Ventricular Refractory Period Research Articles

The importance of scar border zone size in VT presentation and recurrence in post MI patients

Abstract Introduction Available mapping data in post-myocardial infarction patients describe ventricular tachycardia (VT) re-entry circuit characteristics of slow VT, that are typically related to transmural scars. Fast VTs with cycle lengths close to the refractory period may be related to functional re-entry in the scar border zone. Functional re-entry related border zone VTs may be difficult to control by ablation. Purpose The aims of this study are (1) to describe electroanatomical voltage map (EAVM) characteristics in post myocardial infarction (MI) patients with spontaneous and inducible fast VTs and (2) to assess the relation between scar border zone size and ablation outcomes. Methods Consecutive post-MI patients undergoing VT ablation at a tertiary referral center from January 2012 to November 2018 were included. Fast VT was defined as a VT cycle length (VTCL) = ventricular refractory period + max. 30ms. Areas of scar border zone (using 0.5 – 2.1mV/3.0mV cut-offs (according to LV remodeling stage; LVEF<47% and LV end-systolic volume index of >50 ml/m2)) were measured on the EAVM and correlated with clinical outcomes. Results In total, 138 patients were included (86% male; left ventricular ejection fraction 35±10%; 86% remodeled LV). Twenty-three patients (17%) had ≥1 fast VT (mean VTCL 275±52ms) at presentation, mean VTCL of the remaining patients 397±88ms). The median scar border zone size was 27% [IQR 20-38] of the left ventricular endocardial surface. Patients who presented with a spontaneous fast VT had a larger border zone than patients with slower VT (32% [IQR 28 – 41] vs. 25% [IQR 16 – 36], p=0.01). After ablation, 79 (57%) patients remained inducible for any VT, including 59/79 (75%) for a fast VT (median VTCL fast VT 260ms [IQR 236 -280]). Patients who remained inducible for fast VTs had a larger border zone than patients who remained inducible for slower VTs (35% [IQR 27 – 44] vs. 26% [IQR 20 – 36], p<0.001). During a median follow-up of 26 months [IQR 8 – 47], 45 patients (33%) had a VT recurrence (mean VTCL 357±98ms). Patients with a below median (27%) scar border zone area had a lower VT recurrence rate compared to patients with an above median scar border zone area (recurrence rate: 16/66 (24%) vs. 29/72 (40%), p=0.03). Kaplan-Meier survival analysis showed better free VT survival in the below median border zone patients (Log-rank: p<0.05) (Figure 1). Conclusion Patients who present with spontaneous fast VTs or who remain inducible for fast VTs after ablation have larger scar border zones during EAVM compared to patients with presenting or remaining slower VTs. A larger border zone appeared to be associated with higher VT-recurrence rates. The scar border zone may play an important role as VT substrate for (fast) VTs and may not be easily targeted by current ablation techniques.VT-free survival stratified by median BZ

Abstract 14930: A Case of Flecainide Toxicity Causing Wide Complex Tachycardia, Unresponsiveness, Hemodynamic Instability and Pacemaker Under-Sensing

Introduction: Flecainide toxicity (FT) is an uncommon yet potentially lethal complication. We report a case of FT precipitated by acute kidney injury (AKI) in a patient with paroxysmal atrial fibrillation (AF) and a permanent pacemaker (PPM), who presented with wide complex tachycardia (WCT) and PPM under-sensing. Case presentation: An above 85-year-old female with paroxysmal AF and a PPM presented with an episode of unresponsiveness. While en route to the ED via ambulance, she had another episode associated with hemodynamic instability precipitated by a WCT. She regained consciousness after 1 biphasic DC shock. An EKG in the ED revealed sinus rhythm with atrial under-sensing and pacing spikes during ventricular refractory period (see picture). Laboratory data were consistent with AKI and normal electrolytes levels. PPM interrogation showed atrial under-sensing. Flecainide was discontinued and following drug washout the EKG changes resolved and the QRS normalized. She was discharged on amiodarone with no recurrence of arrhythmias on follow up. Discussion: Flecainide is Class 1C Antiarrhythmic drug that blocks fast the sodium channels. Prolongation of PR interval and QRS duration, in addition to supraventricular and ventricular arrhythmias, may occur with FT. Left ventricular dysfunction, myocardial scar, and high serum levels are considered risk factors for proarrhythmia. The drug half-life is prolonged in patients with renal disease/AKI. There are limited data on PPM malfunction due to FT, but it may cause increased pacing thresholds and failure to capture. Sodium bicarbonate, lidocaine, and ECMO have been used in treatment. Conclusion: FT can lead to lethal arrhythmias and PPM malfunction. Since flecainide serum levels are not always readily available, its diagnosis can be challenging. Therefore, physicians should be aware of the clinical presentation and EKG changes that accompany FT.

