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.

Spatial and temporal variability of rotational, focal, and irregular activity: Practical implications for mapping of atrial fibrillation.

BACKGROUND: Charge density mapping of atrial fibrillation (AF) reveals dynamic localized rotational activation (LRA), irregular activation (LIA) and focal firing (FF). Their spatial stability, conduction characteristics and the optimal duration of mapping required to reveal these phenomena and has not been explored. METHODS: Bi-atrial mapping of AF propagation was undertaken using AcQMap (Acutus Medical) and variability of activation patterns quantified up to a duration of 30 s. The frequency of each pattern was quantified at each unique point of the chamber over two separate 30-s recordings before ablation and R2 calculated to quantify spatial stability. Regions with the highest frequency were identified at increasing time durations and compared to the result over 30 s using Cohen's kappa. Properties of regions with the most stable patterns were assessed during sinus rhythm and extrastimulus pacing. RESULTS: In 21 patients, 62 paired LA and RA maps were obtained. LIA was highly spatially stable with R2 between maps of 0.83 (0.71-0.88) compared to 0.39 (0.24-0.57), and 0.64 (0.54-0.73) for LRA and FF, respectively. LIA was most temporally stable with a kappa of >0.8 reached by 12 s. LRA showed greatest variability with kappa >0.8 only after 22 s. Regions of LIA were of normal voltage amplitude (1.09 mv) but showed increased conduction heterogeneity during extrastimulus pacing (p = .0480). CONCLUSION: Irregular activation patterns characterized by changing wavefront direction are temporally and spatially stable in contrast with LRA that is transient with least spatial stability. Focal activation appears of intermediate stability. Regions of LIA show increased heterogeneity following extrastimulus pacing and may represent fixed anatomical substrate.

Bi-atrial high-density mapping reveals inhibition of wavefront turning and reduction of complex propagation patterns as main antiarrhythmic mechanisms of vernakalant.

AIMS: Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF. METHODS AND RESULTS: Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed. CONCLUSIONS: Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs.

Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Differential pacing from two sites to diagnose risk of ventricular arrhythmia and death.

BACKGROUND: QRS abnormalities may not be apparent in sinus rhythm in electrically stable cardiomyopathy patients who can have quiescent but highly arrhythmogenic substrate. Here, we test the hypothesis that differential changes in QRS construction during right-ventricular apex pacing (RVP) as opposed to atrial pacing (AP) will identify latent substrate for ventricular arrhythmias (VA) and death. METHODS: Forty patients with cardiomyopathy free of VA underwent baseline 114-electrode body-surface electrocardiogram during AP (100 beats per minute [bpm]) and RVP (100 and 120 bpm). The filtered-averaged QRS at each electrode was deconstructed into individual intra-QRS and post-QRS ventricular myopotentials (VMP ). The primary outcome was VA or death. Prognostic accuracy of VMP was validated using V1 to V6 leads in another prospective cohort of 44-cardiomyopathy patients. RESULTS: Twenty-six patients were eligible for initial analysis. After 5 ± 2 years of follow-up, eight (31%) patients had VA (VAPos ) while rest were uneventful (VANeg ). During AP100 , VAPos patients expressed more VMP than VANeg patients (16 ± 1 vs 12 ± 1, P = 0.02). RVP100 and RVP120 in VAPos patients introduced an additional 5.5 ± 0.5 and 6.0 ± 0.5 VMP (P < 0.0001 vs AP100 ). The relative change with RVP120 versus AP100 in VANeg patients exceeded VAPos patients by 1.2 ± 0.5 VMP (P = 0.03). Increment in VMP count of <8 in lead-V5 with RVP120 compared to AP100 best predicted VA (area under curve 0.81, P = 0.01). In the validation cohort, primary outcome occurred in 13 (33%) patients. Native QRS features and AP100 alone failed to predict primary outcome. Patients with increment in VMP count of <8 in lead-V5 with RVP120 versus AP100 had 7.9-fold increased risk of primary outcome (95% confidence interval 1.01, 61.61; P = 0.049). CONCLUSION: Cardiomyopathy patients at risk of VA or death perturb the QRS less than low-risk patients with differential pacing. This functional response may be useful to identify arrhythmogenic substrate.

