of fibrosis biomarkers. Atrial tissue from KI rats showed increased infiltration of proinflammatory macrophages associated with increased gene and protein expression of inflammation-associated genes. Pronecrotic genes were also upregulated under KI conditions. These parameters were aggravated as the KI animals aged, reaching a plateau between 15 days and 1 months post-birth for atrial fibrosis and inflammation. This study demonstrates that Myl-4 mutation provokes the development of an arrhythmogenic substrate and cardiac remodelling characterised by atrial fibrosis, inflammation and cell death in an age-dependant manner.

PO-674-02 TRANSESOPHAGEAL PACING STUDIES REDUCE READMISSION BUT PROLONG INITIAL ADMISSION IN INFANTS WITH SUPRAVENTRICULAR TACHYCARDIA

Supraventricular tachycardia (SVT) is a common rhythm disorder in children. Infants diagnosed with SVT are typically admitted to initiate medical therapy and discharged once on stable medication dosing. After initiating medical therapy, transesophageal pacing studies (TEPs) can be used to guide the need for changes to therapy prior to discharge.

Transesophageal Pacing Cardiac Induces Cardiac Arrest and Subsequent Brain Injury in Rats

BackgroundCardiac Arrest (CA) is one of the leading causes of mortality worldwide. The present study aimed to establish a simple and stable rat model of CA induced by transesophageal cardiac pacing for the investigation of cerebral resuscitation.Materials and MethodsA total of 26 healthy adult male Sprague-Dawley rats were randomly allocated into two groups: Sham-operated (n = 6) and experimental (n = 20) groups. High-frequency cardiac pacing (50 Hz, 2 ms and 30 V) was maintained for 3 min to induce CA. Providing CA was not achieved, an additional 2 min of pacing was performed 30 min later. After 4 min following the onset of CA, Cardiopulmonary Resuscitation (CPR) was initiated.ResultsCA was successfully induced in all 20 rats by this setting of high-frequency cardiac pacing. Among them, CA was induced in six rats after 2 min of pacing; the remaining 14 rats underwent CA after 3 min of pacing. When electrical stimulation was terminated the rate of Pulseless Electrical Activity (PEA) was 85% (17/20), the rate of Ventricular Fibrillation (VF) was 15% (3/20) and no asystole occurred. Of the 17 PEA rats, 16 were successfully resuscitated and the average duration of CPR was 106.75 ± 30.81 s. A total of three rats succumbed within 24 h, and one rat succumbed between 24 and 48 h following successful resuscitation; 12 rats survived to <72 h. In addition, three rats with VF were successfully resuscitated and the average duration of CPR was 264.33 ± 130.40 s; one rat succumbed between 24 and 48 h following successful resuscitation, and two rats survived to <72 h. The 72 h-survival rate was 74%. No notable injury the esophagus was observed in the rats. Compared with the Sham group, the neurological function of the CA group was significantly impaired (p < 0.05); cells in the hippocampal CA1 region of the CA group were significantly damaged (p < 0.05).ConclusionThe model of CA induced by transesophageal cardiac pacing in the present study is easy and replicable. Therefore, this model may be used for experimental research into cerebral resuscitation.

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.

Diagnostic efficiency of myocardial perfusion computed tomography with transesophageal pacing in patients with an initial diagnosis of acute coronary syndrome

Introduction. Computed tomography angiography (CTA) is widely used to detect atherosclerotic changes in coronary arteries (CA). However, the method is limited by the impossibility to perform functional assessment of detected stenoses. Perfusion computed tomography of the myocardium (PCT) can be used for this purpose.Aim of the study. To assess diagnostic accuracy of PCT of the myocardium with transesophageal electrocardiostimulation (TEES) and stress-echocardiography (stress-echoCG) with veloergometry (VEM) in detection of transient ischemia in patients with initial diagnosis of “acute coronary syndrome” (ACS) with borderline stenoses (50–75%) in CA in relation to measurements of fractional flow reserve (FFR).Materials and Methods. The study included 30 patients with the initial diagnosis of ACS with borderline (50–75%) stenoses in CA according to CTA or coronary angiography (CAG). Subsequently, they underwent myocardial PCT with 320-row detector with TEES, as well as stress-echoCG with VEM. Invasive FFR measurement was used as a reference method. FFR value &lt; 0.8 indicated hemodynamic significance of stenosis. Myocardial perfusion was assessed visually. Regional myocardial contractility of the left ventricle was assessed by stress-echoCG.Results. All patients were examined according to the stated protocol. PCT with TEES revealed FFR-significant stenoses with sensitivity, specificity, prognostic value of positive result and prognostic value of negative result 56, 93, 90, 65% respectively, stress-echoCG with VEM 62, 93, 91, 68% respectively.Conclusion. Myocardial PCT with TEES enables to detect perfusion defects associated with transient ischemia, and the diagnostic accuracy of the method in comparison with FFR is comparable with the already well-proven stress-echoCG. The use of PCT with TEES in combination with CTA can be considered as a promising diagnostic tool in patients without known coronary anatomy and with suspected ACS.

