Local Conduction Velocity Research Articles

Left Atrial Enhancement Correlates With Myocardial Conduction Velocity in Patients With Persistent Atrial Fibrillation.

BackgroundConduction velocity (CV) heterogeneity and myocardial fibrosis both promote re-entry, but the relationship between fibrosis as determined by left atrial (LA) late-gadolinium enhanced cardiac magnetic resonance imaging (LGE-CMRI) and CV remains uncertain.ObjectiveAlthough average CV has been shown to correlate with regional LGE-CMRI in patients with persistent AF, we test the hypothesis that a localized relationship exists to underpin LGE-CMRI as a minimally invasive tool to map myocardial conduction properties for risk stratification and treatment guidance.Method3D LA electroanatomic maps during LA pacing were acquired from eight patients with persistent AF following electrical cardioversion. Local CVs were computed using triads of concurrently acquired electrograms and were co-registered to allow correlation with LA wall intensities obtained from LGE-CMRI, quantified using normalized intensity (NI) and image intensity ratio (IIR). Association was evaluated using multilevel linear regression.ResultsAn association between CV and LGE-CMRI intensity was observed at scales comparable to the size of a mapping electrode: −0.11 m/s per unit increase in NI (P < 0.001) and −0.96 m/s per unit increase in IIR (P < 0.001). The magnitude of this change decreased with larger measurement area. Reproducibility of the association was observed with NI, but not with IIR.ConclusionAt clinically relevant spatial scales, comparable to area of a mapping catheter electrode, LGE-CMRI correlates with CV. Measurement scale is important in accurately quantifying the association of CV and LGE-CMRI intensity. Importantly, NI, but not IIR, accounts for changes in the dynamic range of CMRI and enables quantitative reproducibility of the association.

Histomolecular fibrotic profile and an extent of the atrial and ventricular electroanatomical substrate in patients with atrial fibrillation and heart failure

Abstract Background and purpose The aim of this pilot study was to investigate the association between an extent of the atrial and ventricular electroanatomical substrate, serum fibrotic biomarkers and histological and immune-histochemical myocardial characteristics in ipatients with atrial fibrillation and heart failure. Methods We prospectively analyzed electroanatomical ultra-high density bipolar maps (HDBM) in 72 patients with AF and CHF, who underwent circular pulmonary veins (PVs) isolation. LA areas outside PVs ostia with bipolar signals ≤0.75mV, associated with local conduction velocity delay were considered as EAS and measured. Relative area of low voltage zones in right (RV) and left ventricles (RV) with bipolar signals in range of 0,5–1,5 mV were also consistently measured. Endomyocardial biopsy samples were taken from low, mediate and high septal areas of RV; histological and immune-histochemical staining was performed and an extent of myocardial interstitial fibrosis (MIF) was calculated. Before the operation we measured plasma MMP2, MMP9, TIMP, MMPs/TIMPs, galectin 3 (Gal3), TGF, soluble ST2 and the cross-linked collagen I/III synthesis and degradation product levels. The patients were divided into groups according to their ejection fraction Simpson (EF) (groups 1: EF≥50%, groups 2: EF 40–49%, and groups 3: EF&amp;lt;40%). Results The data of electroanatomical mapping, serum biomarkers and myocardial expression are presented in the table. According to results of correlation analysis, an extent of LA EAS were correlated with Gal3 and PIIICP plasma level and Gal3 myocardial expression and MIF extent (Rs=0,40, 0,45 and 0,42 respectively). The relative extent of LV EAS was correlated with MMP9 serum level (Rs=0,38); LV volume (LVV) was correlated with sST2 serum level and RVV was correlated with CD 133 myocardial expression (Rs=0,42) (picture 1). The patients with lower EF had larger extent of the LA EAS, (group 3: 28±12.4% vs. 1: 17.7±11.6%, p=0.03), an extent of LV EAS and LVV (group 3: 8,4±4,5% vs. 1: 5,1±3,8% p=0.02; group 3 vs group 1 p=0,05 relatively),higher Gal3 plasma level (group 1: 7,1±2 vs. group 2: 8,9±1,5, p=0.05) and higher MIF extent (group 2: 134±56 vs. 3: 151±30 p=0.04) (picture 2). Conclusion Our data suggest that relative extent of LA EAS in patients with atrial fibrillation is associated with Gal3 plasma level and Gal3 myocardial expression; severity of myocardial remodeling is connected to CD 3/133 myocardial expression and myocardial interstitial fibrosis extent, especially in patients with HF with restricted LV ejection fraction. Funding Acknowledgement Type of funding source: None

Transmural conduction time in an early repolarization syndrome model.