Temporal stability and specificity of high bipolar electrogram entropy regions in sustained atrial fibrillation: Implications for mapping.

BACKGROUND: The potential utility of entropy (En) for atrial fibrillation (AF) mapping has been demonstrated in previous studies by multiple groups, where an association between high bipolar electrogram (EGM) entropy and the pivot of rotors has been shown. Though En is potentially attractive new approach to ablation, no studies have examined its temporal stability and specificity, which are critical to the application of entropy to clinical ablation. In the current study, we sought to objectively measure the temporal stability and specificity of bipolar EGM entropy in medium to long term recordings using three studies: i) a human basket catheter AF study, ii) a tachypaced sheep AF study and iii) a computer simulation study. OBJECTIVE: To characterize the temporal dynamics and specificity of Approximate, Sample and Shannon entropy (ApEn/SampEn/ShEn) in human (H), sheep (S), and computer simulated AF. METHODS: 64-electrode basket bi-atria sustained AF recordings (H:15 min; S:40 min) were separated into 5 s segments. ShEn/ApEn/SampEn were computed, and co-registered with NavX 3D maps. Temporal stability was determined in terms of: (i) global pattern stability of En and (ii) the relative stability the top 10% of En regions. To provide mechanistic insights into underlying mechanisms, stability characteristics were compared to models depicting various propagation patterns. To verify these results, cross-validation was performed across multiple En algorithms, across species, and compared with dominant frequency (DF) temporal characteristics. The specificity of En was also determined by looking at the association of En to rotors and areas of wave cross propagation. RESULTS: Episodes of AF were analysed (H:26 epochs, 6040 s; S:15 epochs, 14,160 s). The global pattern of En was temporally unstable (CV- H:13.42% ±â€¯4.58%; S:14.13% ±â€¯8.13%; Friedman- H: p > 0.001; S: p > 0.001). However, within this dynamic flux, the top 10% of ApEn/SampEn/ShEn regions were relatively temporally stable (Kappa >0.6) whilst the top 10% of DF regions were unstable (Kappa <0.06). In simulated AF scenarios, the experimental data were optimally reproduced in the context of an AF pattern with stable rotating waves surrounded by wavelet breakup (Kappa: 0.610; p < 0.0001). CONCLUSION: En shows global temporal instability, however within this dynamic flux, the top 10% regions exhibited relative temporal stability. This suggests that high En regions may be an appealing ablation target. Despite this, high En was associated with not just the pivot of rotors but also with areas of cross propagation, which suggests the need for future work before clinical application is possible.

Sympathetic and Parasympathetic Coactivation Induces Perturbed Heart Rate Dynamics in Patients with Paroxysmal Atrial Fibrillation.

