Inducible Arrhythmias Research Articles

Secretome of atrial epicardial adipose tissue facilitates reentrant arrhythmias by myocardial remodeling.

Epicardial adipose tissue (EAT) accumulation is associated with cardiac arrhythmias. The effect of EAT secretome (EATs) on cardiac electrophysiology remains largely unknown. The purpose of this study was to investigate the arrhythmogenicity of EATs and its underlying molecular and electrophysiological mechanisms. We collected atrial EAT and subcutaneous adipose tissue (SAT) from 30 patients with atrial fibrillation (AF), and EAT from 3 donors without AF. The secretome was collected after a 24-hour incubation of the adipose tissue explants. We cultured neonatal rat ventricular myocytes (NRVMs) with EATs, subcutaneous adipose tissue secretome (SATs), and cardiomyocytes conditioned medium (CCM) for 72 hours. We implemented the electrophysiological changes observed after EATs incubation into a model of human left atrium and tested arrhythmia inducibility. Incubation of NRVMs with EATs decreased expression of the potassium channel subunit Kcnj2 by 26% and correspondingly reduced the inward rectifier K+ current IK1 by 35% compared to incubation with CCM, resulting in a depolarized resting membrane of cardiomyocytes. EATs decreased expression of connexin43 (29% mRNA, 46% protein) in comparison to CCM. Cells incubated with SATs showed no significant differences in Kcnj2 or Gja1 expression in comparison to CCM, and their resting potential was not depolarized. Cardiomyocytes incubated with EATs showed reduced conduction velocity and increased conduction heterogeneity compared to SATs and CCM. Computer modeling of human left atrium revealed that the electrophysiological changes induced by EATs promote sustainedreentrant arrhythmias if EAT partially covers the myocardium. EAT slows conduction, depolarizes the resting potential, alters electrical cell-cell coupling, and facilitates reentrant arrhythmias.

Dexmedetomidine for sedation during epicardial ablation for ventricular tachycardia: a single-center experience.

Epicardial approach to ventricular tachycardia (VT) ablation is mainly performed under general anesthesia (GA). Although catheter manipulation and ablation in the epicardial space could be painful, GA lowers blood pressure and may interfere with arrhythmia induction and mapping, and the use of muscle relaxants precludes identification of the phrenic nerve (PN). Moreover, an anesthesiologist's presence is required during GA for the whole procedure, which may not always be possible. Therefore, we evaluated the feasibility and safety of epicardial VT ablations performed under conscious sedation using dexmedetomidine in our center. Between January 2018 and January 2022, all patients who underwent epicardial VT ablation under continuous dexmedetomidine infusion were prospectively included in the study. All patients received premedication 30min before the epicardial puncture with paracetamol (acetaminophen 10mg/ml) 1000mg and ketorolac 30mg. Sedation protocol included an intravenous bolus of midazolam hydrochloride (0.03-0.05mg/kg) followed by continuous infusion of dexmedetomidine (0.2-0.7 mcg/kg/h). In addition, an intravenous fentanyl citrate bolus (0.7-1.4 mcg/kg) was given for short-term analgesia, followed by a second dose repeated after 30 to 45min. Sedation-related complications were defined in case of respiratory failure, severe hypotension, and bradycardia requiring treatment. Sixty-nine patients underwent epicardial or endo-epi VT ablation under conscious sedation and were included in the analysis. The mean age was 65.4 ± 12.1years; forty-six patients were males (66.6%). All patients had drug-refractory recurrent VT. Forty-seven patients (68.1%) had non-ischemic cardiomyopathy (NICM), 13 patients (18.9%) had ischemic-cardiomyopathy (ICM), and 9 patients (13%) had myocarditis. Standard percutaneous sub-xiphoid access was attempted in all patients. Non-inducibility of any VT was achieved in 82.6% (9/9 myocarditis, 10/13 ICM, 38/47 NICM, n = 57/69 patients), inducibility of non-clinical VT in 13% (3/13 ICM, 6/38 NICM, n = 9/69 patients), and failure in 4.3% (3/38 NICM, n = 3/69 patients). Although we observed procedural-related complications in five patients (7.2%), one transient PN palsy, two pericarditis, and two vascular complications, those were not related to the conscious sedation protocol. No respiratory failure, severe hypotension, or bradycardia requiring treatment has been observed among the patients. Prompt availability of anesthesiology support remains crucial for complex procedures such as epicardial VT ablation. Continuous infusion of dexmedetomidine and administration of midazolam and fentanyl seem to be a safe and effective sedation protocol in patients undergoing epicardial VT ablation.