In the pathological aspect of J wave syndrome, delayed depolarization is defined as the difference in local conduction velocity of the ventricular myocardium. If polymorphic ventricular tachycardia is induced without local conduction velocity heterogeneity, this contradicts the delayed depolarization theory. In the present study, the transmural conduction time at was evaluated at several transmural locations in a canine early repolarization model. The transmural pseudo-electrocardiogram and endocardial/epicardial action potentials were recorded from coronary-perfused canine left ventricular wedge preparations (n=18). The Ito agonist NS5806 (9-10 µM), Ca2+ channel blocker verapamil (2 µM) and acetylcholine (ACh) (2 µM) were used to pharmacologically mimic early repolarization syndrome genotypes. The transmural conduction times were measured at five fixed epicardial unipolar electrodes before and after the perfusion of provocative agents. The transmural conduction time was defined as the time from endocardial stimulation to the maximal negative deflection (dV/dt) of the endocardial electrogram at the unipolar electrode. Polymorphic ventricular tachycardia developed in 14/18 preparations. In the transmembrane action potentials, there was no definite delayed phase 0 upstroke in any induced polymorphic ventricular tachycardia preparations. In all preparations, the transmural conduction time increased significantly after perfusing the Ito agonist NS5806, verapamil and Ach; however, the increase was only 2.6±0.4 msec, and dispersion of the transmural conduction time did not exhibit significant heterogeneity (7.16±0.93 vs. 7.76±1.21 msec; P=0.240). In the early repolarization model, polymorphic ventricular tachycardia was induced without any regional conduction velocity heterogeneity. This finding suggests that local depolarization heterogeneity would not be a major contributor to the generation of ventricular arrhythmia in the early repolarization syndrome wedge preparation model.

An Uncertainty Modeling Framework for Intracardiac Electrogram Analysis.

Intracardiac electrograms (EGMs) are electrical signals measured within the chambers of the heart, which can be used to locate abnormal cardiac tissue and guide catheter ablations to treat cardiac arrhythmias. EGMs may contain large amounts of uncertainty and irregular variations, which pose significant challenges in data analysis. This study aims to introduce a statistical approach to account for the data uncertainty while analyzing EGMs for abnormal electrical impulse identification. The activation order of catheter sensors was modeled with a multinomial distribution, and maximum likelihood estimations were done to track the electrical wave conduction path in the presence of uncertainty. Robust optimization was performed to locate the electrical impulses based on the local conduction velocity and the geodesic distances between catheter sensors. The proposed algorithm can identify the focal sources when the electrical conduction is initiated by irregular electrical impulses and involves wave collisions, breakups, and spiral waves. The statistical modeling framework can efficiently deal with data uncertainties and provide a reliable estimation of the focal source locations. This shows the great potential of a statistical approach for the quantitative analysis of the stochastic activity of electrical waves in cardiac disorders and suggests future investigations integrating statistical methods with a deterministic geometry-based method to achieve advanced diagnostic performance.