Sacubitril/Valsartan Ameliorates Crizotinib-Induced Cardiotoxicity in Mice.

Lung cancer is one of the major cause of death globally. Crizotinib is a first-line drug used in treating non-small-cell lung cancer (NSCLC). However, the pathophysiological mechanisms underlying its cardiotoxicity are unknown. This study investigated the mechanisms of crizotinib-induced cardiotoxicity and explored whether this toxicity can be prevented by the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan. Male C57BL/6 mice were randomly divided into three groups: control, crizotinib (40 mg for four weeks), and crizotinib + sacubitril/valsartan (40 mg /60 mg for four weeks). Expression of genes in myocardial tissue were detected by transcriptomic sequencing, with verification of the differentially expressed genes (DEGs) using Real time-polymerase chain reaction (RT-PCR). Blood pressure (BP) and cardiac function of animals were measured using non-invasive monitoring and echocardiography approaches. Ventricular refractory period (RP), as well as the induction rate and score of ventricular arrhythmias (VAs) were detected by in vivo electrophysiology. Epicardial conductance was measured by mapping. Expression of Myh7 in myocardium was detected by western blot and RT-PCR. DEGs detected using transcriptomic sequencing included 10 up-regulated and 20 down-regulated genes. The first 5 DEGs identified were Myh7, Ngp, Lcn2, Ciart and Ptgds. Kyoto Encyclopedia of Genes and Genomes (KEGG) result indicated that Myh7 is involved in myocarditis, cardiomyopathy, and cardiac muscle contraction. Crizotinib treatment increased blood pressure, prolonged QTc interval, shortened ventricular RP, increased the incidence and score of right VAs, and increased Myh7 expression. Most of these responses were limited by sacubitril/valsartan. Crizotinib induced a range of cardiotoxic side effects in a mouse model and increased Myh7 expression represents a biomarker for this response. These cardiovascular toxic responses can be largely prevented by sacubitril/valsartan.

Acute Modulation of Left Ventricular Control by Selective Intracardiac Sympathetic Denervation.

The sympathetic nervous system plays an integral role in cardiac physiology. Nerve fibers innervating the left ventricle are amenable to transvenous catheter stimulation along the coronary sinus (CS). The aim of the present study was to modulate left ventricular control by selective intracardiac sympathetic denervation. First, the impact of epicardial CS ablation on cardiac electrophysiology was studied in a Langendorff model of decentralized murine hearts (n=10 each, ablation and control groups). Second, the impact of transvenous, anatomically driven axotomy by catheter-based radiofrequency ablation via the CS was evaluated in healthy sheep (n=8) before and during stellate ganglion stimulation. CS ablation prolonged epicardial ventricular refractory period without (41.8 ± 8.4ms vs 53.0 ± 13.5ms; P=0.049) and with β1-2-adrenergic receptor blockade (47.8 ± 7.8ms vs 73.1 ± 13.2ms; P<0.001) in mice. Supported by neuromorphological studies illustrating a circumferential CS neural network, intracardiac axotomy by catheter ablation via the CS in healthy sheep diminished the blood pressure increase during stellate ganglion stimulation (Δ systolic bloodpressure 21.9 ± 10.9mmHg vs 10.5 ± 12.0mmHg; P=0.023; Δ diastolic blood pressure 9.0 ± 5.5mmHg vs 3.0± 3.5mmHg; P=0.039). Transvenous, anatomically driven axotomy targeting nerve fibers along the CS enables acute modulation of left ventricular control by selective intracardiac sympathetic denervation.

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.

