Repolarization indicates electrical instability in ventricular arrhythmia originating from papillary muscle.

AIMS: Cardiac arrhythmia originating from the papillary muscle (PM) can trigger ventricular fibrillation (VF) and cause sudden cardiac death even in the absence of structural heart disease. Most premature ventricular contractions, however, are benign and hitherto difficult to distinguish from a potentially fatal arrhythmia. Altered repolarization characteristics are associated with electrical instability, but electrophysiological changes which precede degeneration into VF are still not fully understood. METHODS AND RESULTS: Ventricular arrhythmia (VA) was induced by aconitine injection into PMs of healthy sheep. To investigate mechanisms of degeneration of stable VA into VF in structurally healthy hearts, endocardial high-density and epicardial mapping was performed during sinus rhythm (SR) and VA. The electrical restitution curve, modelling the relation of diastolic interval and activation recovery interval (a surrogate parameter for action potential duration), is steeper in VA than in non-arrhythmia (ventricular pacing and SR). Steeper restitution curves reflect electrical instability and propensity to degenerate into VF. Importantly, we find the parameter repolarization time in relation to cycle length (RT/CL) to differentiate self-limiting from degenerating arrhythmia with high specificity and sensitivity. CONCLUSION: RT/CL may serve as a simple index to aid differentiation between self-limiting and electrically instable arrhythmia with the propensity to degenerate to VF. RT/CL is independent of cycle length and could easily be measured to identify electrical instability in patients.

Ultra-high-density mapping of conduction gaps and atrial tachycardias: Distinctive patterns following pulmonary vein isolation with cryoballoon or contact-force-guided radiofrequency current.

INTRODUCTION: The aim of this study was to investigate electrophysiological findings in patients with arrhythmia recurrence undergoing a repeat ablation procedure using ultra-high-density (UHDx) mapping following an index procedure using either contact-force (CF)-guided radiofrequency current (RFC) pulmonary vein isolation (PVI) or second-generation cryoballoon (CB) PVI for treatment of atrial fibrillation (AF). METHODS AND RESULTS: Fifty consecutive patients with recurrence of AF and/or atrial tachycardia (AT) following index CF-RFC PVI (n = 21) or CB PVI (n = 29) were included. A 64-pole mini-basket mapping catheter in combination with an UHDx-mapping system-guided ablation was used. RFC was applied using a catheter tip with three incorporated mini-electrodes. PV reconnection rates were higher after CF-RFC PVI (CF-RFC: 2.5 ± 1.3 PVs vs CB: 1.4 ± 0.9 PVs; P = .0025) and left PVs were more frequently reconnected (CF-RFC: 64% PVs vs CB: 35% PVs; P = .0077). Fractionated signals along the antral index ablation line (FS) were found in 30% of CB-PVI patients (CF-RFC: 9.5% vs CB:30%; P = .098) targeted for ablation. In five cases, FS were a critical part of maintaining consecutive AT. The main AT mechanism found during reablation (n = 45 ATs) was macroreentry (80% [36/45], CF-RFC: 78.9% vs CB: 80.8%; P = 1.0) with a variety of circuits throughout both atria. CONCLUSION: UHDx mapping is sensitive in detecting conduction gaps along the index ablation line. Left PVs are more frequently reconnected after initial CF-RFC PVI. FS are a common finding after CB PVI and can maintain certain forms of ATs. ATs after index PVI are mostly macroreentries with a broad spectrum of entities.

Outcome after tailored catheter ablation of atrial tachycardia using ultra-high-density mapping.

INTRODUCTION: Tailored catheter ablation of atrial tachycardias (ATs) is increasingly recommended as a potentially easy treatment strategy in the era of high-density mapping (HDM). As follow-up data are sparse, we here report outcomes after HDM-guided ablation of ATs in patients with prior catheter ablation or cardiac surgery. METHODS AND RESULTS: In 250 consecutive patients (age 66.5 ± 0.7 years, 58% male) with ATs (98% prior catheter ablation, 13% prior cardiac surgery) an HDM-guided catheter ablation was performed with the support of a 64-electrode mini-basket catheter. A total of 354 ATs (1.4 ± 0.1 ATs per patient; mean cycle length 304 ± 4.3 ms; 64% macroreentry, 27% localized reentry, and 9% focal) with acute termination of 95% were targeted in the index procedure. A similar AT as in the index procedure recurred in five patients (2%) after a median follow-up time of 535 days (interquartile range (IQR) 25th-75th percentile: 217-841). Tailored ablation of reentry ATs with freedom from any arrhythmia was obtained in 53% after a single procedure and in 73% after 1.4 ± 0.4 ablation procedures (range: 1-4). A total of 228 patients (91%) were free from any arrhythmia recurrence after 210 days (IQR: 152-494) when including optimal usual care. CONCLUSIONS: Tailored catheter ablation of ATs guided by HDM has a high acute success rate. The recurrence rate of the index AT is low. In patients with extensive atrial scaring further ablation procedures need to be considered to achieve freedom from any arrhythmia.