P920Understanding arrhythmia mechanisms in patients with atrial septal defects

Abstract Background Atrial arrhythmias represent a major cause of morbidity and hospitalization in patients with atrial septal defects (ASD). Optimum treatment strategies are unknown since the mechanisms of arrhythmia are undefined in this cohort. Purpose We investigated whether percutaneous ASD closure reduces atrial arrhythmias and subsequently examined the electrical and structural changes underpinning arrhythmogenesis in ASD patients. Methods Meta-analysis was used to study the effect of closure on arrhythmias. Bi-atrial electrical dysfunction was assessed through invasive measurement of atrial voltage, refractory periods (ERP) over three drive trains (600, 450 and 300ms) and local conduction velocity (CV) with subsequent assessment of ERP and CV restitution. Structural remodelling was assessed through non-invasive quantification of fibrosis using cardiac MRI (CMR). Origin of ectopy was evaluated invasively using isoprenaline infusion and non-invasively using 24-hour Holter monitoring. Comparison was made to normal heart controls. Results Meta-analysis Meta-analysis of 25 studies found that percutaneous closure was associated with a weak reduction in atrial arrhythmias only in patients &amp;gt;40 years old (OR 0.777, 95% CI 0.616-0.979, P = 0.032). Electrical Remodelling On invasive assessment (21 ASDs; 21 controls), proportion of right atrial low voltage (&amp;lt;0.5mV) and scar (&amp;lt;0.05mV) was greater in ASD vs control patients (P = 0.02 and P = 0.039). In ASD patients, these parameters were greater in the right atrium vs the left atrium (P = 0.002 and P = 0.01). Right atrial ERP restitution slopes were steeper in ASD vs control patients (P = 0.016). Maximum right atrial CV and CV restitution slopes were greater in ASD vs control patients (P= 0.005 and P &amp;lt; 0.001 respectively) and CV decrement occurred at longer coupling intervals in the right atrium in ASD patients (P = 0.015). Structural Remodelling On CMR assessment (36 ASDs; 36 controls), bi-atrial fibrosis was greater in ASD vs control patients (P &amp;lt; 0.001). In ASD patients right atrial fibrosis was burden greater in patients with vs without atrial arrhythmias (P = 0.034). Arrhythmia Triggers On 24-hour Holter monitoring and during invasive isoprenaline infusion right and left atrial ectopy was equally prevalent in ASD vs control patients. Conclusion This study highlights the importance of right atrial electrical dysfunction to the occurrence of arrhythmias in ASD patients with extensive right atrial remodelling (fibrosis, low voltage, steeper ERP and CV restitution) seen in ASD patients compared to normal heart controls. From the results of the meta-analysis it appears that percutaneous closure alone is insufficient to treat arrhythmias in ASD patients. Given the predominance of right atrial remodelling, right-sided ablation as an adjunct to conventional left-sided ablation should be investigated as a strategy to treat atrial arrhythmias in these patients. Abstract Figure.

Mechanism and magnitude of bipolar electrogram directional sensitivity: Characterizing underlying determinants of bipolar amplitude

The amplitude of bipolar electrograms (EGMs) is directionally sensitive, decreasing when measured from electrode pairs oriented oblique to a propagating wavefront. The purpose of this study was to use a computational model and clinical data to establish the mechanism and magnitude of directional sensitivity. Simulated EGMs were created using a computational model with electrode pairs rotated relative to a passing wavefront. A clinical database of 18,740 EGMs with varying electrode separation and orientations was recorded from the left atrium of 10 patients with atrial fibrillation during pacing. For each EGM, the angle of incidence between the electrodes and the wavefront was measured using local conduction velocity (CV) mapping. A theoretical model was derived describing the effect of the changing angle of incidence, electrode spacing, and CV on the local activation time difference between a pair of electrodes. Model predictions were validated using simulated and clinical EGMs. Bipolar amplitude measured by an electrode pair is decreased (directionally sensitive) at angles of incidence resulting in local activation time differences shorter than unipolar downstroke duration. Directional sensitivity increases with closer electrode spacing, faster CV, and longer unipolar EGM duration. For narrowly spaced electrode pairs (<5 mm), it is predicted at all orientations. Directional sensitivity occurs because bipolar amplitude is reduced when the component unipolar EGMs overlap, such that neither electrode is "indifferent." At the electrode spacing of clinical catheters, this is predicted to occur regardless of catheter orientation. This suggests that bipolar directional sensitivity can be lessened but not overcome by recently introduced catheters with additional rotated electrode pairs.

Performance of Different Atrial Conduction Velocity Estimation Algorithms Improves with Knowledge about the Depolarization Pattern

Abstract Quantifying the atrial conduction velocity (CV) reveals important information for targeting critical arrhythmia sites that initiate and sustain abnormal electrical pathways, e.g. during atrial flutter. The knowledge about the local CV distribution on the atrial surface thus enhances clinical catheter ablation procedures by localizing pathological propagation paths to be eliminated during the intervention. Several algorithms have been proposed for estimating the CV. All of them are solely based on the local activation times calculated from electroanatomical mapping data. They deliver false values for the CV if applied to regions near scars or wave collisions. We propose an extension to all approaches by including a distinct preprocessing step. Thereby, we first identify scars and wave front collisions and provide this information for the CV estimation algorithm. In addition, we provide reliable CV values even in the presence of noise. We compared the performance of the Triangulation, the Polynomial Fit and the Radial Basis Functions approach with and without the inclusion of the aforementioned preprocessing step. The evaluation was based on different activation patterns simulated on a 2D synthetic triangular mesh with different levels of noise added. The results of this study demonstrate that the accuracy of the estimated CV does improve when knowledge about the depolarization pattern is included. Over all investigated test cases, the reduction of the mean velocity error quantified to at least 25 mm/s for the Radial Basis Functions, 14 mm/s for the Polynomial Fit and 14 mm/s for the Triangulation approach compared to their respective implementations without the preprocessing step. Given the present results, this novel approach can contribute to a more accurate and reliable CV estimation in a clinical setting and thus improve the success of radio-frequency ablation to treat cardiac arrhythmias.