Abstract P3026: The Effects Of Diet Modification On The Progression Of Heart Failure With Preserved Ejection Fraction

Introduction: Hypertension is a major risk factor for the development of heart failure with preserved ejection fraction (HFpEF). A high-salt diet has shown to induce hypertension and HFpEF in Dahl salt-sensitive rats; however, once developed, it is unclear if HFpEF resolves after a return to low-salt diet. Hypothesis: Dietary modification to reduce salt content will decrease blood pressure and lead to resolution of HFpEF in Dahl salt-sensitive rats. Methods: Dahl salt-sensitive rats (n=12) were fed a high-salt (HS) diet (8% NaCl) from 7 weeks of age to induce HFpEF. Rats fed a normal-salt (NS) diet (0.3% NaCl; n=6) served as controls. The development of HFpEF was verified with an echocardiogram at 14 weeks of age in HS-fed rats. HS diet was then switched to NS diet in a subset of the HFpEF rats (HFpEF s/p NS, n=6) at 16 weeks of age, while the rest of the HFpEF rats continued to consume HS diet (HFpEF s/p HS, n=6). Blood pressure was measured non-invasively using a tail artery cuff. Echocardiography was performed to measure systolic and diastolic function. Programmed electrical stimulation was performed to induce ventricular arrhythmias. Results: In rats with HFpEF, a switch to NS diet improved diastolic function (E/E’ ratio 14.9±3.0 in HFpEF s/p NS vs. 25.3±8.2 in HFpEF s/p HS, p=0.045). However, the diet switch did not reduce systolic blood pressure (204±15 mmHg in HFpEF s/p HS vs. 194±21 mmHg in HFpEF s/p NS, p=0.44). Lung congestion was also significantly reduced after NS diet in rats with HFpEF (lung/body weight 0.39±0.03% in HFpEF s/p NS vs. 0.50±0.06% in HFpEF s/p HS, p=0.0040). Ventricular arrhythmia inducibility did not change after diet switch (100% in both HFpEF s/p HS and HFpEF s/p NS rats), nor did the duration of induced ventricular arrhythmias (75±3 beats in HFpEF s/p HS vs. 67±8 beats in HFpEF s/p NS, p=0.0749). QTc intervals did not decrease after diet changes in rats with HFpEF (226±29 ms in HFpEF s/p HS vs. 225±4 ms in HFpEF s/p NS, p=0.095). Conclusions: Diet modification improves diastolic function and reduces pulmonary congestion in Dahl salt-sensitive rats with HFpEF, but it did not reduce blood pressure or inducibility of ventricular arrhythmias. Further mechanistic study is warranted to further investigate the effects of diet on HFpEF progression.

Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells.

Background: Previous studies have indicated that vascular endothelial growth factor B186 (VEGF-B186) supports coronary vascular growth in normal and ischemic myocardium. However, previous studies also indicated that induction of ventricular arrhythmias is a severe side effect preventing the use of VEGF-B186 in cardiac gene therapy, possibly mediated by binding to neuropilin 1 (NRP1). We have designed a novel VEGF-B186 variant, VEGF-B186R127S, which is resistant to proteolytic processing and unable to bind to NRP1. Here, we studied its effects on mouse heart to explore the mechanism of VEGF-B186-induced vascular growth along with its effects on cardiac performance. Methods: Following the characterization of VEGF-B186R127S, we performed ultrasound-guided adenoviral VEGF-B186R127S gene transfers into the murine heart. Vascular growth and heart functions were analyzed using immunohistochemistry, RT-PCR, electrocardiogram and ultrasound examinations. Endothelial progenitor cells (EPCs) were isolated from the circulating blood and characterized. Also, in vitro experiments were carried out in cardiac endothelial cells with adenoviral vectors. Results: The proteolytically resistant VEGF-B186R127S significantly induced vascular growth in mouse heart. Interestingly, VEGF-B186R127S gene transfer increased the number of circulating EPCs that secreted VEGF-A. Other proangiogenic factors were also present in plasma and heart tissue after the VEGF-B186R127S gene transfer. Importantly, VEGF-B186R127S gene transfer did not cause any side effects, such as arrhythmias. Conclusion: VEGF-B186R127S induces vascular growth in mouse heart by recruiting EPCs. VEGF-B186R127S is a novel therapeutic agent for cardiac therapeutic angiogenesis to rescue myocardial tissue after an ischemic insult.

An automated near-real time computational method for induction and treatment of scar-related ventricular tachycardias.