Local impedance guides catheter ablation in patients with ventricular tachycardia.

AIMS: Catheter contact and local tissue characteristics are relevant information for successful radiofrequency current (RFC)-ablation. Local impedance (LI) has been shown to reflect tissue characteristics and lesion formation during RFC-ablation. Using a novel ablation catheter incorporating three mini-electrodes, we investigated LI in relation to generator impedance (GI) in patients with ventricular tachycardia (VT) and its applicability as an indicator of effective RFC-ablation. METHODS AND RESULTS: Baseline impedance, Δimpedance during ablation and drop rate (Δimpedance/time) were analyzed for 625 RFC-applications in 28 patients with recurrent VT undergoing RFC-ablation. LI was lower in scarred (87.0 Ω [79.0-95.0]) compared to healthy myocardium (97.5 Ω ([82.75-111.50]; P = .03) while GI did not differ between scarred and healthy myocardium. ΔLI was higher (18 Ω [9.4-26.0]) for VT-terminating as compared to non-terminating RFC-ablation (ΔLI 13 Ω [8.85-18.0]; P = .03), but did not differ for ΔGI between terminating vs nonterminating RFC-ablation. Correspondingly, LI drop rate was higher for RFC-ablation terminating the VT compared with RFC-ablation not terminating the VT (0.63 Ω/s [0.52-0.76] vs 0.32 Ω [0.20-0.58]; P = .008) while there was no difference for GI drop rate. ΔLI was higher in patients with nonischemic cardiomyopathy vs patients with ischemic cardiomyopathy (16 Ω [11.0-20.0] vs 11.0 Ω [7.85-17.00]; P = .003). CONCLUSION: Our findings suggest that LI is a sensitive parameter to guide RFC-ablation in patients with VT. LI indicates differences in tissue characteristics and generally is higher in patients with nonischemic cardiomyopathy. Hence, the etiology of the underlying cardiomyopathy needs to be considered when adopting LI for monitoring catheter ablation of VT.

Impact of the ablation technique on release of the neuronal injury marker S100B during pulmonary vein isolation.

AIMS: S100B, a well-known damage-associated molecular pattern protein is released acutely by central and peripheral nerves and upon concomitant denervation in pulmonary vein isolation (PVI). We aimed to investigate whether the ablation technique used for PVI impacts S100B release in patients with paroxysmal atrial fibrillation (AF). METHODS AND RESULTS: The study population consisted of 73 consecutive patients (age: 62.7 ± 10.9 years, 54.8% males) undergoing first-time PVI with either radiofrequency (RF; n = 30) or cryoballoon (CB; n = 43) for paroxysmal AF. S100B determined from venous plasma samples taken immediately before and after PVI increased from 33.5 ± 1.8 to 91.1 ± 5.3 pg/mL (P < 0.0001). S100B release in patients undergoing CB-PVI was 3.9 times higher compared to patients with RF-PVI (ΔS100B: 21.1 ± 2.7 vs. 83.1 ± 5.2 pg/mL, P < 0.0001). During a mean follow-up of 314 ± 186 days, AF recurrences were observed in 18/71 (25.4%) patients (RF-PVI: n = 9/28, CB-PVI: n = 9/43). Univariate Cox regression analysis indicated that an increase in S100B was associated with higher freedom from AF in follow-up (hazard ratio per 10 pg/mL release of S100B: 0.83; 95% confidence interval: 0.72-0.95; P = 0.007). CONCLUSION: The ablation technique used for PVI has an impact on the release of S100B, a well-established biomarker for neural damage.

Long-term efficacy and safety of radiofrequency catheter ablation of atrial fibrillation in patients with cardiac implantable electronic devices and transvenous leads.