Local Conduction Velocity in the Presence of Late Gadolinium Enhancement and Myocardial Wall Thinning: A Cardiac Magnetic Resonance Study in a Swine Model of Healed Left Ventricular Infarction.

Conduction velocity (CV) is an important property that contributes to the arrhythmogenicity of the tissue substrate. The aim of this study was to investigate the association between local CV versus late gadolinium enhancement (LGE) and myocardial wall thickness in a swine model of healed left ventricular infarction. Six swine with healed myocardial infarction underwent cardiovascular magnetic resonance imaging and electroanatomic mapping. Two healthy controls (one treated with amiodarone and one unmedicated) underwent electroanatomic mapping with identical protocols to establish the baseline CV. CV was estimated using a triangulation technique. LGE+ regions were defined as signal intensity >2 SD than the mean of remote regions, wall thinning+ as those with wall thickness <2 SD than the mean of remote regions. LGE heterogeneity was defined as SD of LGE in the local neighborhood of 5 mm and wall thickness gradient as SD within 5 mm. Cardiovascular magnetic resonance and electroanatomic mapping data were registered, and hierarchical modeling was performed to estimate the mean difference of CV (LGE+/-, wall thinning+/-), or the change of the mean of CV per unit change (LGE heterogeneity, wall thickness gradient). Significantly slower CV was observed in LGE+ (0.33±0.25 versus 0.54±0.36 m/s; P<0.001) and wall thinning+ regions (0.38±0.28 versus 0.55±0.37 m/s; P<0.001). Areas with greater LGE heterogeneity ( P<0.001) and wall thickness gradient ( P<0.001) exhibited slower CV. Slower CV is observed in the presence of LGE, myocardial wall thinning, high LGE heterogeneity, and a high wall thickness gradient. Cardiovascular magnetic resonance may offer a valuable imaging surrogate for estimating CV, which may support noninvasive identification of the arrhythmogenic substrate.

Multiple factors influence the morphology of the bipolar electrogram: An in silico modeling study.

Although bipolar electrograms (Bi-egms) are commonly used for catheter mapping and ablation of cardiac arrhythmias, the accuracy and reproducibility of Bi-egms have not been evaluated. We aimed to clarify the influence of the catheter orientation (CO), catheter contact angle (CA), local conduction velocity (CV), scar size, and catheter type on the Bi-egm morphology using an in silico 3-dimensional realistic model of atrial fibrillation. We constructed a 3-dimensional, realistic, in silico left atrial model with activation wave propagation including bipolar catheter models. Bi-egms were obtained by computing the extracellular potentials from the distal and proximal electrodes. The amplitude and width were measured on virtual Bi-egms obtained under different conditions created by changing the CO according to the wave direction, catheter-atrial wall CA, local CV, size of the non-conductive area, and catheter type. Bipolar voltages were also compared between virtual and clinically acquired Bi-egms. Bi-egm amplitudes were lower for a perpendicular than parallel CO relative to the wave direction (p<0.001), lower for a 90° than 0° CA (p<0.001), and lower for a CV of 0.13m/s than 0.48m/s (p<0.001). Larger sized non-conductive areas were associated with a decreased bipolar amplitude (p<0.001) and increased bipolar width (p<0.001). Among three commercially available catheters (Orion, Pentaray, and Thermocool), those with more narrowly spaced and smaller electrodes produced higher voltages on the virtual Bi-egms (p<0.001). Multiple factors including the CO, CA, CV, and catheter design significantly influence the Bi-egm morphology. Universal voltage cut-off values may not be appropriate for bipolar voltage-guided substrate mapping.