376 CARDIAC CONTRACTILITY MODULATION: A NEW THERAPY FOR HEART FAILURE

Abstract Introduction Cardiac Contractility Modulation is a therapy for chronic Heart Failure patients with EF 25-45% in sinus rhythm with QRS &amp;lt; 130 ms clinically symptomatic (NYHA Class &amp;gt; II) despite optimised medical therapy. It is made possible by the implantation of the OPTIMIZER SMART® device. The CCM works by delivering a non-excitatory high-energy bipolar signal, synchronised with local electrical activity (or cooperating with another pre-existing CIED), in the absolute ventricular refractory period, by means of two actively fixating leads, positioned in the interventricular septum and spaced at least 1-2 cm apart. Purpose Assessment and feedback of the CCM therapy process in patients with dilated cardiomyopathy. Educational update for health professionals. Patient education. Method A Pubmed search correlated with clinical data and field experience was performed. Results Patients with severe Dilated Cardiomyopathy already on optimised medical therapy. The mechanism of action demonstrated a remodelling of the left ventricle with a so-called 'metabolic' therapy. In CCM therapy, electrical stimulation is delivered to the heart muscle during the absolute refractory period. In this phase, electrical signals activate the mobilisation of calcium ions in cardiomyocytes. CCM signals applied during the absolute refractory period cause an increase in cytosolic calcium during systole, resulting in improved cardiac contraction without an increase in oxygen consumption. Conclusions CCM therapy has shown to improve contractility and cardiac performance improving the quality of life of patients undergoing this treatment by reducing symptoms of fatigue and dyspnoea; it has reduced the number of hospitalisations for moderate to severe heart failure. Healthcare professionals recognise The typical ECG of a patient implanted with a CCM device shows a 'spike' in the absolute refractory period of the cardiac cycle: the 'R wave' of the QRS complex without being alarmed. The patient has been trained to be autonomous in charging. OPTIMIZER SMART® is recharged externally with a weekly rechargeable battery through a mini induction charger, rechargeable by itself.

Selective intracardiac sympathetic denervation acutely modulates left ventricular control

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Centre for Cardiovascular Research (DZHK) Background The sympathetic nervous system plays an integral role in cardiac physiology. Neuromodulation is emerging as a treatment option for ventricular arrhythmias, but selective intracardiac approaches are rare. Sympathetic nerve fibers innervating the left ventricle have been demonstrated to be amenable to transvenous catheter stimulation along the coronary sinus (CS). Purpose The aim of the present study was to modulate left ventricular control by selective sympathetic denervation using epicardial or standard catheter ablation for intracardiac axotomy at the level of the CS. Methods First, the impact of epicardial CS ablation on cardiac electrophysiology was studied in a Langendorff model of murine hearts (n=10 each, ablation and control). Second, the impact of transvenous, anatomically-driven axotomy by catheter-based radiofrequency ablation along the CS was evaluated in a healthy ovine in vivo model (n=8) before and during left stellate ganglion stimulation (LSGS). Results CS ablation for intracardiac sympathetic axotomy prolonged epicardial ventricular refractory period (VRP) without (41.8±8.4 ms vs. 53.0±13.5 ms; P=0.0487) and with beta1-2-adrenergic receptor blockade (47.8±2.8 ms vs. 73.1±5.0 ms; P=0.0009) and enhanced the increasing effect of beta1-2-adrenergic receptor blockade on epicardial VRP (∆VRP 6.3±7.0 ms vs. 20.0±7.5 ms; P=0.0045) in mice (Figure, A). Mean epicardial wave propagation velocity in the left ventricle was faster in ablated hearts than in controls (1.13±0.05 m/s vs. 1.00±0.02 m/s; P=0.0463), but did not differ in the right ventricle (1.15±0.05 m/s vs. 1.20±0.08 m/s; P=0.7938). Transvenous catheter ablation of the CS reduced systolic (SBP, 57.7±5.0 mmHg vs. 46.9±3.6 mmHg; P=0.0428) and diastolic blood pressure (DBP, 35.5±3.0 mmHg vs. 26.7±1.8 mmHg; P=0.0106) and diminished the blood pressure increase during LSGS in sheep (∆SBP 21.9±3.8 mmHg vs. 10.5±4.2 mmHg; P=0.0234; ∆DBP 9.0±1.9 mmHg vs. 3.0±1.2 mmHg; P=0.0391) (Figure, B, C). Cycle length remained unchanged by LSGS, both before (baseline 653.2±20.6 ms vs. LSGS 627.8±27.5 ms; P=0.2309) and after CS ablation (baseline 734.8±24.2 ms vs. LSGS 746.2±37.3 ms; P=0.7145). Conclusions Anatomically-driven axotomy targeting nerve fibers along the CS enables selective intracardiac sympathetic denervation resulting in acute modulation of left ventricular control.

Selective epicardial pulsed field ablation of atrial ganglionated plexi causes anti-arrhythmic prolongation of refractoriness: demonstration of feasibility in cardiac surgery patients