Ефективність кардіоверсії в пацієнтів з поєднанням фібриляції і тріпотіння передсердь

The aim – to compare the effectiveness of restoration of sinus rhythm by transesophageal pacing (TEECP) in patients with prolonged episodes of isolated typical atrial flutter (AFl) and in patients with a combination of atrial fibrillation (AF) and AFl.Materials and methods. 325 procedures of TEECP were performed in cases of longlasting episodes of AFl: from 8 days to 2 years (average 68.2±4.76 days). Prior to hospitalization, all subjects underwent ineffective medical cardioversion. The sinus rhythm was restored using TEECP, and in case of its ineffectiveness by means of electropulse therapy (EPT). All patients were divided into two groups: group I (n=237) – patients with a lone atrial flutter, and group II (n=88) – patients with the history of AF or in case of transformation AF into AFl because of antiarrhythmic therapy. Both groups were comparable by age, paroxysm duration, presence of hypertension and organic disorders of the heart conductive system, comorbidities, echocardiographic and hemodynamic parameters. Electrocardiographical parameters revealed no significant differences in the tachycardia cycle length and the average frequency of ventricular contractions.Results and discussion. Patients in the group II were characterized by a significantly longer history of arrhythmia, more severe heart failure, higher frequency of arrhythmia paroxysms and detection of thyroid disorders; recorded significantly lower amplitudes of the F wave on the surface electrocardiogram and A wave on the esophageal electrogram, which was associated with the processes of electrophysiological remodeling of the atria. Also, in contrast to patients with typical AFl, there was a significant decrease in the effectiveness of TEECP (63.6 and 89 %); more frequent use of EPT (10.2 and 3 %) and more often arrhythmia has transformed into a permanent form (25 and 7.2 %).Conclusions. In patients with prolonged episodes of typical AFl, a highly effective method of cardioversion is TEECP, regardless of the arrhythmia duration. In patients with concomitant AF, the restoration of sinus rhythm should be performed by EPT, due to its higher efficancy.

Successful treatment with transesophageal pacemaker for medically refractory bradycardia during endovascular thoracoabdominal aortic aneurysm surgery: 2 case reports

We present two cases of external pacing using esophageal atrial pacing for the treatment of medically refractory bradycardia during endovascular treatment of thoracoabdominal aortic aneurysms (TAAA) under general anesthesia. TAAA are life-threatening medical emergencies. Prompt management is required to prevent rupture or further dissection. Management focuses on impulse and blood pressure control followed by endovascular repair. Beta-blockers and antihypertensives are considered first line agents. General anesthetics can potentiate the effect of these medications intraoperatively. In our patients, favorable outcome was achieved using transesophageal pacing. Currently, there is limited literature supporting the use of transesophageal pacing in the perioperative setting.

The bradycardic agent ivabradine decreases conduction velocity in the AV node and in the ventricles in-vivo

Ivabradine blocks hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels, thereby lowering the heart rate, an action that is used clinically for the treatment of heart failure and angina pectoris. We and others have shown previously that ivabradine, in addition to its HCN channel blocking activity, also inhibits voltage-gated Na channels in vitro at concentrations that may be clinically relevant. Such action may reduce conduction velocity in cardiac atria and ventricles.Here, we explore the effect of administration of ivabradine on parameters of ventricular conduction and repolarization in the surface ECG of anesthetized mice. We found that 5 min after i.p. administration of 10 mg/kg ivabradine spontaneous heart rate had declined by ~13%, which is within the range observed in human clinical studies. At the same time a significant increase in QRS duration by ~18% was observed, suggesting a reduction in ventricular conduction velocity. During transesophageal pacing at heart rates between 100 and 220 beats/min there was no obvious rate-dependence of ivabradine–induced QRS prolongation. On the other hand, ivabradine produced substantial rate-dependent slowing of AV nodal conduction. We conclude that ivabradine prolongs conduction in the AV-node and in the ventricles in vivo.