Association of regional myocardial conduction velocity with the distribution of hypoattenuation on contrast-enhanced perfusion computed tomography in patients with postinfarct ventricular tachycardia

Cardiac magnetic resonance imaging has been shown to be beneficial for identification of the ventricular tachycardia (VT) substrate before catheter ablation. Contrast-enhanced perfusion multidetector computed tomography (CEP-MDCT) is more generalizable to clinical practice, and wall thickness and regional hypoenhancement on CEP-MDCT can identify potential substrate sites, albeit with decreased specificity. The purpose of this study was to evaluate the association between wall thickness and attenuation on CEP-MDCT with local conduction velocity (CV) and electrogram abnormalities in patients with postinfarct VT. Fourteen patients with postinfarct VT underwent preprocedural CEP-MDCT followed by endocardial electroanatomic mapping (EAM) and ablation. Myocardial attenuation and wall thickness were calculated from 3-dimensional MDCT images using ADAS-VT software (Galgo Medical). EAM was registered with 3-dimensional MDCT images using the CartoMERGE module of CARTO3 software (Biosense Webster). Local CV was calculated by averaging the velocity between each point and 5 adjacent points with concordant wavefront direction. A total of 3689 points were included. In multivariable regression analysis clustered by patient, local CV was positively associated with myocardial attenuation, bipolar voltage, unipolar voltage, and wall thickness. Each 10-HU drop in full-thickness attenuation correlated to 2.6% decrease in CV (P <.001) and 5.5% decrease in bipolar voltage amplitude (P <.001), after adjusting for wall thickness. Myocardial attenuation distribution on CEP-MDCT is associated with regional CV and electrogram amplitude. Regions with low CV identified with low attenuation on CEP-MDCT may serve as important VT substrates in postinfarct patients.

A work flow to build and validate patient specific left atrium electrophysiology models from catheter measurements.

Biophysical models of the atrium provide a physically constrained framework for describing the current state of an atrium and allow predictions of how that atrium will respond to therapy. We propose a work flow to simulate patient specific electrophysiological heterogeneity from clinical data and validate the resulting biophysical models. In 7 patients, we recorded the atrial anatomy with an electroanatomical mapping system (St Jude Velocity); we then applied an S1-S2 electrical stimulation protocol from the coronary sinus (CS) and the high right atrium (HRA) whilst recording the activation patterns using a PentaRay catheter with 10 bipolar electrodes at 12 ± 2 sites across the atrium. Using only the activation times measured with a PentaRay catheter and caused by a stimulus applied in the CS with a remote catheter we fitted the four parameters for a modified Mitchell-Schaeffer model and the tissue conductivity to the recorded local conduction velocity restitution curve and estimated local effective refractory period. Model parameters were then interpolated across each atrium. The fitted model recapitulated the S1-S2 activation times for CS pacing giving a correlation ranging between 0.81 and 0.98. The model was validated by comparing simulated activations times with the independently recorded HRA pacing S1-S2 activation times, giving a correlation ranging between 0.65 and 0.96. The resulting work flow provides the first validated cohort of models that capture clinically measured patient specific electrophysiological heterogeneity.

LEFT ATRIAL ELECTROANATOMIC SUBSTRATE AS A PREDICTOR OF ATRIAL FIBRILLATION RECURRENCE AFTER CIRCULAR RADIOFREQUENCY PULMONARY VEINS ISOLATION. OBSERVATIONAL PROSPECTIVE STUDY RESULTS

Aim . To evaluate an extent of left arrial (LA) electroanatomical substrate (EAS) by the method of high density contact mapping in patients with atrial fibrillation (AF) and estimate its impact on recurrence rate following circular radiofrequency pulmonary veins (PV) isolation in prospective observational study. Material and methods. Totally 181 high symptomatic subjects with paroxysmal (142 pts) and persistent (39 pts) AF, who underwent circular RF PVI were enrolled. We created and prospectively analyzed LA electroanatomical high density bipolar maps. Bipolar signals ≤0.75mV, associated with local conduction velocity delay &lt;1 m/s were tagged on LA maps and considered as EAS. Relative EAS areas outside PV ostia were consistently measured. All of the patients were followed up at least for 3 years and AF recurrence rate and redo procedures were recorded. Results . A mean relative EAS area was 13.8±10.3% and 32.6±18.5% in patients with paroxysmal and persistent AF, respectively (P=0,02). During a mean follow-up of 32±7 months, AF recurrence was diagnosed in 69 (38%) of patients. Following a redo ablation in 51 (28%) of patients, subsequent AF recurrence developed in 31 pts (19%). Multivariate analysis showed that only relative EAS areas was independently associated with AF recurrence (HR 1.05, CI 95% 1.02-1.09, P=0.002) and ach 10% increase in the extent of relative EAS area was associated with a 1.6-fold elevation of AF recurrence rate after the index ablation. But the impact of the EAS on clinical outcome after redo ablation was even higher (HR =1,09, p=0,0018) and each 10% increase in the extent of relative EAS area was associated with a 2.4-fold elevation of AF recurrence rate after a redo ablation. Conclusion. The present study suggests that an extent of LA EAS in patients undergoing PVI — is a significant and independent predictor of AF recurrence. This data can have important role for further development and personalization of strategy of interventional treatment in patients with AF.