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): EU Horizon 2020 SME Instrument. Background Epicardial ganglionated plexi (GP) play a significant role in the initiation and maintenance of atrial fibrillation. However, modulation of this effect, through GP ablation, has had limited success; outcomes being confounded by unnecessary atrial tissue ablation and inability to access and ablate all of the atrial GPs. Selective pulsed field ablation (PFA) of GPs, using epicardial access, provides the opportunity to better identify the role of GP ablation in the treatment of atrial fibrillation. Purpose This study aimed to assess the safety and feasibility of selective GP ablation in patients undergoing elective coronary artery bypass grafting (CABG). It was hypothesized that GP ablation would provide an acute extension of atrial tissue refractoriness, which constitutes its antiarrhythmic effect. Methods Using a monopolar, monophasic PFA system, atrial GPs were ablated in nineteen patients with or without atrial fibrillation, undergoing CABG. The Oblique Sinus GP, Right Superior GP, Transverse Sinus GP, Left Superior GP and Ligament of Marshall GP were each ablated with up to sixty PFA pulses of 1000 V amplitude and 100 µs pulse width. Atrial Effective Refractory Period (AERP) was measured before and after all GP ablations, at the left atrial appendage (LAA) and on the right atrium (RA). Patients were monitored through to discharge for post-operative atrial fibrillation (POAF). Results Complete ablation of the GPs was performed in nineteen patients (aged 63.4 ± 6.6 years, 63.1% male) immediately after sternotomy. Electric field pulses were ECG-gated, with energy delivery during the ventricular refractory period. All GP sites were successfully accessed and ablated; all patients progressed immediately to their planned elective surgery and were discharged on schedule. Procedure time, for all GP ablations and AERP measurements was in the range 35-45 minutes. Thirteen valid pre- and post-ablation datasets were obtained. AERP (LAA and RA combined) increased upon GP ablation on average by 23% (220 ± 46 ms pre-ablation versus 269 ± 59 ms post-ablation, p = 0.002). Four patients experienced POAF; there was no evident correlation between POAF and AERP data. Only three of the enrolled patients had a prior history of AF; none of these exhibited AF on 24-hour Holter monitoring at 3-month follow-up. Conclusions Selective epicardial PFA of GPs is feasible and safe. An acute increase in atrial tissue refractoriness is promising but further studies are required to see how this translates to longer term outcomes in symptomatic AF patients and in a percutaneous epicardial access setting.

Cardiac Contractility Modulation (CCM) Italian Registry: preliminary analysis

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiac contractility modulation (CCM) therapy is a treatment option for patients suffering symptomatic Chronic Heart Failure (HF) with reduced left ventricular ejection fraction (LVEF) despite optimal medical therapy (OMT) [1]. CCM, by delivering high-output electrical impulses during ventricular absolute refractory period, increases the activity of proteins involved in intracellular calcium handling. This therapy has been associated with improvement in quality of life (QoL) and reduction of HF-hospitalizations [2,3]. Our aim is to present preliminary data from the CCM Italian Registry. Methods The CCM Italian Registry is a prospective, observational, multicentre study investigating the long-term impact of CCM therapy in HF patients on LVEF, Minnesota Living With HF Questionnaire (MLWHFQ) and 6-minutes walking test (6MWT) [4]. Preliminary results after one year of follow-up have been analysed in this abstract. Data are expressed as median and interquartile range. Changes from baseline have been tested with Wilcoxon signed-rank test. Results A total of 42 patients suffering HF, with LVEF&amp;lt;45%, NYHA class&amp;gt;II despite OMT, have been enrolled and implanted with CCM device in 10 Centres. Most of patients were male (41 patients, 98%), with a median age of 76 years (70-79). The most frequent aetiology was ischemic (29 patients, 69%) and 32 (79%) had another implanted device (24 ICD, 8 CRT-D). Twelve (29%) patients presented chronic atrial fibrillation (AF). Thirty-eight (90%) patients were treated with beta-blockers and 32 (76%) received sacubitril/valsartan (15) or ACE-inhibitors (17). A significant reduction in HF-related hospitalization has been observed after 6 and 12 months of CCM therapy, compared to the incidence in the 12 months before CCM implantation (Figure 1), with a relative risk reduction of 75% at 12 months (p&amp;lt;0.001). As shown in Figure 2, LVEF significantly improved both at 6 and 12-month follow up (p=0.042 and p=0.004, respectively), as well as MLWHFQ score (p=0.001 and p=0.032, respectively). The 6MWT distance did not show significant changes (6-month, p=0.252 and 12-month, p=0.281), mainly due to physical limitations in some patients. NYHA class improved significantly both at 6 (p=0.001) and 12-months (p=0.012), with 80% of patients showing an improvement of at least 1 class compared to baseline. After stratifying by HF aetiology, LVEF at 12-months improved significantly in non-ischaemic HF (p=0.028), while in patients with ischaemic aetiology improved significantly at 6-months (p=0.0416) but not at 12-months (p=0.135). Conclusion CCM proved to be effective in improving symptoms, QoL and in reducing CHF-hospitalizations in patients with symptomatic CHF with reduced LVEF despite OMT. This prospective Italian Registry will be fundamental to gather more evidence, to assess the long-term effect of CCM, and also to measure the impact of CCM therapy in the Italian clinical practice.