BACKGROUND Recent evidence indicates that sympathetic/parasympathetic coactivation (CoA) is causally linked to changes in heart rate (HR) dynamics. Whether this is relevant for patients with atrial fibrillation (AF) is unknown. MATERIAL AND METHODS In patients with paroxysmal AF (n=26) and age-matched controls, (n=10) we investigated basal autonomic outflow and HR dynamics during separate sympathetic (cold hand immersion) and parasympathetic activation (O2-inhalation), as well as during CoA (cold face test). In an additional cohort (n=7), HR response was assessed before and after catheter-based pulmonary vein isolation (PVI). Ultra-high-density endocardial mapping was performed in patients (n=6) before and after CoA. RESULTS Sympathetic activation increased (control: 74±3 vs. 77±3 bpm, p=0.0098; AF: 60±2 vs. 64±2 bpm, p=0.0076) and parasympathetic activation decreased HR (control: 71±3 vs. 69±3 bpm, p=0.0547; AF: 60±1 vs. 58±2 bpm, p<0.0009), while CoA induced a paradoxical HR increase in patients with AF (control: 73±3 vs. 71±3 bpm, p=0.084; AF: 59±2 vs. 61±2 bpm, p=0.0006), which was abolished after PVI. Non-linear parameters of HR variability (SD1) were impaired during coactivation in patients with AF (control: 61±7 vs. 69±6 ms, p=0.042, AF: 44±32 vs. 32±5 ms, p=0.3929). CoA was associated with a shift of the earliest activation site (18±4 mm) of the sinoatrial nodal region, as documented by ultra-high-density mapping (3442±343 points per map). CONCLUSIONS CoA perturbs HR dynamics and shifts the site of earliest endocardial activation in patients with paroxysmal AF. This effect is abolished by PVI, supporting the value of emerging methods targeting the intrinsic cardiac autonomic nervous system to treat AF. CoA might be a valuable tool to assess cardiac autonomic function in a clinical setting.

Substrate characterization and catheter ablation in patients with scar-related ventricular tachycardia using ultra high-density 3-D mapping.

BACKGROUND: Ablation of scar-related ventricular tachycardia (VT), especially in noninducible VT or hemodynamically unstable patients, can be challenging. Thus, we evaluated feasibility of an ultra high-density 3-D mapping approach to characterize the ventricular substrate and, if possible, to map VT. METHODS AND RESULTS: Twenty-two patients (67 ± 2 years, mean LV-EF 36 ± 3%) with both ischemic and nonischemic cardiomyopathy and documented VT underwent mapping and catheter ablation using a 64-electrode mini-basket catheter. Substrate characterization included ultra high-density voltage maps, identification of areas of slow conduction and late potentials. Whenever VT was inducible activation mapping was performed. In 13 of 22 patients, the presumed clinical VT (in 16 of 22 any VT) was inducible. A total of 50 maps were generated (22 substrate maps, 28 during VT), mapping time was 33 ± 4 minutes, number of points was 10,937 ± 1,923. Low voltage areas were related with the site of origin in all mapped VT. Isochronal maps indicated areas of slow conduction in 14 of 22 patients, all in border zone scar. In 95% of patients, late potentials were found. Mapping time during VT was 9 ± 2 minutes, number of points 6,740 ± 1,140. Covered cycle length was 82 ± 5% (16 re-entry, 10 focal, and two undetermined). During 4 months follow-up, 90% remained free from VT recurrence. CONCLUSION: Ultra high-density mapping in patients with scar-related VT is feasible, safe and enables detailed insight into tachycardia mechanisms. Critical sites can be identified (1) by precise substrate characterization when VT is not inducible or hemodynamically not tolerated and (2) during short lasting episodes of VT in order to guide catheter ablation.

How disruption of endo-epicardial electrical connections enhances endo-epicardial conduction during atrial fibrillation.

Aims: Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions ('breakthroughs'). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability. Methods and Results: In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 ± 1.9 to 24.6 ± 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 ± 1.15 and 40.2 ± 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges. Conclusion: Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections.

Characterization, Mapping, and Ablation of Complex Atrial Tachycardia: Initial Experience With a Novel Method of Ultra High-Density 3D Mapping.