Abstract 17405: Chronic Treatment of Ibrutinib Reduces PI3K Activation and Causes Increased Mitochondrial Oxidative Stress Leading to Heightened AF in Pitx2c +/- Mice

Background: Ibrutinib, a Bruton’s tyrosine kinase inhibitor which is currently used as first line treatment to various B-cell malignancies is known to cause proarrhythmic effects in patients thus limiting its continual use. Ibrutinib treated patients have been shown to be at a 4-fold increased risk of developing atrial fibrillation (AF), but the underlying molecular mechanisms remain unclear. Studies have shown that Pitx2 , the nearest gene to the 4q25 locus has been implicated in AF pathology and thus can serve as an experimental model for clinical AF. Objective: The goal of this study is to assess the role of the late cardiac Na current (I Na,L ), PI3K activation, and oxidative stress in mediating the increased susceptibility to AF in Pitx2c +/- mice and atrial human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to ibrutinib. Method: Pitx2c +/- mice were administered ibrutinib (30mg/kg/day IP) for 23 days after which their AF burden were assessed using transesophageal rapid pacing (TErP) along with their weight, BP, and plasma glucose. Atrial hiPSC-CMs were exposed to ibrutinib for 48 hrs. ELISA, IHC, Western blotting, cellular patch clamping and, qPCR studies were performed. Results: Pitx2c +/- mice were exposed to ibrutinib showed a graded increase in AF burden. ( Fig. 1A-C ). There was a decreased activation of the PI3K pathway and pAkt leading to overall decrease in SERCA2a expression ( Fig. 1D-F ). There was a significant increase in mitochondrial fragmentation and superoxide production in ibrutinib treated atrial hiPSC-CMs ( Fig G ) and the action potential duration at 90% repolarization and the I Na-L were markedly prolonged after ibrutinib exposure( Fig H ). Conclusion: We showed in Pitx2c +/- mice and atrial hiPSC-CMs that ibrutinib-mediated AF may in part be related to enhanced I Na-L , decreased activation of PI3K and SERCA2a and increased fibrosis leading to mitochondrial fragmentation and increased oxidative stress.

Abstract 14785: The Reactive Lipid Mediators Isolevuglandins Promote Atrial Fibrillation Mediated by Inflammation

Introduction: Inflammation and oxidative stress are linked to multiple risk factors for atrial fibrillation (AF), and to AF itself in the setting of sterile injury (e.g. after catheter ablation or cardiac surgery). However, anti-inflammatory therapies and conventional antioxidants cause adverse effects or are ineffective to prevent AF. Highly reactive mediators of lipid peroxidation such as isolevuglandins (IsoLGs) have been identified as a major component of oxidative stress-related injury. We hypothesized that during AF promoted by cardiac inflammation, a scavenger of IsoLG will decrease AF susceptibility. Methods: We studied mice with a systemic inflammatory phenotype due to deficiency in the lymphocyte adaptor protein ( Lnk -/- ), a negative regulator of cytokine signaling. At weaning, Lnk -/- mice and their wild-type (WT) littermates received either vehicle or a potent IsoLG scavenger, 2-hydroxybenzylamine (2-HOBA), by oral administration. At age 14 weeks, animals underwent transesophageal burst pacing, echocardiography, and tissue harvest or flow cytometry to measure atrial inflammation and IsoLG-adducts. Results: Cardiac histology and echocardiography revealed no major histologic or structural abnormalities in Lnk -/- mice. Nevertheless, Lnk -/- mice demonstrated a significant increase in AF burden compared to WT controls (124.8±43.3 vs 6.8±3 sec, respectively [mean±SEM, n=28, 12; P&lt;0.05]), as well as increased sustained AF (&gt; 30 sec; 48.1% vs 0%; P&lt;0.01]). Leukocyte infiltration was present in the atria of Lnk -/- mice, with a significant increase in CD3, CD19, NK1.1, and CD11b/MHCII positive cells, compared to atria from WT control mice. Furthermore, there was a 2 to 4-fold increase in IsoLG-adducts for Lnk -/- atrial immune cells positive for CD3, CD19, NK1.1 and CD11b/MHCII, compared to cells from WT atria. Lnk -/- mice treated with 2-HOBA had significantly reduced AF burden (4.7±4.5 sec, n=7; P&lt;0.05) with a trend towards reduction in sustained AF (0%, n=7; P=0.057). Conclusions: IsoLGs play a critical role in the pathogenesis of inflammation-mediated AF, and 2-HOBA, a scavenger of IsoLGs, represents a potentially novel therapeutic strategy for AF in this clinical setting.