PO-630-08 INFLUENCE OF TWO NARCOSIS REGIMENS ON CARDIAC ELECTROPHYSIOLOGY IN MICE

Mouse models are commonly used to study arrhythmia mechanisms in vivo. Different narcosis regimens have proven feasibility in rodents with medetomidine (0.5 mg/kg), midazolam (5 mg/kg) and fentanyl (0.005 mg/kg) (MMF) and isoflurane (1-3 %)/fentanyl (0.05 mg/kg) (IF) among the most commonly used regimens, but little data is available regarding their effects on cardiac electrophysiology. To investigate the effects of MMF and IF narcosis in C57BL/6 wildtype mice on cardiac electrophysiology in vivo. Telemetry transmitters were implanted in 4 C57/BL6 mice which served as controls for ECG analysis without narcosis. In 22 mice ECG and invasive electrophysiology studies were performed under narcosis (n=10 MMF, n=12 IF). We assessed ECG, heart rate variability (HRV), sinus node recovery time (SNRT), atrial, atrioventricular and ventricular refractory periods (AERP, AVERP and VERP), Wenckebach point, VA conduction and arrhythmia inducibility by burst stimulation. MMF causes significant bradycardia (452 bpm baseline vs. 271 bpm MMF, ****p < 0.0001), affects HRV indicated by increased pRR50 (1.6 % baseline vs. 67.4 % MMF, ****p < 0.0001), reduced LF/HF ratio (0.62 baseline vs. 0.16 MMF, *p = 0.019) and both increased SD1 (15 ms baseline vs. 94 ms MMF, ****p < 0.0001) and SD2 (19.6 ms baseline vs. 48.5 ms MMF *p =0.017), and prolongs QRS duration (8.1 ms baseline vs. 11.6 ms MMF, *p = 0.015) and QT interval (50 ms baseline vs. 68 ms MMF, ****p < 0.0001). MMF prolongs SNRT (at 120 ms basic cycle length 234 ms MMF vs. 145 ms IF, ***p < 0.001), antegrade (69 ms MMF vs. 56 ms IF, ****p < 0.0001), and retrograde conduction in the AV node (118 ms MMF vs. 89 ms IF, ***p < 0.001), AVERP (67 ms MMF vs. 50 ms IF, **p < 0.01) and ultimately leads to increased susceptibility for ventricular arrhythmias (1.3 % MMF vs. 0 % IF, **p < 0.01) compared to IF. Our results highlight a significant impact of MMF narcosis on cardiac electrophysiology in mice. While IF only moderately reduces heart rate, MMF leads to significant bradycardia, QRS/QT prolongation and HRV alterations as well as impaired sinus node and AV node function, ultimately resulting in an increased inducibility of ventricular arrhythmias. Based on these effects we suggest using IF narcosis to study cardiac electrophysiology in mice.

Arrhythmic Mitral Valve Prolapse and Mitral Annular Disjunction: Clinical Features, Pathophysiology, Risk Stratification, and Management

Mitral valve prolapse (MVP) is a common cause of valvular heart disease. Although many patients with MVP have a benign course, there is increasing recognition of an arrhythmic phenotype associated with ventricular arrhythmias and sudden cardiac death (SCD). Pathophysiologic mechanisms associated with arrhythmias include cardiac fibrosis, mechanical stress induced changes in ventricular refractory periods, as well as electrophysiologic changes in Purkinje fibers. Clinically, a variety of risk factors including demographic, electrocardiographic, and imaging characteristics help to identify patients with MVP at the highest at risk of SCD and arrhythmias. Once identified, recent advances in treatment including device therapy, catheter ablation, and surgical interventions show promising outcomes. In this review, we will summarize the incidence of ventricular arrhythmias and SCD in patients with MVP, the association with mitral annular disjunction, mechanisms of arrhythmogenesis, methods for arrhythmic and SCD risk stratification including findings with multimodality imaging, and treatments for the primary and secondary prevention of SCD.

Arrhythmias in adults with congenital heart disease and heart failure.