INTRODUCTION: Long-term efficacy and safety are uncertain in patients with cardiac implantable electronic devices (CIED) and transvenous leads (TVL) undergoing radiofrequency catheter ablation of atrial fibrillation (AF). Thus, we assessed the outcome of AF ablation in those patients during long-term follow-up using continuous atrial rhythm monitoring (CARM). METHODS AND RESULTS: A total of 190 patients (71.3 ± 10.7 years; 108 (56.8% men) were included in this study. At index procedure 81 (42.6%) patients presented with paroxysmal AF and 109 (57.4%) with persistent AF. The ablation strategy included pulmonary vein isolation in all patients and biatrial ablation of complex fractionated electrograms with additional ablation lines, if appropriate. AF recurrences were assessed by CARM- and CIED-related complications by device follow-up. After a mean follow-up of 55.4 ± 38.1 months, freedom of AF was found in 86 (61.4%) and clinical success defined as an AF burden less than or equal to 1% in 101 (72.1%) patients. Freedom of AF was reported in 74.6% and 51.9% (P = 0.006) and clinical success in 89.8% and 59.3% (P < 0.001) of patients with paroxysmal and persistent AF, respectively. In 3 of 408 (0.7%) ablation procedures, a TVL malfunction occurred within 90 days after catheter ablation. During long-term follow-up 9 (4.7%) patients showed lead dislodgement, 2 (1.1%) lead fracture, and 2 (1.1%) lead insulation defect not related to the ablation procedure. CONCLUSION: Our findings using CARM demonstrate long-term efficacy and safety of radiofrequency catheter ablation of AF in patients with CIED and TVL.

A novel assessment of local impedance during catheter ablation: initial experience in humans comparing local and generator measurements.

AIMS: A novel measure of local impedance (LI) has been found to predict lesion formation during radiofrequency current (RFC) catheter ablation. The aim of this study was to investigate the utility of this novel approach, while comparing LI to the well-established generator impedance (GI). METHODS AND RESULTS: In 25 consecutive patients with a history of atrial fibrillation, catheter ablation was guided by a 3D-mapping system measuring LI in addition to GI via an ablation catheter tip with three incorporated mini-electrodes. Local impedance and GI before and during RFC applications were studied. In total, 381 RFC applications were analysed. The baseline LI was higher in high-voltage areas (>0.5 mV; LI: 110.5 ± 13.7 Ω) when compared with intermediate-voltage sites (0.1-0.5 mV; 90.9 ± 10.1 Ω, P < 0.001), low-voltage areas (<0.1 mV; 91.9 ± 16.4 Ω, P < 0.001), and blood pool LI (91.9 ± 9.9 Ω, P < 0.001). During ablation, mean LI drop (△LI; 13.1 ± 9.1 Ω) was 2.15 times higher as mean GI drop (△GI) (6.1 ± 4.2 Ω, P < 0.001). Baseline LI correlated with △LI: a mean LI of 99.9 Ω predicted a △LI of 12.9 Ω [95% confidence interval (12.1-13.6), R2 0.41; P < 0.001]. This relationship was weak for baseline GI predicting △GI (R2 0.06, P < 0.001). Catheter movements were represented by rapid LI changes. The duration of an RFC application was not predictive for catheter-tissue coupling with no further change of △LI (P = 0.247) nor △GI (P = 0.376) during prolonged ablation. CONCLUSION: Local impedance can be monitored during ablation. Compared with the sole use of GI, baseline LI is a better predictor of impedance drops during ablation and may provide useful insights regarding lesion formation. However, further studies are needed to investigate if this novel approach is useful to guide catheter ablation.

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

BACKGROUND: 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). OBJECTIVES: The aim of the present study was to modulate left ventricular control by selective intracardiac sympathetic denervation. METHODS: 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. RESULTS: CS ablation prolonged epicardial ventricular refractory period without (41.8 ± 8.4 ms vs 53.0 ± 13.5 ms; P = 0.049) and with ß1-2-adrenergic receptor blockade (47.8 ± 7.8 ms vs 73.1 ± 13.2 ms; 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 blood pressure 21.9 ± 10.9 mm Hg vs 10.5 ± 12.0 mm Hg; P = 0.023; Δ diastolic blood pressure 9.0 ± 5.5 mm Hg vs 3.0 ± 3.5 mm Hg; P = 0.039). CONCLUSIONS: Transvenous, anatomically driven axotomy targeting nerve fibers along the CS enables acute modulation of left ventricular control by selective intracardiac sympathetic denervation.