Catheter ablation is currently the only curative treatment for scar-related ventricular tachycardias (VTs). However, not only are ablation procedures long, with relatively high risk, but success rates are punitively low, with frequent VT recurrence. Personalized in-silico approaches have the opportunity to address these limitations. However, state-of-the-art reaction diffusion (R-D) simulations of VT induction and subsequent circuits used for in-silico ablation target identification require long execution times, along with vast computational resources, which are incompatible with the clinical workflow. Here, we present the Virtual Induction and Treatment of Arrhythmias (VITA), a novel, rapid and fully automated computational approach that uses reaction-Eikonal methodology to induce VT and identify subsequent ablation targets. The rationale for VITA is based on finding isosurfaces associated with an activation wavefront that splits in the ventricles due to the presence of an isolated isthmus of conduction within the scar; once identified, each isthmus may be assessed for their vulnerability to sustain a reentrant circuit, and the corresponding exit site automatically identified for potential ablation targeting. VITA was tested on a virtual cohort of 7 post-infarcted porcine hearts and the results compared to R-D simulations. Using only a standard desktop machine, VITA could detect all scar-related VTs, simulating activation time maps and ECGs (for clinical comparison) as well as computing ablation targets in 48 minutes. The comparable VTs probed by the R-D simulations took 68.5 hours on 256 cores of high-performance computing infrastructure. The set of lesions computed by VITA was shown to render the ventricular model VT-free. VITA could be used in near real-time as a complementary modality aiding in clinical decision-making in the treatment of post-infarction VTs.

Accessory pathway properties are similar in symptomatic and asymptomatic preexcitation

PurposePatients with WPW syndrome have an increased mortality rate compared to the general population. Although asymptomatic preexcitation has previously been considered benign, recent studies have found that also asymptomatic patients have clinical and electrophysiological factors associated with increased risk of sudden cardiac death. This study compares the baseline electrophysiological characteristics of accessory pathways in symptomatic and asymptomatic patients with preexcitation. We hypothesized that a significant proportion of asymptomatic patients has inducible orthodromic tachycardia during programmed electrical stimulation.MethodsThis retrospective study includes 1853 patients with preexcitation who underwent invasive electrophysiological testing in two Swedish University Hospitals between 1991 and 2018. The mean age was 36 ± 17 years with a range of 3–89 years. Thirty-nine percent was women. A total of 269 patients (15%) were children younger than 18 years. Electrophysiological data included effective refractory period of the accessory pathway (APERP, in 1069 patients), tachycardia cycle length, inducibility and type of tachycardia, and AP localization.ResultsA total of 1703 (93%) patients reported symptoms suggesting tachyarrhythmias before the study and 128 (7%) were asymptomatic. The proportion of potentially dangerous pathways with short APERP (≤ 250 ms) were similar in symptomatic and asymptomatic patients (187/949, 20% vs. 25/108, 23%) (P = 0.40) as was the mean APERP (303 ± 68 ms vs. 307 ± 75) (P = 0.61). The proportion of patients who had inducible arrhythmia was larger in the symptomatic group (64% vs. 31%) (P < 0.001).ConclusionThe results of this study strengthen the present guideline recommendation (IIA) to consider invasive risk assessment in patients with asymptomatic preexcitation.

Virtual induction and treatment of arrhythmias (VITA): a fast automated computational tool to induce scar-related tachycardia and identify ablation targets

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation, Wellcome Trust Background Catheter ablation therapy of post-infarction ventricular tachycardia (VT) is often a lengthy procedure, with a high risk profile, and VT recurrence remains common. While computational modeling may aid pre-procedure planning and target identification, state-of-the-art reaction diffusion (R-D) simulations require access to high performance computing facilities, making them incompatible with clinical workflows. Purpose To present the Virtual Induction and Treatment of Arrhythmias (VITA), a novel, fast and fully automated computational tool to induce VT and identify subsequent ablation targets. Methods VITA employs multisite pacing to automatically find split activation wavefronts associated with the presence of channel isthmuses of viable myocytes within the inexcitable scar. The algorithm probes for all possible associated reentrant pathways and refines these to obtain a set of unique circuits sustaining potential clinical VTs. VT sustenance is assessed by comparing the electrical wavelength with the anatomical circuit path length. Corresponding exit sites of susceptible circuits are automatically identified, and a minimal lesion set constructed for ablation targeting. VITA also allows for rapid simulation of ECGs for clinical comparison. A summary of the VITA is shown in the Figure. VITA was tested on a virtual cohort of 7 post-infarcted porcine hearts and results compared to R-D simulations. Results Using only a desktop computer, VITA successfully identified all possible scar-related VT circuits and optimal ablation targets in just 48mins (per model), compared to 68.5hrs using a high-performance computer required by the R-D approach. Furthermore, VITA consistently identified more VTs associated with intra-scar circuits than R-D (Figure C). Conclusion VITA provides the first near real-time computational tool to aid treatment of post-infarction VTs.