Arrhythmias and heart failure are among the most common complications encountered by adults with congenital heart disease (CHD). In this contemporary review, we explore the interactions between arrhythmias and heart failure and discuss management strategies. Major knowledge gaps are highlighted throughout. Interactions between arrhythmias and heart failure are complex and bidirectional, with one begetting the other. Arrhythmias can provoke heart failure through various mechanisms: conduction disturbances may contribute to inefficient ventricular filling and contraction patterns; bradyarrhythmias and tachyarrhythmias can result in a reduction in cardiac output; hypoxemia may be exacerbated by right-to-left shunting; and tachycardia-induced cardiomyopathy has potentially devastating consequences if the diagnosis is delayed. In turn, heart failure promotes arrhythmogenesis through various structural (eg, fibrosis, chamber dilation, hypertrophy) and electrical remodeling effects that include changes to ion currents and channels and connexin expression, along with shortening of atrial and ventricular refractory periods with increased heterogeneity. Several shared comorbidities can contribute to, and modulate the impact of, arrhythmias and heart failure. Preemptive arrhythmia management can potentially mitigate effects on heart failure exacerbations. Similarly, optimal heart failure control could curtail its impact on arrhythmogenesis. Treatment strategies to prevent or treat heart failure in adults with CHD encompass pharmacological agents, catheter ablation, and device therapies including defibrillators, cardiac resynchronization therapy, and His bundle pacing. High-priority research avenues with major knowledge gaps include tachycardia-induced cardiomyopathy, catheter ablation of atrial fibrillation, defibrillator indications in high-risk subsets, and the role of cardiac resynchronization therapy and His bundle pacing in diverse forms of CHD.

Translational investigation of electrophysiology in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) patients are at increased risk of ventricular arrhythmias and sudden cardiac death, which can occur even in the absence of structural changes of the heart. HCM mouse models suggest mutations in myofilament components to affect Ca2+ homeostasis and thereby favor arrhythmia development. Additionally, some of them show indications of pro-arrhythmic changes in cardiac electrophysiology. In this study, we explored arrhythmia mechanisms in mice carrying a HCM mutation in Mybpc3 (Mybpc3-KI) and tested the translatability of our findings in human engineered heart tissues (EHTs) derived from CRISPR/Cas9-generated homozygous MYBPC3 mutant (MYBPC3hom) in induced pluripotent stem cells (iPSC) and to left ventricular septum samples obtained from HCM patients.We observed higher arrhythmia susceptibility in contractility measurements of field-stimulated intact cardiomyocytes and ventricular muscle strips as well as in electromyogram recordings of Langendorff-perfused hearts from adult Mybpc3-KI mice than in wild-type (WT) controls. The latter only occurred in homozygous (Hom-KI) but not in heterozygous (Het-KI) mouse hearts. Both Het- and Hom-KI are known to display pro-arrhythmic increased Ca2+ myofilament sensitivity as a direct consequence of the mutation. In the electrophysiological characterization of the model, we observed smaller repolarizing K+ currents in single cell patch clamp, longer ventricular action potentials in sharp microelectrode recordings and longer ventricular refractory periods in Langendorff-perfused hearts in Hom-KI, but not Het-KI. Interestingly, reduced K+ channel subunit transcript levels and prolonged action potentials were already detectable in newborn, pre-hypertrophic Hom-KI mice. Human iPSC-derived MYBPC3hom EHTs, which genetically mimicked the Hom-KI mice, did exhibit lower mutant mRNA and protein levels, lower force, beating frequency and relaxation time, but no significant alteration of the force-Ca2+ relation in skinned EHTs. Furthermore, MYBPC3hom EHTs did show higher spontaneous arrhythmic behavior, whereas action potentials measured by sharp microelectrode did not differ to isogenic controls. Action potentials measured in septal myectomy samples did not differ between patients with HCM and patients with aortic stenosis, except for the only sample with a MYBPC3 mutation.The data demonstrate that increased myofilament Ca2+ sensitivity is not sufficient to induce arrhythmias in the Mybpc3-KI mouse model and suggest that reduced K+ currents can be a pro-arrhythmic trigger in Hom-KI mice, probably already in early disease stages. However, neither data from EHTs nor from left ventricular samples indicate relevant reduction of K+ currents in human HCM. Therefore, our study highlights the species difference between mouse and human and emphasizes the importance of research in human samples and human-like models.

Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice.

The tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b/PEX5R) is an interaction partner and auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are key for rhythm generation in the brain and in the heart. Since TRIP8b is expressed in central neurons but not in cardiomyocytes, the TRIP8b-HCN interaction has been studied intensely in the brain, but is deemed irrelevant in the cardiac conduction system. Still, to date, TRIP8b has not been studied in the intrinsic cardiac nervous system (ICNS), a neuronal network located within epicardial fat pads. In vitro electrophysiological studies revealed that TRIP8b-deficient mouse hearts exhibit increased atrial refractory and atrioventricular nodal refractory periods, compared to hearts of wild-type littermates. Meanwhile, heart rate, sino-nodal recovery time, and ventricular refractory period did not differ between genotypes. Trip8b mRNA was detected in the ICNS by quantitative polymerase chain reaction. RNAscope in situ hybridization confirmed Trip8b localization in neuronal somata and nerve fibers. Additionally, we found a very low amount of mRNAs in the sinus node and atrioventricular node, most likely attributable to the delicate fibers innervating the conduction system. In contrast, TRIP8b protein was not detectable. Our data suggest that TRIP8b in the ICNS may play a role in the modulation of atrial electrophysiology beyond HCN-mediated sino-nodal control of the heart.