The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease.

Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD. Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

Effects of occlusal disharmony on susceptibility to atrial fibrillation in mice

Tooth loss or incorrect positioning causes occlusal disharmony. Furthermore, tooth loss and atrial fibrillation (AF) are both risk factors for ischemic stroke and coronary heart disease. Therefore, we hypothesized that occlusal disharmony-induced stress increases susceptibility to AF, and we designed the present study to test this idea in mice. Bite-opening (BO) was done by cementing a suitable appliance onto the mandibular incisor to cause occlusal disharmony by increasing the vertical height of occlusion by 0.7 mm for a period of 2 weeks. AF susceptibility, evaluated in terms of the duration of AF induced by transesophageal burst pacing, was significantly increased concomitantly with atrial remodeling, including fibrosis, myocyte apoptosis and oxidative DNA damage, in BO mice. The BO-induced atrial remodeling was associated with increased calmodulin kinase II-mediated ryanodine receptor 2 phosphorylation on serine 2814, as well as inhibition of Akt phosphorylation. However, co-treatment with propranolol, a non-selective β-blocker, ameliorated these changes in BO mice. These data suggest that improvement of occlusal disharmony by means of orthodontic treatment might be helpful in the treatment or prevention of AF.

P927Electrophysiological features in children with premature ventricular contractions

Abstract Background Premature ventricular contractions (PVCs) is the one of the most frequent arrhythmias in children. There is no clear understanding regarding the causes of PVCs in children without structural heart diseases. There is also little information about the state of the conduction system (CS) of the heart in children with PVCs. Purpose:The aims of the study were to estimate the electrophysiological properties of the sinus node (SN) and atrioventricular node (AVN) in children with PVCs, and to evaluate the effect of atropine test on the frequency and nature of the PVCs. Methods: 167 children(54(32,3%) girls and 113(67,7%) boys with PVCs without structural heart disease were examined. Mean age at the time of the first examination was 14,5 ± 5,3years (6-18 years). Examination included: ECG, 24-hour Holter monitor (HM), echocardiogram, treadmill test, transesophageal pacing study (TEPS), atropine test.Results:The duration of the PVCs was 3,3 ± 1,5years (6-14 years). The burden of the PVCs was 7-29% according to HM data. 5(3%) children had syncope. Frequent PVCs were recorded in 43(25,7%) patients, single PVC in 59 (35,3%), and the rest of children did not have PVCs during TEPS. SN recovery time (SNRT) was 1118,1 ± 292,4ms (541-2300ms) which exceeded the age-dependent limit in 23(13,7%) children. Corrected SNRT was 350,1 ± 171,1ms (41-1317ms), which exceeded the age-dependent limit in 15(8,9%) children. Max.rate of 1:1 conduction through AVN was 166,7 ± 39,1 imp/min (90-220 imp/min); in 16(9,6%) children it was less than 120 imp/min, while 8 (4,8%) children had enhanced AV nodal conduction (more than 200imp/min). The effective refractory period (ERP) of AVN was 325,1 ± 91,7ms (190-650ms), exceeding the age norm in 18(10,7%) children. 16(9,6%) children had a discontinuous AV nodal conduction. The frequency of stimulation which suppressed PVCs was 100-160imp/min. Atropine test was performed in 100(59,9%) children (0,1% sol. Atropini sulfatis 0,02 mg/kg IV). After administration of atropine the increase in heart rate constituted 7-131%, with an average of 57%. The SNRT was 665,5 ± 154,4 ms (406-1512ms), maximal rate of 1:1 conduction through AVN was 213,2 ± 31,9 imp/min (150-270 imp/min). Among patients who initially had PVCs during TEPS, after atropine test PVCs disappeared in 61(59,8%) children, in 16(15,7%) children there was a significant decrease, and 4(3,9%) patients had an increase in the number of PVCs and episodes of stable ventricular bigeminy, and in 1(0.9%) child there were short runs of ventricular tachycardia (up to 8 QRS complexes).Conclusions: In children with PVCs normal electrophysiological parameters of cardiac CS were noted in most cases. In 35% of children there was a hypervagotonic influence on SN or AVN, and in 75,5% cases there was a disappearance or decrease in PVCs after atropine test. This suggests that the preferential nature of PVCs in children without structural heart diseases is autonomic system dependent