A novel algorithm for 3-D visualization of electrogram duration for substrate-mapping in patients with ischemic heart disease and ventricular tachycardia.

BACKGROUND: Myocardial slow conduction is a cornerstone of ventricular tachycardia (VT). Prolonged electrogram (EGM) duration is a useful surrogate parameter and manual annotation of EGM characteristics are widely used during catheter-based ablation of the arrhythmogenic substrate. However, this remains time-consuming and prone to inter-operator variability. We aimed to develop an algorithm for 3-D visualization of EGM duration relative to the 17-segment American Heart Association model. METHODS: To calculate and visualize EGM duration, in sinus rhythm acquired high-density maps of patients with ischemic cardiomyopathy undergoing substrate-based VT ablation using a 64-mini polar basket-catheter with low noise of 0.01 mV were analyzed. Using a custom developed algorithm based on standard deviation and threshold, the relationship between EGM duration, endocardial voltage and ablation areas was studied by creating 17-segment 3-D models and 2-D polar plots. RESULTS: 140,508 EGMs from 272 segments (n = 16 patients, 94% male, age: 66±2.4, ejection fraction: 31±2%) were studied and 3-D visualization of EGM duration was performed. Analysis of signal processing parameters revealed that a 40 ms sliding SD-window, 15% SD-threshold and >70 ms EGM duration cutoff was chosen based on diagnostic odds ratio of 12.77 to visualize rapidly prolonged EGM durations. EGMs > 70 ms matched to 99% of areas within dense scar (<0.2 mV), in 95% of zones within scar border zone (0.2-1.0 mV) and detected ablated areas having resulted in non-inducibility at the end of the procedure. Ablation targets were identified with a sensitivity of 65.6% and a specificity of 94.6% avoiding false positive labeling of prolonged EGMs in segments with healthy myocardium. CONCLUSION: The novel algorithm allows rapid visualization of prolonged EGM durations. This may facilitate more objective characterization of arrhythmogenic substrate in patients with ischemic cardiomyopathy.

Ablation of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy: Treatment Strategy, Characteristics of Consecutive Atrial Tachycardia and Long-Term Outcome.

Background Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and is associated with a deterioration of clinical status. Ablation of symptomatic AF is an established therapy, but in HCM, the characteristics of recurrent atrial arrhythmias and the long-term outcome are uncertain. Methods and Results Sixty-five patients with HCM (aged 64.5±9.9 years, 42 [64.6%] men) underwent AF ablation. The ablation strategy included pulmonary vein isolation in all patients and ablation of complex fractionated atrial electrograms or subsequent atrial tachycardias (AT) if appropriate. Paroxysmal, persistent AF, and a primary AT was present in 13 (20.0%), 51 (78.5%), and 1 (1.5%) patients, respectively. Twenty-five (38.4%) patients developed AT with a total number of 54 ATs. Stable AT was observed in 15 (23.1%) and unstable AT in 10 (15.3%) patients. The mechanism was characterized as a macroreentry in 37 (68.5%), as a localized reentry in 12 (22.2%), a focal mechanism in 1 (1.9%), and not classified in 4 (7.4%) ATs. After 1.9±1.2 ablation procedures and a follow-up of 48.1±32.5 months, freedom of AF/AT recurrences was demonstrated in 60.0% of patients. No recurrences occurred in 84.6% and 52.9% of patients with paroxysmal and persistent AF, respectively (P<0.01). Antiarrhythmic drug therapy was maintained in 24 (36.9%) patients. Conclusions AF ablation in patients with HCM is effective for long-term rhythm control, and especially patients with paroxysmal AF undergoing pulmonary vein isolation have a good clinical outcome. ATs after AF ablation are frequently observed in HCM. Freedom of atrial arrhythmia is achieved by persistent AF ablation in a reasonable number of patients even though the use of antiarrhythmic drug therapy remains high.

Outcomes in patients with dual antegrade conduction in the atrioventricular node: insights from a multicentre observational study.