INTRODUCTION: Conventional mapping of complex atrial tachycardias (ATs) can be challenging. Thus, we evaluated feasibility and utility of a novel, ultra high-density 3D mapping approach to characterize and map AT in these cases. METHODS AND RESULTS: Overall, 21 patients (67.4 ± 7.6 years; male: 52.4%, 1.9 ± 1.4 previous ablation procedures) with documented AT referred to our center underwent catheter ablation including ultra high-density mapping using a novel 64-electrode mini-basket catheter and an adjunctive 3D mapping system. A total of 24 AT (20 left atrial, 4 right atrial AT) were analyzed in 19 cases. In 2 patients, map acquisition failed due to scarce local electrograms and unstable AT cycle length, respectively. Underlying mechanisms were focal (n = 3), as well as local (n = 8) and macro (n = 13) reentry tachycardias with a mean cycle length of 311.8 ± 67.7 milliseconds. The analysis of propagation waves, activation and voltage revealed complex activation patterns and allowed for the identification of critical sites of AT initiation or maintenance without the need for further mapping techniques. In all cases critical sites could be verified by successful consecutive ablation. Mean mapping time was 19.4 ± 7.6 minutes, mean number of mapping points was 19,217 ± 10,270. Radiofrequency application until first effect was 165.1 ± 374.2 seconds; total procedure time was 157.6 ± 51.4 minutes, fluoroscopy time 21.7 ± 13.8 minutes, and total radiofrequency duration 1,016 ± 951.9 seconds, respectively. No severe complications occurred. CONCLUSION: Ultra high-density mapping of complex AT is safe and feasible. Further, it enables detailed insight into AT mechanisms. Critical AT sites can be identified precisely in order to guide successful catheter ablation.

Simultaneous conduction mapping and intracellular membrane potential recording in isolated atria.

We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 × 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MΩ) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease.

Slowed atrial and atrioventricular conduction and depressed HRV in a murine model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disorder with diverse clinical outcomes including sudden death, heart failure, and stroke. Depressed heart rate variability (HRV), a measure of cardiac autonomic regulation, has been shown to predict mortality in patients with cardiovascular disease. Cardiac autonomic remodelling in animal models of HCM are not well characterised. This study analysed Gly203Ser cardiac troponin-I transgenic (TG) male mice previously demonstrated to develop hallmarks of HCM by age 21 weeks. 33 mice aged 30 and 50 weeks underwent continuous electrocardiogram (ECG) recording for 30 min under anaesthesia. TG mice demonstrated prolonged P-wave duration (P < 0.001) and PR intervals (P < 0.001) compared to controls. Additionally, TG mice demonstrated depressed standard deviation of RR intervals (SDRR; P < 0.01), coefficient of variation of RR intervals (CVRR; P < 0.001) and standard deviation of heart rate (SDHR; P < 0.001) compared to controls. Additionally, total power was significantly reduced in TG mice (P < 0.05). No significant age-related difference in either strain was observed in ECG or HRV parameters. Mice with HCM developed slowed atrial and atrioventricular conduction and depressed HRV. These changes were conserved with increasing age. This finding may be indicative of atrial and ventricular hypertrophy or dysfunction, and perhaps an indication of worse clinical outcome in heart failure progression in HCM patients.

Loss of Pace Capture on the Ablation Line During Pulmonary Vein Isolation versus "Dormant Conduction": Is Adenosine Expendable?

INTRODUCTION: Permanent pulmonary vein isolation (PVI) remains an essential goal of ablation therapy in patients with atrial fibrillation. Aim of this study was the intraindividual comparison of unexcitability to pacing along the ablation line versus dormant conduction (DC) as additional procedural endpoints. METHODS: A total of 58 patients with paroxysmal atrial fibrillation (PAF) underwent PVI by circumferential ablation of ipsilateral pulmonary veins (PVs), followed by testing for DC by adenosine administration. Irrespective of the presence of DC, pacing along the ablation line for left atrium capture was performed and additional radio frequency energy applied if necessary. PVs with initial DC were retested after achieving unexcitability. RESULTS: PVI was achieved in 224 of 224 PVs. In 33 of 224 PVs (15%) DC was revealed. At 92 of 112 ablation lines (82%) sites of excitability were found. Three (9%) of the initial 33 PVs with DC showed further DC after achieving unexcitability at repeated testing. Thirty-two of 33 assumed areas of unmasked PV-LA reconduction as revealed by DC-testing showed a corresponding site of excitability on the ablation line. After a follow-up of 11.6 ± 3.4 months 79% of patients were free of arrhythmia. CONCLUSIONS: Pacing for unexcitability can safely identify potential sites of DC and even sites that would have not been detected by testing for DC. Unexcitability, therefore, serves as a suitable and safe procedural endpoint not only for patients with contraindications to adenosine administration. Our data suggest that adenosine may be expendable when achieving unexcitability along the ablation line.