Programmed ventricular stimulation for predicting arrhythmic events in patients with myocardial infarction: a systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Background Left ventricular ejection fraction (LVEF) is at present the main parameter used to guide the implantation of cardioverter-defibrillators (ICD) in patients with ischaemic cardiomyopathy. However, LVEF alone is a poor predictor of ventricular arrhythmias (VA) and sudden cardiac death (SCD). The majority of ICDs implanted for the primary prevention of SCD never deliver appropriate therapies, while being an expensive therapy and being potentially iatrogenic. Therefore, insertion of ICDs based solely on LVEF is not efficient and calls for an improvement in the risk-stratification of post-myocardial infarction patients. Inducibility of ventricular arrhythmias with programmed ventricular stimulation (PVS) has been used in the past to assess the risk of malignant arrhythmias. However, its current role in clinical practice is unknown. Purpose The aim of this meta-analysis was to study the role of PVS to predict future arrhythmic events in patients with previous myocardial infarction. Methods We performed a systematic review and a random-effect meta-analysis of studies reporting VAs –defined as SCD, sudden cardiac arrest, sustained monomorphic ventricular tachycardia (SMVT) or appropriate ICD therapies– after PVS in patients with ischaemic heart disease. Whenever possible, we used inducibility of SMVT as the positive response to PVS. Otherwise, we used the definition pre-specified in the corresponding study. The primary outcome was to estimate the positive and negative predictive value (PPV and NPV, respectively) of PVS. Subgroup analyses were performed according to the PVS timing (&amp;lt;1 or ≥1 month after infarction), definition of a positive PVS, use of ICD, or study era (before or after 2000). We searched in MEDLINE, EMBASE and Cochrane Library electronic databases up to November 2021. Results Thirty studies were included with a total of 8253 patients (mean age 58.5 years, mean LVEF 38.8%). A total of 909 arrhythmic events occurred after a mean follow-up of 24.5 months. Overall, 23% (95% confidence interval [CI] 18-29%) of subjects had inducible arrhythmias with PVS. Inducibility was associated with a higher risk of subsequent VAs (odds ratio 6.26, 95% CI 3.97-9.89, p&amp;lt;0.001). The pooled NPV was 95%, (95% CI 93-96%, p&amp;lt;0.001) and the PPV was 25% (95% CI 20-31%, p&amp;lt;0.001). There was significant heterogeneity between studies (I2 78% for the odds ratio, 96% for the NPV and 68% for the PPV). There were no statistically significant differences in any of the values according to the pre-specified subgroups. Meta-regression showed a reduction of the NPV with longer follow-up (B coefficient –0.033; p=0.012). Conclusion PVS has a high NPV (95%) and could be useful to rule out subjects at low risk of arrhythmic events. However, it decreases with longer follow-ups and, thus, the arrhythmic risk may need to be reassessed.

P5 ACCESSORY PATHWAYS HIGH–DENSITY MAPPING IN WOLFF–PARKINSON–WHITE SYNDROME

Abstract Wolff–Parkinson–White syndrome is a common condition characterized by atrioventricular accessory pathways (AP), which can be asymptomatic or can be responsible for atrioventricular reentrant tachycardia or rapid conduction of atrial fibrillation to the ventricles: for this reason, patients are referred for catheter ablation procedures. Although success rates of ablation are &amp;gt;95%, late recurrences can occur in 2–21% of cases mainly depending on the anatomical position. Current approaches remain suboptimal, and when failures occur, they may be due to technical difficulties such as poor contact or catheter stability, inability to access the target site as well as mapping errors resulting in inaccurate location of the AP itself. High–density mapping represents an alternative approach to mapping arrhythmias since the collection of a high density of points allows pathway conduction to be mapped more efficiently. The use of a new software called open–window mapping proved to be reliable in the localization of AP and therefore in the determination of the effective ablation site. A 41–year–old male patient was referred to our Centre following the ECG finding of manifest ventricular preexcitation and short–lasting paroxysmal palpitations. In the Electrophysiology Lab, the diagnostic catheters were inserted with the “fluoroless” technique using the EnSite Precision™ mapping system (Abbott): the ECG and the endocavitary electrograms were indicative of a right Parahissian accessory pathway. The mapping was performed with a multipolar catheter (Advisor™ HD Grid). Once the location of the pathway had been estimated, the roving acquisition interval (RAI) was set according to the expected position of atrial and ventricular electrogram. The RAI window was centered at this point and was opened in both directions (open window mapping) to fully include signals leading up to and traveling away from the AP. It accurately showed the location of the pathway just few millimeters from the Hissian potential. The baseline electrophysiological study revealed an effective antegrade refractory period (PREAP) of 320 msec. In isoproterenol, antegrade PREAP was reduced to 300 msec and inducibility of arrhythmias was not observed. Therefore, in consideration of the poor conductive properties and the non–inducibility of arrhythmias, as well as the anatomical site near the conduction system, it was decided not to proceed with the ablation due to the significant risk of atrio–ventricular block.