BACKGROUND: Supraventricular tachycardias induced by dual antegrade conduction via the atrioventricular (AV) node are rare but often misdiagnosed with severe consequences for the affected patients. As long-term follow-up in these patients was not available so far, this study investigates outcomes in patients with dual antegrade conduction in the AV node. METHODS AND RESULTS: In this multicentre observational study, patients from six European centres were studied. Catheter ablation was performed in 17 patients (52 ± 16 years) with dual antegrade conduction via both AV nodal pathways between 2012 and 2018. Patients with the final diagnosis of a manifest dual AV nodal non-re-entrant tachycardia had a mean delay of the correct diagnosis of over 1 year (range 2-31 months). Two patients received prescription of non-indicated oral anticoagulation, two further patients suffered from inappropriate shocks of an implantable cardioverter defibrillator. In 12 patients, a co-existence of dual antegrade and re-entry conduction in the AV node was present. Mean fast pathway conduction time was 138 ± 61 ms and mean slow pathway conduction time was 593 ± 134 ms. Successful radiofrequency catheter ablation was performed in all patients. Post-procedurally oral anticoagulation was discontinued, without detection of cerebrovascular events or atrial fibrillation during a long-term follow-up of median 17 months (range 6-72 months). CONCLUSION: This first multicentre study investigating patients with supraventricular tachycardia and dual antegrade conduction in the AV node demonstrates that catheter ablation is safe and effective while long-term patient outcome is good. Autonomic tone dependent changes in ante- vs. retrograde conduction via slow and/or fast pathway can challenge the diagnosis and therapy in some patients.

Respiratory sinus arrhythmia is reduced after pulmonary vein isolation in patients with paroxysmal atrial fibrillation.

INTRODUCTION: Respiratory sinus arrhythmia (RSA) describes heart rate (HR) changes in synchrony with respiration. It is relevant for exercise capacity and mechanistically linked with the cardiac autonomic nervous system. After pulmonary vein isolation (PVI), the current therapy of choice for patients with paroxysmal atrial fibrillation (AF), the cardiac vagal tone is often diminished. We hypothesized that RSA is modulated by PVI in patients with paroxysmal AF. MATERIAL AND METHODS: Respiratory sinus arrhythmia, measured by using a deep breathing test and heart rate variability parameters, was studied in 10 patients (64 ±3 years) with paroxysmal AF presenting in stable sinus rhythm for their first catheter-based PVI. Additionally, heart rate dynamics before and after PVI were studied during sympathetic/parasympathetic coactivation by using a cold-face test. All tests were performed within 24 h before and 48 h after PVI. RESULTS: After PVI RSA (E/I difference: 7.9 ±1.0 vs. 3.5 ±0.6 bpm, p = 0.006; E/I ratio: 1.14 ±0.02 vs. 1.05 ±0.01, p = 0.003), heart rate variability (SDNN: 31 ±3 vs. 14 ±3 ms, p = 0.006; RMSSD: 17 ±2 vs. 8 ±2 ms, p = 0.002) and the HR response to sympathetic/parasympathetic coactivation (10.2 ±0.7% vs. 5.7 ±1.1%, p = 0.014) were diminished. The PVI-related changes in RSA correlated with the heart rate change during sympathetic/parasympathetic coactivation before vs. after PVI (E/I difference: r = 0.849, p = 0.002; E/I ratio: r = 0.786, p = 0.007). One patient with vagal driven arrhythmia experienced AF recurrence during follow-up (mean: 6.5 ±0.6 months). CONCLUSIONS: Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.

Catheter Ablation of Atrial Fibrillation: State of the Art and Future Perspectives.

PURPOSE OF REVIEW: Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with high rates of morbidity and mortality. Maintenance of stable sinus rhythm (SR) is the intended treatment target in symptomatic patients, and catheter ablation aimed at isolating the pulmonary veins provides the most effective treatment option, supported by encouraging clinical outcome data. A variety of energy sources and devices have been developed and evaluated. In this review, we summarize the current state of the art of catheter ablation of AF and describe future perspectives. RECENT FINDINGS: Catheter ablation is a well-established treatment option for patients with symptomatic AF and is more successful at maintaining SR than antiarrhythmic drugs. Antral pulmonary vein isolation (PVI) as a stand-alone ablation strategy results in beneficial clinical outcomes and is therefore recommended as first-line strategy for both paroxysmal and persistent AF. While radiofrequency-based PVI in conjunction with a three-dimensional mapping system was for many years considered to be the "gold standard", the cryoballoon has emerged as the most commonly used alternative AF ablation tool, especially in patients with paroxysmal AF. Patients with persistent or long-standing persistent AF and with arrhythmia recurrence after previous PVI may benefit from additional ablation strategies, such as substrate modification of various forms or left atrial appendage isolation. New technologies and techniques, such as identification of the AF sources and magnetic resonance imaging-guided substrate modification, are on the way to further improve the success rates of catheter ablation for selected patients and might help to further reduce arrhythmia recurrence. CONCLUSIONS: Pulmonary vein isolation is the treatment of choice for symptomatic patients with paroxysmal and persistent drug-refractory AF. The reconnection of previously isolated pulmonary veins remains the major cause of AF recurrence. Novel ablation tools, such as balloon technologies or alternative energy sources, might help to overcome this limitation. Patients with non-paroxysmal AF and with AF recurrence might benefit from alternative ablation strategies. However, further studies are warranted to further improve our knowledge of the underlying mechanisms of AF and to obtain long-term clinical outcomes on new ablation techniques.