Atrial Conduction Velocity Correlates with Frequency Content of Bipolar Signal.

Anisotropy in conduction velocity (CV) is a key substrate abnormality influencing atrial arrhythmias. In skeletal muscle fibers, CV and frequency content of the surface electromyogram signal are directly related. We hypothesized that in human atria the frequency content of the bipolar signal, recorded on the endocardial surface, is directly related to the local CV. In 15 patients submitted to ablation of supraventricular arrhythmias, incremental pacing was performed through an octapolar catheter inserted into the coronary sinus (CS), alternatively from both extremities in two different sequences: CS bipole 1-2 as the pacing site and CS bipole 7-8 as the detection site in the first, and vice versa in the second. The pacing cycle length (PCL) was stepwise decreased from 600 ms to 500 ms, 400 ms, 300 ms, until 250 ms. Estimation of the CV was performed as the ratio between the distance traveled by the propagating pulse and the propagation time. The frequency distribution of the signal energy was estimated using the fast Fourier transform, and the characteristic frequency (CF) was estimated as the barycenter of the frequency spectrum. A total of 2,496 bipolar signals were analyzed; CV and CF were estimated and compared. The single patient and group data analysis showed a significant direct correlation between CV and CF of the local bipolar signal. Comparing the degree of spectral compression among signals registered in different points of the endocardial cardiac surface in response to decreasing PCL enables to map local differences in CV, a useful arrhythmogenic substrate index.

Virtualizing clinical cases of atrial flutter in a fast marching simulation including conduction velocity and ablation scars

Abstract Diagnosis of atrial flutter caused by ablation of atrial fibrillation is complex due to ablation scars. This paper presents an approach to replicate the clinically measured flutter circuit in a dynamic computer model. In a first step, important anatomical features of the flutter circuit are extracted manually based on the clinical measurement. With the help of this information, the electrical excitation propagation is simulated on the atrial geometry using the fast marching method. The simulated flutter circuit is used to estimate the global and local conduction velocity by approximating it iteratively. The parameterized flutter simulation is supposed to support the physician during diagnosis and treatment of atrial flutter.

Techniques for automated local activation time annotation and conduction velocity estimation in cardiac mapping

Measurements of cardiac conduction velocity provide valuable functional and structural insight into the initiation and perpetuation of cardiac arrhythmias, in both a clinical and laboratory context. The interpretation of activation wavefronts and their propagation can identify mechanistic properties of a broad range of electrophysiological pathologies. However, the sparsity, distribution and uncertainty of recorded data make accurate conduction velocity calculation difficult. A wide range of mathematical approaches have been proposed for addressing this challenge, often targeted towards specific data modalities, species or recording environments. Many of these algorithms require identification of activation times from electrogram recordings which themselves may have complex morphology or low signal-to-noise ratio. This paper surveys algorithms designed for identifying local activation times and computing conduction direction and speed. Their suitability for use in different recording contexts and applications is assessed.

Neuronally released vasoactive intestinal polypeptide alters atrial electrophysiological properties and may promote atrial fibrillation.

Vagal hyperactivity promotes atrial fibrillation (AF), which has been almost exclusively attributed to acetylcholine. Vasoactive intestinal polypeptide (VIP) and acetylcholine are neurotransmitters co-released during vagal stimulation. Exogenous VIP has been shown to promote AF by shortening action potential duration (APD), increasing APD spatial heterogeneity, and causing intra-atrial conduction block. The purpose of this study was to investigate the effects of neuronally released VIP on atrial electrophysiologic properties during vagal stimulation. We used a specific VIP antagonist (H9935) to uncover the effects of endogenous VIP released during vagal stimulation in canine hearts. H9935 significantly attenuated (1) the vagally induced shortening of atrial effective refractory period and widening of atrial vulnerability window during stimulation of cervical vagosympathetic trunks (VCNS) and (2) vagal effects on APD during stimulation through fat-pad ganglion plexus (VGPS). Atropine completely abolished these vagal effects during VCNS and VGPS. In contrast, VGPS-induced slowing of local conduction velocity was completely abolished by either VIP antagonist or atropine. In pacing-induced AF during VGPS, maximal dominant frequencies and their spatial gradients were reduced significantly by H9935 and, more pronouncedly, by atropine. Furthermore, VIP release in the atria during vagal stimulation was inhibited by atropine, which may account for the concealment of VIP effects with muscarinic blockade. Neuronally released VIP contributes to vagal effects on atrial electrophysiologic properties and affects the pathophysiology of vagally induced AF. Neuronal release of VIP in the atria is inhibited by muscarinic blockade, a novel mechanism by which VIP effects are concealed by atropine during vagal stimulation.