P408 CERTIFICATION FOR COMPETITIVE SPORTS ACTIVITY IN A TEENAGER WITH WPW BY VIA INTRAHYSSIAN ACCESSORY PATHWAY

Abstract The case of a 12–year–old male, height 160 cm, weight 46 kg, who practices water polo at a competitive level is reported. Negative family history of cardiovascular pathologies, general and cardiovascular physical examination within the limits of normality. On the electrocardiographic trace (ECG) presence of delta wave from ventricular pre–excitation from intrahyssian accessory pathway (Fig. 1). Echocardiography + color Doppler was normal. The subject underwent a cardiopulmonary stress test with an incremental ramp protocol and steps of 20 watts / min. Shutdown at 190 watts for muscle exhaustion with peak oxygen consumption (VO2) = 43.9 mL / Kg / min, Heart rate = 197 beats / minute, BP = 210/70 mmHg, VE / VCO2 slope = 27.6. Normal course of the cronotropic and pressure curve. The ventricular pre–excitation delta wave persisted for the entire duration of the test and in recovery (Fig. 2, Fig. 3). Secondary disturbances of ventricular repolarization characterized by ST segment sub–leveling and negative T wave appeared at high load and persisted in the first minutes of recovery, delta VO2 / delta WR = 12. Given the non–disappearance of the delta wave from ventricular pre–excitation during the maximal stress test, the subject was sent to an electrophysiological study and subsequent ablation of the accessory pathway. The electrophysiological study was negative for inducibility of atrial fibrillation (AF) and ventricular arrhythmias. Safe ablation was impossible given the intrahyssian position of the accessory pathway. Considering the negativity of the electrophysiological study due to non inducibility of supraventricular and ventricular arrhythmias, eligibility for competitive sports was granted.

P377 CHALLENGING RISK STRATIFICATION IN BRUGADA SYNDROME: A CASE OF VENTRICULAR TACHYCARDIA IN A LOW–RISK PATIENT

Abstract A 22–year–old healthy athlete was referred to our hospital for electrocardiographic findings consistent with intermittent type–1 Brugada pattern. A routine electrocardiogram (ECG) performed during a check–up showed sinus rhythm, normal PR interval and QRS duration, rSR’ with a coved type ST–segment elevation in V2 lead (Figure 1).The patients denied history of syncope or palpitations and his family history did not show sudden cardiac death or Brugada syndrome (BrS). Transthoracic echocardiography was normal and a 12–lead Holter monitoring revealed the intermittence of the type–1 Brugada pattern. The patient was hospitalized for further investigation. On admission, ECG showed a type–2 Brugada pattern; therefore, Ajmaline challenge test (1 mg/kg injection in 10 minutes) was performed and resulted positive. Subsequently, the patient underwent an electrophysiological study (EPS) which was negative for induction of sustained arrhythmias. The protocol adopted consisted of double extrastimuli programmed electrical stimulation until refractoriness (drive 600/220 ms and 400/210 ms), at double sites (right ventricle apex and right ventricular outflow tract). Furthermore a genetic test was performed using next–generation sequencing, showing a heterozygous mutation in the SCN5A gene, encoding for sodium channel alpha subunit (variant c.5363delA), not previously described in the literature. Since the low arrhythmic risk, the patient was implanted with a loop recorder (ILR, Medtronic Reveal LINQ), entering a program of home monitoring. After a 15–months follow–up, an episode of ventricular polymorphic tachycardia lasting 2 minutes and 11 seconds, associated with lightheadedness and palpitations, was detected by the remote monitoring (Figure 2). The patient was therefore hospitalized. During the in–hospital stay a cardiac magnetic resonance was performed to exclude other underlying diseases, identifying an enlarged right ventricle (EDVi 114 ml/m2) and abnormal free wall motion (Figure 3), thus reaching one major criteria of arrhythmogenic cardiomyopathy (however not sufficient for the diagnosis). The patient was then implanted with a subcutaneous implantable cardiac defibrillator (Boston Scientific EMBLEM MRI S–ICD). We presented a case of complex arrhythmic risk stratification in a possible overlap of an arrhythmogenic cardiomyopathy and a Brugada Syndrome in a young athlete who experienced a sustained ventricular tachycardia during loop–recorder monitoring.