Reduction of Radiation Exposure in Atrial Fibrillation Ablation Using a New Image Integration Module: A Prospective Randomized Trial in Patients Undergoing Pulmonary Vein Isolation.

INTRODUCTION: Recently, a new image integration module (IIM, CartoUnivu™ Module) has been introduced to combine and merge fluoroscopy images with 3-dimensional-(3D)-electroanatomical maps (Carto® 3 System) into an accurate 3D view. The aim of the study was to investigate the influence of IIM on the fluoroscopy exposure during pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) in a prospective randomized trial. METHODS AND RESULTS: Between June and November 2014, a total of 60 patients with PAF (73.3% male, 64.0 ± 9.2 years), who underwent PVI with the endpoint of unexcitability of the ablation line, were randomized to either a conventional 3D mapping system (Carto® 3 System) or to an additional IIM on the basis of an assumed reduction of fluoroscopy exposure by the use of IIM. There were no significant differences in baseline characteristics. The median ablation procedure time was identical in both groups (140.7 ± 27.8 minutes vs. 140.8 ± 39.5 minutes; P = 0.851). A significant decrease of mean fluoroscopy time from 11.9 ± 2.1 to 7.4 ± 2.6 minutes (P < 0.0006) and median fluoroscopy dose from 882.9 to 476.5 cGycm(2) (P < 0.001) was achieved. The main reduction of radiation could be realized during creation of the 3D-map. No major complications occurred during the procedures. After a median follow-up of 125.7 ± 45.6 days 80% of the patients were free from any atrial arrhythmias. CONCLUSION: CartoUnivu™ module easily integrates into the workflow of PVI with the endpoint of unexcitability of the ablation line without prolonging the procedure time. It is associated with a marked reduction in fluoroscopic dose when compared to a conventional 3D mapping system.

Application of phase coherence in assessment of spatial alignment of electrodes during simultaneous endocardial-epicardial direct contact mapping of atrial fibrillation.

AIMS: Mapping and interpretation of wave conduction patterns recorded during simultaneous mapping of the electrical activity on both endocardial and epicardial surfaces are challenging because of the difficulty of reconstruction of reciprocal alignment of electrodes in space. Here, we suggest a method to overcome this difficulty using a concept of maximized endo-epicardial phase coherence. METHODS AND RESULTS: Endo-epicardial mapping was performed in six humans during induced atrial fibrillation (AF) in right atria using two sets of 8 × 8 electrode plaques. For each electrode, mean phase coherence (MPC) with all electrodes on the opposite side of the atrial wall was calculated. Localization error was defined as a distance between the directly opposing electrode and the electrode with the maximal MPC. Overall, there was a linear correlation between MPC and distance between electrodes with R(2) = 0.34. Localization error obtained for electrodes of the plaque in six patients resulted in a mean 2.3 ± 1.9 mm for 25 s electrogram segment length. Eighty-four per cent of the measurements resulted in error smaller than 3.4 mm. The duration of the recording used to compute MPC was negatively correlated with localization error; however, the effect reached plateau for segment durations longer than 15 s. CONCLUSION: Application of the concept of maximized endo-epicardial phase coherence to electrograms during AF allows reconstruction of reciprocal alignment of the electrodes on the opposite side of the atrial wall. This approach may be especially useful in settings where the spatial position of endo- and epicardial electrodes for intracardiac mapping cannot otherwise be determined.

Cardiovascular magnetic resonance of total and atrial pericardial adipose tissue: a validation study and development of a 3 dimensional pericardial adipose tissue model.