High-Density Mapping and Ablation of Primary Nonfocal Left Atrial Tachycardia: Characterizing a Distinct Arrhythmogenic Substrate.

OBJECTIVES: This study sought to characterize primary left atrial tachycardia (LAT) mechanisms, electrical properties and substrate using high-density mapping. BACKGROUND: Nonfocal LAT can be found in patients without prior substrate modifying interventions. METHODS: Of 223 catheter ablation procedures for LAT 15 patients (60% male, age 74 ± 6 years) had nonfocal AT and no history of LA ablation or cardiac surgery. RESULTS: AT (mean cycle length 244 ± 32 ms) were identified as macro-re-entry (12 of 15) or localized re-entry (3 of 15). High-density electroanatomical mapping (EAM, performed in 13 patients) revealed a high proportion of low voltage areas (LVA, <0.45 mV, 41 ± 22%). Anterior LVA regions were predominantly related to the macro-re-entry and directly perpetuating the re-entrant circuit in 8 patients by formation of a conductive channel (width: 14 ± 7 mm, length: 11 ± 3 mm) between the inferior pole of the scar and the mitral valve (MV) annulus with electrophysiological features of diseased tissue. A tailored anterior ablation line successfully terminated AT in 9 patients (6 dominant circuit MV dependent, 3 dominant circuit scar dependent AT), while a lateral isthmus line was performed in 2 patients. Localized re-entries were successfully targeted by local ablation. Acute successful ablation could be achieved in 14 of 15 patients leading to a freedom from any arrhythmias in 9 of 15 patients (60%) after follow-up of 343 ± 203 days. CONCLUSIONS: Patients with nonfocal left atrial tachycardia without previous iatrogenic interventions show evidence for advanced atrial myopathy. High-density mapping revealed involvement of the anterior LA and allows for an individualized ablation approach beyond strategies usually applied in consecutive AT.

Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation.

Atrial fibrillation (AF), the most common sustained heart rhythm disorder worldwide, is linked to dysfunction of the intrinsic cardiac autonomic nervous system (ICNS). The role of ICNS damage occurring during catheter-based treatment of AF, which is the therapy of choice for many patients, remains controversial. We show here that the neuronal injury marker S100B is expressed in cardiac glia throughout the ICNS and is released specifically upon catheter ablation of AF. Patients with higher S100B release were more likely to be AF free during follow-up. Subsequent in vitro studies revealed that murine intracardiac neurons react to S100B with diminished action potential firing and increased neurite growth. This suggests that release of S100B from cardiac glia upon catheter-based treatment of AF is a hallmark of acute neural damage that contributes to nerve sprouting and can be used to assess ICNS damage.

Advanced mapping strategies for ablation therapy in adults with congenital heart disease.