P29 AICD IMPLANTATION IN A PATIENT RESURRECTED FROM CARDIAC ARREST, WITH THE R / T PHENOMENON AT THE HOLTER

Abstract A 72–year–old woman with hypertension for thirty years, resuscitated from cardiac arrest during prosthetic surgery of the right knee in January 2020, with external heart massage and orotracheal intubation. On examination Holter performed in February 2021, presence of couples and R / T phenomenon with Lown 1B–3–4A–5 class. The patient is subjected to coronary angiography which showed only mild atheroma without stenosis hemodynamically significant of the arterial districts explored. On the Echocardiogram, FE estimated at 60%. Based on the anamnestic data and the feedback from the fifth class of Lown at the Holter, it was decided to implant a dual chamber defibrillator for secondary prevention. The vulnerable point of refractory ventricular notoriously falls below 300 msec and in the clinical case in question there is a comparison to the holter of fifth class of lown with phenomenon R on T and coupling interval of 276 msec. The precocity of the ventricular ectopias is already in itself a risk factor for MI, reinforced in the case of clincio in question from a history of resuscitated cardiac arrest in a hospital setting. Not indicated to ours opinion of the electrophysiological inducibility study, given the positive clinical history and dynamic ECG according to Holter who examines the arrhythmic phenomenon in its spontaneous and natural way of presenting itself in circadian rhythm. The reproducibility in the laboratory with the SEI, of the electrical vulnerability was in fact in the recent years downsized, due to high specificity but low sensitivity, as there is in the clinical reality of patient neurovegetative and biohumoral fluxuonary factors, which favor the induction of malignant arrhythmias and that escape the predictive laboratory analysis. Making the patient safe with the implant of the bicameral AICD resulted from a clinical – diagnostic – instrumental analysis and after extensive discussion by the heart team in our Operating Unit.

Mog1 deficiency promotes cardiac contractile dysfunction and isoproterenol-induced arrhythmias associated with cardiac fibrosis and Cx43 remodeling

Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes. Genetic studies have identified MOG1 variants responsible for cardiac arrhythmias. However, the physiological functions of MOG1 in vivo remain incompletely characterized. In this study, we generated Mog1 knockout (Mog1−/−) mice. Mog1−/− mice did not develop spontaneous arrhythmias at the baseline, but exhibited a prolongation of QRS duration. Mog1−/− mice treated with isoproterenol (ISO), but not with flecainide, exhibited an increased risk of arrhythmias and even sudden death. Mog1−/− mice had normal cardiac morphology, however, LV systolic dysfunction was identified and associated with an increase in ventricular fibrosis. Whole-cell patch-clamping and Western blotting analysis clearly demonstrated the normal cardiac expression and function of Nav1.5 in Mog1−/− mice. Further RNA-seq and iTRAQ analysis identified critical pathways and genes, including extracellular matrix (Mmp2), gap junction (Gja1), and mitochondrial components that were dysregulated in Mog1−/− mice. RT-qPCR, Western blotting, and immunofluorescence assays revealed reduced cardiac expression of Gja1 in Mog1−/− mice. Dye transfer assays confirmed impairment of gap-junction function; Cx43 gap-junction enhancer ZP123 decreased arrhythmia inducibility in ISO-treated Mog1−/− mice. Transmission electron microscopy analysis revealed abnormal sarcomere ultrastructure and altered mitochondrial morphology in Mog1−/− mice. Mitochondrial dynamics was found to be disturbed, and associated with a trend toward increased mitochondrial fusion in Mog1−/− mice. Meanwhile, the level of ATP supply was increased in the hearts of Mog1−/− mice. These results indicate that MOG1 plays an important role in cardiac electrophysiology and cardiac contractile function.

Pulmonary vein isolation alone versus pulmonary vein isolation with additional extensive ablation for paroxysmal and persistent atrial fibrillation.