Reverse cardiac remodeling after renal denervation: Atrial electrophysiologic and structural changes associated with blood pressure lowering.

Hypertension is the most common modifiable risk factor associated with atrial fibrillation. The purpose of this study was to determine the effects of blood pressure (BP) lowering after renal denervation on atrial electrophysiologic and structural remodeling in humans. Fourteen patients (mean age 64 ± 9 years, duration of hypertension 16 ± 11 years, on 5 ± 2 antihypertensive medications) with treatment-resistant hypertension underwent baseline 24-hour ambulatory BP monitoring, echocardiography, cardiac magnetic resonance imaging, and electrophysiologic study. Electrophysiologic study included measurements of P-wave duration, effective refractory periods, and conduction times. Electroanatomic mapping of the right atrium was completed using CARTO3 to determine local and regional conduction velocity and tissue voltage. Bilateral renal denervation was performed, and all measurements repeated after 6 months. After renal denervation, mean 24-hour BP reduced from 152/84 mm Hg to 141/80 mm Hg at 6-month follow-up (P < .01). Global conduction velocity increased significantly (0.98 ± 0.13 m/s to 1.2 ± 0.16 m/s at 6 months, P < .01), conduction time shortened (32 ± 5 ms to 27 ± 6 ms, P < .01), and complex fractionated activity was reduced (37% ± 14% to 19% ± 12%, P = .02). Changes in conduction velocity correlated positively with changes in 24-hour mean systolic BP (R(2) = 0.55, P = .01). There was a significant reduction in left ventricular mass (139 ± 37 g to 120 ± 29 g, P < .01) and diffuse ventricular fibrosis (T1 partition coefficient 0.39 ± 0.07 to 0.31 ± 0.09, P = .01) on cardiac magnetic resonance imaging. BP reduction after renal denervation is associated with improvements in regional and global atrial conduction and reductions in ventricular mass and fibrosis. Whether changes in electrical and structural remodeling are solely due to BP lowering or are due in part to intrinsic effects of renal denervation remains to be determined.

High Correlation of Estimated Local Conduction Velocity with Natural Logarithm of Bipolar Electrogram Amplitude in the Reentry Circuit of Atrial Flutter

Low conduction velocity (CV) in the area showing low electrogram amplitude (EA) is characteristic of reentry circuit of atypical atrial flutter (AFL). The quantitative relationship between CV and EA remains unclear. We characterized AFL reentry circuit in the right atrium (RA), focusing on the relationship between local CV and bipolar EA on the circuit. We investigated 26 RA AFL (10 with typical AFL; 10 atypical incisional AFL; 6 atypical nonincisional AFL) using CARTO system. By referring to isochronal and propagation maps delineated during AFL, points activated faster on the circuit were selected (median, 7 per circuit). At the 196 selected points obtained from all patients, local CV measured between the adjacent points and bipolar EA were analyzed. There was a highly significant correlation between local CV and natural logarithm of EA (lnEA) (R(2) = 0.809, P < 0.001). Among 26 AFL, linear regression analysis of mean CV, calculated by dividing circuit length (152.3 ± 41.7 mm) by tachycardia cycle length (TCL) (median 246 msec), and mean lnEA, calculated by dividing area under curve of lnEA during one tachycardia cycle by TCL, showed y = 0.695 + 0.191x (where: y = mean CV, x = lnEA; R(2) = 0.993, P < 0.001). Local CV estimated from EA with the use of this formula showed a highly significant linear correlation with that measured by the map (R(2) = 0.809, P < 0.001). The lnEA and estimated local CV show a highly positive linear correlation. CV is possibly estimated by EA measured by CARTO mapping.