BACKGROUND: Recently pericardial adipose tissue (PAT) has been shown to be an independent predictor of atrial fibrillation (AF). Atrial PAT may influence underlying atrial musculature creating a substrate for AF. This study sought to validate the assessment of total and atrial PAT by standard cardiovascular magnetic resonance (CMR) measures and describe and validate a three dimensional atrial PAT model. METHODS: 10 merino cross sheep underwent CMR using a 1.5 Tesla system (Siemens, Sonata, Erlangen, Germany). Atrial and ventricular short axis (SA) images were acquired, using ECG -gated steady state free precession sequences. In order to quantify total volume of adipose tissue, a three dimensional model was constructed from consecutive end-diastolic images using semi-automated software. Regions of adipose tissue were marked in each slice followed by linear interpolation of pixel intensities in spaces between consecutive image slices. Total volume of adipose tissue was calculated as a total volume of the three dimensional model and the mass estimated from volume measurements. The sheep were euthanized and pericardial adipose tissue was removed and weighed for comparison to the corresponding CMR measurements. RESULTS: All CMR adipose tissue estimates significantly correlated with autopsy measurements (ICC > 0.80; p < 0.03). Intra- observer reliability in CMR measures was high, with 95% levels of agreement within 5.5% (ICC = 0.995) for total fat mass and its individual atrial (95% CI ± 8.3%, ICC = 0.993) and ventricular components (95% CI ± 6.6%, ICC = 0.989). Inter- observer 95% limits of agreement were within ± 10.7% (ICC = 0.979), 7.4% (ICC = 0.991) and 7.2% (ICC = 0.991) for atrial, ventricular and total pericardial adipose tissue, respectively. CONCLUSION: This study validates the use of a semi-automated three dimensional atrial PAT model utilizing standard (clinical) CMR sequences for accurate and reproducible assessment of atrial PAT. The measurement of local cardiac fat stores via this methodology could provide a sensitive tool to examine the regional effect of fat deposition on atrial substrate which potentially may influence AF ablation strategies in obese patients.

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.

Identification of Subclinical Heart Failure With Preserved Ejection Fraction in Patients With Symptomatic Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) commonly coexist. We hypothesize that patients with symptomatic AF but without overt clinical HF commonly exhibit subclinical HFpEF according to established hemodynamic criteria. OBJECTIVES: The authors sought to use invasive hemodynamics to investigate the prevalence and implications of subclinical HFpEF in AF ablation patients. METHODS: Consecutive symptomatic AF ablation patients were prospectively recruited. Diagnosis of subclinical HFpEF was undertaken by invasive assessment of left atrial pressure (LAP). Participants had HFpEF if the baseline mean LAP was >15 mm Hg and early HFpEF if the mean LAP was >15 mm Hg after a 500-mL fluid challenge. LA compliance was assessed invasively by monitoring the LAP and LA diameter during direct LA infusion of 15 mL/kg normal saline. LA compliance was calculated as Δ LA diameter/ΔLAP. LA cardiomyopathy was further studied with exercise echocardiography and electrophysiology study. Functional impact was evaluated using cardiopulmonary exercise testing and the AF Symptom Severity questionnaire. RESULTS: Of 120 participants, 57 (47.5%) had HFpEF, 31 (25.8%) had early HFpEF, and 32 (26.7%) had no HFpEF. Both HFpEF and early HFpEF were associated with lower LA compliance compared with those without HFpEF (P < 0.001). Participants with HFpEF and early HFpEF also displayed decreased LA emptying fraction (P = 0.004), decreased LA voltage (P = 0.001), decreased VO2peak (P < 0.001), and increased AF symptom burden (P = 0.002) compared with those without HFpEF. CONCLUSIONS: Subclinical HFpEF is common in AF ablation patients and is characterized by a LA cardiomyopathy, decreased cardiopulmonary reserve and increased symptom burden. The diagnosis of HFpEF may identify patients with AF with the potential to benefit from novel HFpEF therapies. (Characterising Left Atrial Function and Compliance in Atrial Fibrillation; ACTRN12620000639921).