BackgroundThe value of additional ablation beyond pulmonary vein isolation for atrial fibrillation (AF) ablation is unclear, especially for persistent AF. It is uncertain whether substrate modification with additional extensive ablation improves outcomes. We reviewed our experience to determine whether pulmonary vein isolation with additional extensive ablation (PVIEA) improves outcomes compared to pulmonary vein isolation alone (PVIA) for AF ablation.MethodsConsecutive cases of patients with PVIA versus PVIEA were compared between September 9, 2013 and December 12, 2020. Procedural data collected include radiofrequency ablation delivery time (RADT) and arrhythmia inducibility. Clinical data collected include sinus rhythm maintenance post‐procedure.ResultsA total of 235 patients were studied (67 PVIA and 168 PVIEA). RADT was shorter when comparing ablation with PVIA versus PVIEA (32 vs. 40 min; p = .04). More arrhythmias were inducible with PVIEA (p < .01). There was no difference in sinus rhythm maintenance by Kaplan–Meier survival analysis (log‐rank test p = .75), after 3 or 12 months between groups overall, and when stratified by AF type (paroxysmal and persistent), left atrial volume, CHA2DS2‐VASc score, left ventricular ejection fraction, or catheter ablation setting (high‐power short‐duration, standard‐power standard‐duration, temperature‐controlled non‐contact‐force).ConclusionAF ablation with PVIA or PVIEA produces similar sinus rhythm maintenance overall and when stratified by catheter setting and AF type. PVIA reduced procedure times and less arrhythmias were inducible post‐ablation.

BS-516-02 OPTICAL MAPPING OF EXPLANTED HUMAN HEARTS ENABLES REFINED IONIC MODELS OF ACTION POTENTIAL AND CONDUCTION VELOCITY RESTITUTION CURVES FOR ARRHYTHMIA SIMULATION

Dynamics and stability of electrical waves in the heart has been attributed to the action potential duration (APD) restitution curve, which is a measure of how the tissue responds to a given cycle length (CL) and the conduction velocity (CV). The restitution curves have been used to investigate how changes in stimulation CL can lead to the induction of alternans and arrhythmias. Only few restitution curves are available from clinical measurements in human hearts, and they were generated using monophasic action potential measurements or from single human cardiomyocytes. To obtain APD and CV restitution curves from explanted human hearts with optical mapping, and take advantage of the experimental data to refine the dynamics of an ionic model, which can be valuable for arrhythmia simulation studies. Optical mapping of membrane potentials was performed on explanted human hearts (n=2 from recipient patients and n=1 from a rejected donor) at high resolutions (256x256 pixels, at 500 Hz) and a large field of view of 8 x 8 cm2. Action potential was measured across the anterior epicardial RV and LV and the endocardium LV, paced at CLs from 3 sec and shorter, until conduction block or VF induction. APD and CV restitution were obtained across the mapped tissue. Optical voltage signals were obtained by pacing the heart at different CLs (Panel A). APDs and CVs were calculated, and restitution curves for APD and CV were calculated for different regions in the hearts. APD alternans, between even and odd beats, were observed and quantified (panels B and C). A human ventricular cardiomyocyte model was fitted to the experimentally obtained APD and CV restitution curves to reproduce AP duration (APD restitution) and conduction velocity (CV restitution) at all CLs. The resultant ionic model recapitulates the experimental data including the bifurcation period and magnitude of alternans as well as the wave propagations. Optical mapping of action potential from explanted human hearts were used to refine the dynamics of an ionic model of human ventricular myocytes. The refined model reproduced the experimental wave propagations at all CLs, including alternans. Our study presents a clinically relevant in silico model to study the induction and dynamics of arrhythmias in whole heart simulations.

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.