Dexmedetomidine reduces ventricular arrhythmias in a model of drug-induced QT-prolongation

Abstract Background Dexmedetomidine is increasingly employed for conscious sedation during electrophysiological procedures. Recent experimental data have suggested direct effects of dexmedetomidine on cardiac electrophysiology. The aim of the present study was to assess the effects of dexmedetomidin on drug-induced QT-prolongation. Methods and results In 12 isolated rabbit hearts the macrolide antibiotic erythromycin (300μM) was infused as a potent Ikr blocker after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant prolongation of QT-interval (+25ms, p&amp;lt;0.05) accompanied by a moderate increase of action potential duration (APD, +5ms, p=ns) after infusion of erythromycin as compared with baseline. Effective refractory period (ERP) was also elevated (+33ms, p&amp;lt;0.05). Erythromycin (+26ms, p&amp;lt;0.05) also significantly increased spatial dispersion of repolarisation. Additional infusion of dexmedetomidine (3μM) resulted in a rather stable QT-interval (+7ms, p=ns) and APD (+7ms, p=ns) as compared with sole erythromycin treatment. Of note, a significant decrease of spatial dispersion (−24ms, p&amp;lt;0.05) was observed while ERP was moderately increased (+13ms, p=ns). Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) and drug induced proarrhythmia with torsade de pointes in 6 of 12 erythromycin-treated hearts (40 episodes). Additional infusion of dexmedetomidine reduced the occurrence of torsade de pointes (4 of 12 hearts, 9 episodes). Conclusion Infusion of dexmedetomidine resulted in a reduction of spatial dispersion of repolarization in the presence of a prolonged repolarization period. This resulted in a reduction of torsade de pointes with dexmedetomidine. Furthermore, an increase of ventricular refractory periods reduced inducibility of ventricular arrhythmias. Thus, in an experimental setting dexmedetomidine shows significant antiarrhythmic effects, which may influence electrophysiologic findings during clinical electrophysiologic studies. This needs to be studied in the clinical setting. Funding Acknowledgement Type of funding source: None

His bundle pacing: Clinical consequences of unnecessary right ventricle backup pacing

As a backup lead in right ventricle (RV) is often used in His-bundle pacing (HBP) implants, in sinus rhythm patients the His lead is connected to the left ventricular (LV) port of a CRT device. In current devices, the backup pacing will be delivered 100% of time due to cross-channel ventricular refractory periods. Beyond an impact on battery, unnecessary RV pacing could find excitable tissue and capture a portion of the myocardium tissue potentially reducing the benefits of physiological HBP as shown in this case report where the switch from biventricular to LV-only pacing improved acute and 2-month echocardiography parameters.

Renal denervation ameliorates the risk of ventricular fibrillation in overweight and heart failure.

Both obesity and heart failure (HF) are associated with sudden cardiac death. The current study aimed to investigate the effects of overweight and HF on the substrate for ventricular fibrillation (VF), and whether renal denervation (RDN) can protect the heart from sympathetic activation and cardiac remodelling in HF rabbits fed with high-fat diet (HFD). Twenty-four rabbits randomized into control group fed with regular diet (Control), HFD, HFD-HF, and HFD-HF-RDN groups. Rapid ventricular pacing of 400 b.p.m. for 4 weeks was applied in HFD-HF and HFD-HF-RDN. Surgical and chemical RDNs were approached through bilateral retroperitoneal flank incisions in HFD-HF-RDN. All rabbits received electrophysiological study and a VF inducibility test. The ventricular myocardium was harvested for trichrome stain. After 3 months, mean body weight was heavier in HFD, compared with control (3.5 ± 0.1 kg vs. 2.6 ± 0.1 kg, P < 0.01). No differences in body weight among the three groups fed with HFD were observed. The ventricular refractory periods were longer in HFD-HF and HFD-HF-RDN than in control. An extension of ventricular fibrosis was observed in HFD and HFD-HF compared with control, and the degree of ventricular fibrosis was suppressed in HFD-HF-RDN compared with HFD-HF. The level of tyrosine hydroxylase staining was reduced in HFD-HF-RDN compared with HFD and HFD-HF. Importantly, VF inducibility was lower in HFD-RDN-HF (10 ± 4%), when compared with those in HFD-HF (58 ± 10%, P < 0.01) and HFD (42 ± 5%, P < 0.05), respectively. Our results suggest that overweight and HF increase sympathetic activity, structural remodelling, and VF inducibility, but RDN prevents them.