Localising re-entry in atrial fibrillation: Anatomical clues to the substrate of rotors

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Although AF prevalence is lower in Asian populations ( 1%) than in Caucasians, the absolute numbers of patients in Asia suggest that the overall disease burden attributable to AF may eclipse that found in Western countries [1]. To combat this surging regional AF epidemic, new strategies resting on a more detailed understanding of the AF pathophysiology will be needed. A fundamental challenge in the field is that arrhythmia dynamics during AF remain unclear, despite over a century of research [2]. AF has been hypothesised to involve a combination of local drivers, including re-entrant circuits known as rotors and focal sources, or due to multiple simultaneous re-entrant wavelets, with a related postulated role for endo-epicardial wavefront dissociation [3]. It is clear that AF arises in the context of electrophysiological and structural remodelling occurring in the context of clinical risk factors including aging, heart failure, valvular heart disease, sinus node disease, hypertension, obesity and obstructive sleep apnoea. These factors are known to modulate local conduction velocity, refractoriness and heterogeneity to create the critical substrate for AF arrhythmogenesis. Recently, increasing attention has been paid to the role of detailed muscular architecture of the atrium in providing the substrate for AF re-entrant circuits. The complex interlacing myoarchitecture of the atrium, whose detailed structure was first outlined by Papez [4], may provide a functional substrate for AF, even in the absence of disease. Specific attention has been focused on the histoanatomy of the pulmonary vein (PV)–posterior left atrium (LA) junction. Klos et al. identified source–sink mismatch at the PV–LA junction as a possible mechanism for wavebreak at the onset of AF in the sheep heart [5]. Simulation studies have further delineated the 3-dimensional nature of myofiber orientation as a critical player. In humans, the PV–LA junction and posterior LA have similarly been determined as locations for conduction delay and block, providing an intrinsic histologically pre-determined substrate for re-entry [6]. It is in this context, that the recent study of Matsuyama et al. sheds further light on the relationships between histoanatomy and atrial arrhythmogenesis [7]. This investigation used high-density optical mapping to study atrial flutter/atrial fibrillation in isolated rat hearts [7]. Atrial arrhythmia was induced in 15 of 19 hearts tested by programmed stimulation from the right atrium [7]. Atrial arrhythmia in this model was predominantly initiated by a common re-entrant mechanism, with conduction slowing and block at the left atrial roof, with rapid antegrade conduction along the coronary sinus, providing the basis for a re-entry on the posterior wall of the LA. For the first time, these findings were correlated with the intrinsic histology of the regions [7]. Myocyte density was reduced and fibrosis increased on the roof and posterior LA compared to the CS [7]. Myocytes in the LA roof had a broader distribution of cut lengths than in the CS, with more lateralised expression on

Inhibition of intercellular coupling stabilizes spiral-wave reentry, whereas enhancement of the coupling destabilizes the reentry in favor of early termination

Spiral-wave (SW) reentry is a major organizing principle of ventricular tachycardia/fibrillation (VT/VF). We tested a hypothesis that pharmacological modification of gap junction (GJ) conductance affects the stability of SW reentry in a two-dimensional (2D) epicardial ventricular muscle layer prepared by endocardial cryoablation of Langendorff-perfused rabbit hearts. Action potential signals were recorded and analyzed by high-resolution optical mapping. Carbenoxolone (CBX; 30 μM) and rotigaptide (RG, 0.1 μM) were used to inhibit and enhance GJ coupling, respectively. CBX decreased the space constant (λ) by 36%, whereas RG increased it by 22-24% (n = 5; P < 0.01). During centrifugal propagation, there was a linear relationship between the wavefront curvature (κ) and local conduction velocity (LCV): LCV = LCV(0) - D·κ (D, diffusion coefficient; LCV(0), LCV at κ = 0). CBX decreased LCV(0) and D by 27 ± 3 and 57 ± 3%, respectively (n = 5; P < 0.01). RG increased LCV(0) and D by 18 ± 3 and 54 ± 5%, respectively (n = 5, P < 0.01). The regression lines with and without RG crossed, resulting in a paradoxical decrease of LCV with RG at κ > ~60 cm(-1). SW reentry induced after CBX was stable, and the incidence of sustained VTs (>30 s) increased from 38 ± 4 to 85 ± 4% after CBX (n = 18; P < 0.01). SW reentry induced after RG was characterized by decremental conduction near the rotation center, prominent drift and self-termination by collision with the anatomical boundaries, and the incidence of sustained VTs decreased from 40 ± 5 to 17 ± 6% after RG (n = 13; P < 0.05). These results suggest that decreased intercellular coupling stabilizes SW reentry in 2D cardiac muscle, whereas increased coupling facilitates its early self-termination.