BACKGROUND: Ultra-high density mapping (HDM) is a promising tool in the treatment of patients with complex arrhythmias. In adults with congenital heart disease (CHD), rhythm disorders are among the most common complications but catheter ablation can be challenging due to heterogenous anatomy and complex arrhythmogenic substrates. Here, we describe our initial experience using HDM in conjunction with novel automated annotation algorithms in patients with moderate to great CHD complexity. METHODS: We studied a series of consecutive adult patients with moderate to great CHD complexity and an indication for catheter ablation due to symptomatic arrhythmia. HDM was conducted using the Rhythmia™ mapping system and a 64-electrode mini-basket catheter for identification of anatomy, voltage, activation pattern and critical areas of arrhythmia for ablation guidance. To investigate novel advanced mapping strategies, postprocedural signal processing using the Lumipoint™ software was applied. RESULTS: In 19 patients (53±3 years; 53% male), 21 consecutive ablation procedures were conducted. Procedures included ablation of atrial fibrillation (n=7; 33%), atrial tachycardia (n=11; 52%), atrioventricular accessory pathway (n=1; 5%), the atrioventricular node (n=1; 5%) and ventricular arrhythmias (n=4; 19%). A total of 23 supraventricular and 8 ventricular arrhythmias were studied with the generation of 56 complete high density maps (atrial n=43; ventricular n=11, coronary sinus n=2) and an average of 12,043±1,679 mapping points. Multiple arrhythmias were observed in n=7 procedures (33% of procedures; range of arrhythmias detected 2-4). A total range of 1-4 critical areas were defined per procedure and treated within a radiofrequency application time of 16 (interquartile range 12-45) minutes. Postprocedural signal processing using Lumipoint™ allowed rapid annotation of fractionated signals within specific windows of interest. This supported identification of a practical critical isthmus in 20 out of 27 completed atrial and ventricular tachycardia activation maps. CONCLUSIONS: Our findings suggest that HDM in conjunction with novel automated annotation algorithms provides detailed insights into arrhythmia mechanisms and might facilitate tailored catheter ablation in patients with moderate to great CHD complexity.

Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System.

Since its invention in the late 19th century, the Langendorff ex vivo heart perfusion system continues to be a relevant tool for studying a broad spectrum of physiological, biochemical, morphological, and pharmacological parameters in centrally denervated hearts. Here, we describe a setup for the modulation of the intracardiac autonomic nervous system and the assessment of its influence on basic electrophysiology, arrhythmogenesis, and cyclic adenosine monophosphate (cAMP) dynamics. The intracardiac autonomic nervous system is modulated by the mechanical dissection of atrial fat pads-in which murine ganglia are located mainly-or by the usage of global as well as targeted pharmacological interventions. An octapolar electrophysiological catheter is introduced into the right atrium and the right ventricle, and epicardial-placed multi-electrode arrays (MEA) for high-resolution mapping are used to determine cardiac electrophysiology and arrhythmogenesis. Förster resonance energy transfer (FRET) imaging is performed for the real-time monitoring of cAMP levels in different cardiac regions. Neuromorphology is studied by means of antibody-based staining of whole hearts using neuronal markers to guide the identification and modulation of specific targets of the intracardiac autonomic nervous system in the performed studies. The ex vivo Langendorff setup allows for a high number of reproducible experiments in a short time. Nevertheless, the partly open nature of the setup (e.g., during MEA measurements) makes constant temperature control difficult and should be kept to a minimum. This described method makes it possible to analyze and modulate the intracardiac autonomic nervous system in decentralized hearts.

Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias.

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesis.

Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model.

Hypertension is a major risk factor for many cardiovascular diseases and leads to subsequent concomitant pathologies such as left ventricular hypertrophy (LVH). Translational approaches using large animals get more important as they allow the use of standard clinical procedures in an experimental setting. Therefore, the aim of this study was to establish a minimally invasive ovine hypertension model using chronic angiotensin II (ANG II) treatment and to characterize its effects on cardiac remodeling after 8 weeks. Sheep were implanted with osmotic minipumps filled with either vehicle control (n = 7) or ANG II (n = 9) for 8 weeks. Mean arterial blood pressure in the ANG II-treated group increased from 87.4 ± 5.3 to 111.8 ± 6.9 mmHg (P = 0.00013). Cardiovascular magnetic resonance imaging showed an increase in left ventricular mass from 112 ± 12.6 g to 131 ± 18.7 g after 7 weeks (P = 0.0017). This was confirmed by postmortem measurement of left ventricular wall thickness which was higher in ANG II-treated animals compared to the control group (18 ± 4 mm vs. 13 ± 2 mm, respectively, P = 0.002). However, ANG II-treated sheep did not reveal any signs of fibrosis or inflammatory infiltrates as defined by picrosirius red and H&E staining on myocardial full thickness paraffin sections of both atria and ventricles. Measurements of plasma high-sensitivity C-reactive protein and urinary 8-iso-prostaglandin F2α were inconspicuous in all animals. Furthermore, multielectrode surface mapping of the heart did not show any differences in epicardial conduction velocity and heterogeneity. These data demonstrate that chronic ANG II treatment using osmotic minipumps presents a reliable, minimally invasive approach to establish hypertension and nonfibrotic LVH in sheep.