Direction-dependent conduction abnormalities in the chronically stretched atria.

AIMS: There is increasing evidence of the role direction-dependent conduction plays in the arrhythmogenic interaction between ectopic triggers and abnormal atrial substrates. We thus sought to characterize direction-dependent conduction in chronically stretched atria. METHODS AND RESULTS: Twenty-four patients with chronic atrial stretch due to mitral stenosis and 24 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium, crista terminalis, and coronary sinus (CS) characterized direction-dependent conduction along linear catheters and across the crista terminalis. Bi-atrial electroanatomic maps were created in both sinus rhythm and an alternative wavefront direction by pacing from the distal CS. This allowed an assessment of conduction velocities, electrogram, and voltage characteristics during wavefronts propagating in different directions.  While differing wavefront directions caused changes in both chronic atrial stretch and reference patients (P< 0.001 for all), these direction-dependent changes were greater in chronic atrial stretch compared with reference patients, who exhibited greater slowing in conduction velocities (P= 0.09), prolongation of bi-atrial activation time (P= 0.04), increase in number (P< 0.001) and length (P< 0.001) of lines of conduction block, increase in fractionated electrograms (P< 0.001), and decrease in voltage (P= 0.08) during left-to-right compared with right-to-left atrial activation. These direction-dependent changes were associated with a greater propensity for chronically stretched atria to develop atrial fibrillation (P= 0.02). CONCLUSIONS: Atrial remodelling in chronic atrial stretch exacerbates physiological direction-dependent conduction characteristics. Our data suggest that the greater direction-dependent conduction seen in patients with chronic atrial stretch may promote arrhythmogenesis due to ectopic triggers from the left atrium.

Impact of Adenosine on Wavefront Propagation in Persistent Atrial Fibrillation: Insights From Global Noncontact Charge Density Mapping of the Left Atrium.

Background Adenosine shortens action potential duration and refractoriness and provokes atrial fibrillation. This study aimed to evaluate the effect of adenosine on mechanisms of wavefront propagation during atrial fibrillation. Methods and Results The study included 22 patients undergoing catheter ablation for persistent atrial fibrillation. Left atrial mapping was performed using the AcQMap charge density system before and after administration of intravenous adenosine at 1 or more of 3 time points during the procedure (before pulmonary vein isolation, after pulmonary vein isolation, and after nonpulmonary vein isolation ablation). Wave-front propagation patterns were evaluated allowing identification and quantification of localized rotational activation (LRA), localized irregular activation, and focal firing. Additional signal processing was performed to identify phase singularities and calculate global atrial fibrillation cycle length and dominant frequency. A total of 35 paired maps were analyzed. Adenosine shortened mean atrial fibrillation cycle length from 181.7±14.3 to 165.1±16.3, (mean difference 16.6 ms; 95% CI, 11.3-21.9, P<0.0005) and increased dominant frequency from 6.0±0.7 Hz to 6.6±0.8 Hz (95% CI, 0.4-0.9, P<0.0005). This was associated with a 50% increase in the number of LRA occurrences (16.1±7.6-24.2±8.1; mean difference 8.1, 95% CI, 4.1-12, P<0.0005) as well as a 20% increase in the number of phase singularities detected (30.1±7.8-36.6±9.3; mean difference 6.5; 95% CI, 2.6-10.0, P=0.002). The percentage of left atrial surface area with LRA increased with adenosine and 42 of 70 zones (60%) with highest density of LRA coincided with high density LRA zones at baseline with only 28% stable across multiple maps. Conclusions Adenosine accelerates atrial fibrillation and promotes rotational activation patterns with no impact on focal activation. There is little evidence that rotational activation seen with adenosine represents promising targets for ablation aimed at sites of stable arrhythmogenic sources in the left atrium.