Atriale en ventriculaire elektrische en contractiele “remodelling” en “reverse remodelling” van chronisch “pacing”-geïnduceerde atriale fibrillatie bij paarden: eerste resultaten

Na een langdurige periode van atriumfibrillatie neemt de elektrische en contractiele herstelperiode bij de mens meerdere weken in beslag. Momenteel is er maar weinig bekend over dit fenomeen bij het paard. In de voorliggende studie werden bij zes paarden een neurostimulator en een pacemaker ingepland om atriumfibrillatie (AF) te kunnen induceren en te onderhouden via een “burst-pacing”-mechanisme; en om de atriale en ventriculaire elektrofysiologie te kunnen bestuderen. Bij alle paarden ontstond persisterende AF na “burst pacing” gedurende twee tot vier weken. Parameters, zoals de atriale fibrillatiecyclus, de rechter atriale en ventriculaire refractaire periode en de gevoeligheid van het hart voor ritmestoornissen, zoals atriale aritmieën, atriale tachyaritmieën of AF, werden zowel voor en tijdens een AF-periode van vier maanden en gedurende een herstelperiode van twee maanden opgevolgd. De atriale en ventriculaire contractiliteit uitgedrukt in fractionele “shortening” en de grootte van de hartcompartimenten werden opgevolgd via 2D-echocardiografie. Bij twee van de zes paarden kon de procedure niet volledig opgevolgd worden ten gevolge van te hoge drempelwaarden (1 paard) of door een infectie ter hoogte van de “pocket” (1 paard). Bij de andere vier paarden konden er reeds na 48 uur van AF significante verschillen gemeten worden ten opzichte van de basale waarden. Tijdens de herstelperiode keerden alle waarden na één tot twee maanden naar de basale waarden terug. In dit onderzoek wordt aangetoond dat geïnduceerde chronische AF, elektrische en contractiele veranderingen teweegbrengt ter hoogte van het hart bij het paard maar dat deze veranderingen omkeerbaar zijn eens het sinusritme hersteld is. Deze resultaten suggereren dat er geen permanente schade veroorzaakt wordt door vier maanden pacing-geïnduceerde AF en dat een rustperiode van zes tot acht weken gunstig zou zijn alvorens het werk te hervatten.

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

P5702Non-invasive epicardial and endocardial mapping in patients with idiopathic right ventricular outflow tract premature ventricular contractions: new insights into arrhythmia substrate

Abstract Background It has been accepted for years that idiopathic premature ventricular contractions (PVCs) with origin in the right ventricular outflow tract (RVOT) are benign. They are thought to result from triggered activity and most studies do not describe abnormal findings during electroanatomical mapping Dispersion of ventricular repolarization is associated with the susceptibility to ventricular arrhythmias and may indicate the presence of diseased myocardium. The activation recovery interval (ARI) has been used as a surrogate measure of ventricular action potential duration and refractory period. Purpose The aim of this study was to use the new non-invasive epicardial and endocardial mapping system (NEES) to study patients with RVOT PVCs in order to evaluate the ARI in the epicardium of RVOT during sinus rhythm (SR). Methods Non-invasive mapping was performed with the NEES, based on body surface electrocardiograms of a maximum of 224 electrodes and computed tomography imaging data. Unipolar electrograms were reconstructed on the epicardial and endocardial surfaces. Patients were excluded if they had structural heart disease, previous ablation or conduction abnormalities. ARI was defined as the interval between times of minimum derivative of the QRS and the maximum derivative of the T wave in the unipolar electrograms. We evaluated the ARI map in patients with RVOT PVCs and in a control group of patients without PVCs (Figure). We assessed the maximum value of ARI (Max ARI), the minimum value of ARI (Min ARI) and the difference between the Max ARI and the Min ARI (Diff ARI). Results We studied 8 patients with RVOT PVCs and 8 patients without PVCs. The results are presented in the table. Demographic and NEES data RVOT PVCs (n=8) Control (n=8) P value* Demographic data Age in years, median (IQR) 53 (48–65) 59 (52–67) 0.536 Male gender, n (%) 4 (50) 6 (75) 0.608 NEES data Max ARI in msec, median (IQR) 285 (236–331) 228 (197–298) 0.195 Min ARI in msec, median (IQR) 176 (138–192) 216 (185–255) 0.161 ARI diff in msec, median (IQR) 111 (83–147) 15 (4–34) &lt;0.0001 NEES map Conclusion In this group of patients we found a significantly higher dispersion of the ARI measurements through the epicardium of the RVOT in patients with PVCs in comparison with patients without PVCs.