PO-691-08 ASSESSING THE MECHANISTIC ROLE OF DIFFUSE FIBROSIS TOWARDS ARRHYTHMOGENESIS IN HYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in the young and is a significant cause of SCD in adults. Myocardial fibrosis takes the form of both dense (focal) and diffuse fibrosis, with histopathological evidence showing diffuse fibrosis as the hallmark feature of the disease. Diffuse fibrosis, however, is not well captured by standard LGE-CMR and its contribution to arrhythmogenic propensity in HCM patients has never been assessed before. We introduce information from post-contrast T1 mapping, a quantitative and parametric imaging modality to represent the extensive diffuse fibrotic remodeling in HCM. To investigate the mechanistic role of diffuse fibrosis towards arrhythmogenesis with personalized, image-based models of fibrotic remodeling. In this retrospective study, we reconstructed 3D left ventricular models using contrast-enhanced LGE-MRI from 26 HCM patients, but with only 13 having experienced VA. We incorporated parametric post-contrast T1 mapping to define new, personalized thresholds of the LGE-MRI signal intensity to delineate regions of non-fibrotic myocardium, and diffuse and dense fibrosis at the tissue level. At the cellular level, we incorporated HCM-specific cell remodeling (Fig A). Rapid pacing was used to assess VA inducibility from the personalized distributions of diffuse fibrosis. Clinical characteristics, amount of fibrotic remodeling, and distribution of hypertrophy were not significantly associated with clinical VA (Fig B). T1-based thresholding increased the amount of diffuse fibrosis to 40.5 ± 9.4% from 8.9 ± 9.4% achieved by standard LGE-MRI thresholding (p<0.0001), but the amount of dense scar did not change significantly (3.8 ± 2.3 vs 3.2 ± 1.3, p=0.30). An average of 1.5 [0-3] unique VAs were induced in models reconstructed from patients with clinical VA compared to 0.3 [0-2] in models reconstructed from patients without clinical VA (p<0.001). Overall, one or more VA was induced in 11/13 models with clinical VA compared to 2/13 without clinical VA. The arrhythmogenic propensity of the ventricular substrate with diffuse fibrosis is patient-specific; it is not the amount of fibrosis, but its distribution (shape and location) that determines inducibility of arrhythmia.

Caffeine Induces Spontaneous Ventricular Tachyarrhythmias and Bidirectional Ventricular Tachycardia: Increased Vulnerability with Aging

IntroductionCaffeine is generally suspected to trigger or exacerbate cardiac arrhythmias in patients, but so far clinical data have been conflicting. We have demonstrated previously that caffeine plus dobutamine challenge can induce ventricular tachyarrhythmias in normal rats (Heart Rhythm O2 2020;1:359‐367). However, whether caffeine alone can induce cardiac arrhythmias has not been investigated. We hypothesize that caffeine alone could trigger spontaneous cardiac arrhythmias, which may be affected by aging and sexes. In this study we have investigated the effect of caffeine on spontaneous cardiac arrhythmias in younger and older adult rats of both sexes.MethodsThis study used Sprague‐Dawley rats. Younger (5‐month‐old) and older (1‐year‐old) adult rats of both sexes were enrolled. The study consisted of the following groups: 5‐month‐old male rats (younger male, n=8) and 1‐year‐old male rats (older male, n=9), 5‐month‐old female rats (younger female, n=6) and 1‐year‐old female rats (older female, n=5). These rats received caffeine (80mg/kg, IP) injection. In addition, a group of 5‐month‐old rats (both sexes, n=8) receiving saline injection without caffeine served as the control group. Surface electrocardiogram (ECG, standard Lead II) was continuously monitored and recorded during the experiments.ResultsNo arrhythmia was induced in the control group with saline injection. Caffeine injection induced ventricular tachyarrhythmias in 8/9 older male rats, while only in 2/8 younger male rats (younger versus older male rats, p=0.0152, Fisher's exact test). Similarly, ventricular arrhythmias were induced in 5/5 older female rats, and only in 1/6 younger female rats (older versus younger female rats, p=0.0152). There were no significant differences in male versus female rats in both age groups. Induced ventricular arrhythmias include various premature ventricular contractions (PVC, Figure‐Panel A) in all rats, monomorphic ventricular tachycardia (VT, Panel B) in 3 rats and polymorphic VT and bidirectional VT (Panel C) in all rats. No atrial arrhythmia was observed.ConclusionCaffeine can induce spontaneous ventricular arrhythmias in normal rats, and the younger rats are more resistant to arrhythmia induction. Arrhythmia inducibility increases significantly in older rats. There is no sex difference in caffeine induced ventricular arrhythmias. Although different types of ventricular arrhythmias are induced, the characteristic bidirectional VT is highly prevalent among the caffeine induced arrhythmias and no atrial arrhythmia was observed.

Highlights From the Circulation Family of Journals

Highlights From the <i>Circulation</i> Family of Journals

Proarrhythmic Effects of Sympathetic Activation Are Mitigated by Vagal Nerve Stimulation in Infarcted Hearts.

The goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation. Sympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI). In Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n=17), and a basket catheter was positioned in the left ventricle (n=6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS. During BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from-18.3% ± 6.3% to-2.1% ± 14.7%) and ARI dispersion (from 104ms2 [1 to 1,108ms2] to -108ms2 [IQR: -588 to 30ms2]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P< 0.05). After chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility.