Left Ventricular Epicardial Surface Research Articles

Role of activation signatures in re-entrant ventricular tachycardia circuits.

Development of a rapid means to verify the ventricular tachycardia (VT) isthmus location from heart surface electrogram recordings would be a helpful tool for the electrophysiologist. Myocardial infarction was induced in 22 canines by left anterior descending coronary artery ligation under general anesthesia. After3-5 days, VT was inducible via programmed electrical stimulation at the anterior left ventricular epicardial surface. Bipolar VT electrograms were acquired from 196 to 312 recording sites using a multielectrode array. Electrograms were marked for activation time, and activation maps were constructed. The activation signal, or signature, is defined as the cumulative number of recording sites that have activated per millisecond, and it was utilized to segment each circuit into inner and outer circuit pathways, and as an estimate of best ablation lesion location to prevent VT. VT circuit components were differentiable by activation signals as: inner pathway (mean: 0.30 sites activating/ms) and outer pathway (mean: 2.68 sites activating/ms). These variables were linearly related (p < .001). Activation signal characteristics were dependent in part upon the isthmus exit site. The inner circuit pathway determined by the activation signal overlappedand often extended beyondthe activation map isthmus location for each circuit. The best lesion location estimated by the activation signal would likely block an electrical impulse traveling through the isthmus, to prevent VT in all circuits. The activation signal algorithm, simple to implement for real-time computer display, approximates the VT isthmus location and shape as determined from activation marking, and best ablation lesion location to prevent reinduction.

Dynamics of local unipolar electrograms during epicardial pulsed field ablation (PFA)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III Background The use of irreversible electroporation (IRE) as a method for cardiac ablation in the treatment of cardiac arrhythmias, known as Pulsed Field Ablation (PFA), has rapidly moved from preclinical studies to clinic. The reference indicator of acute lesion formation during cardiac ablation with thermal techniques consists in recording the local electrical activity changes. In the case of PFA, modifications in the electrical activity have been observed in areas that are not permanently damaged (reversible electroporation) but this is still poorly characterized. Of particular interest from a clinical perspective is to determine how and when the electrical activity of the reversible electroporation areas recovers after PFA. Purpose The purpose of this work was to simultaneously characterize the dynamic evolution of local electrograms after PFA in areas exposed to different levels of tissue damage. Methods High-density local unipolar electrograms were acquired at baseline, and continuously and during 60 min after each PFA application. The measurements were performed in different points of the right and left ventricular epicardial surface of 5 swine weighing 57±8 kg using an open-chest approach following the Principles of laboratory animal care" (NIH Publication no. 85-23 revised 1985). Under general anesthesia, a median sternotomy was made to create a surgical window. Unipolar electrograms were recorded using a 128-channel electrode matrix attached to the epicardial surface. For PFA ablation, a standard 8F, 3.5 mm tip monopolar catheter was positioned in the region corresponding to the center of the electrode array and a return electrode patch was attached to the back of the animals (see Fig. 1). At least 3 hours after the last ablation point, animals were euthanized and tissue was processed and stained with Triphenyltetrazolium Chloride (TTC) to assess acute lesion morphology. Results Our results show an immediate change in the morphology of unipolar electrograms: from basal biphasic electrograms to monophasic electrograms displaying a sudden ST-segment elevation (from 0.0±0.3 mV to 5.9±1.7mv; p&amp;lt;0.01), reduction in the R-S amplitude (from 3.4±3.3 mV to 0.3±0.2 mV; p&amp;lt;0.01) and reduction in the maximum derivative of the QRS-complex (from 3051±2473 mV/s to 394±242 mV/s; p&amp;lt;0.01). Interestingly, the extent and dynamics of the observed changes clearly depended on the ablation level (distance from the ablation point) (see Fig 2.). Conclusions Our observations confirmed that the electrical activity of the reversible electroporation area was also acutely modified while the recovery dynamics were different from the irreversible damaged areas. Our preliminary analysis suggests that the different recovery dynamics observed could help in differentiating between reversible and irreversible electroporation areas.

3D fusion between fluoroscopy angiograms and SPECT myocardial perfusion images to guide percutaneous coronary intervention

BackgroundPercutaneous coronary intervention (PCI) in stable coronary artery disease (CAD) is commonly triggered by abnormal myocardial perfusion imaging (MPI). However, due to the possibilities of multivessel disease, serial stenoses and variability of coronary artery perfusion distribution, an opportunity exists to better align anatomic stenosis with perfusion abnormalities to improve revascularization decisions. This study aims to develop a multi-modality fusion approach to assist decision-making for PCI. Methods and ResultsCoronary arteries from fluoroscopic angiography (FA) were reconstructed into 3D artery anatomy. Left ventricular (LV) epicardial surface was extracted from SPECT. The artery anatomy and epicardial surface were non-rigidly fused. The accuracy of the 3D fusion was evaluated via both computer simulation and real patient data. Simulated FA and MPI were integrated and then compared with the ground truth from a digital phantom. The distance-based mismatch errors between simulated fluoroscopy and phantom arteries were 1.86 ± 1.43 mm for left coronary arteries (LCA) and 2.21 ± 2.50 mm for right coronary arteries (RCA). FA and SPECT images in 30 patients were integrated and then compared with the ground truth from CT angiograms. The distance-based mismatch errors between the fluoroscopy and CT arteries were 3.84 ± 3.15 mm for LCA and 5.55 ± 3.64 mm for RCA. The presence of the corresponding fluoroscopy and CT arteries in the AHA-17-segment model agreed well with a Kappa value of 0.91 (CI 0.89-0.93) for LCA and a Kappa value of 0.80 (CI 0.67-0.92) for RCA. ConclusionsOur fusion approach is technically accurate to assist PCI decision-making and is clinically feasible to be used in the catheterization laboratory. Future studies are necessary to determine if fusion improves PCI-related outcomes.

Effects of sympatho-vagal interaction on ventricular electrophysiology and their modulation during beta-blockade

AimsThe effects of sympatho-vagal interaction on heart rate (HR) changes are characterized by vagal dominance resulting in accentuated antagonism. Complex autonomic modulation of ventricular electrophysiology may exert prognostic arrhythmic impact. We examined the effects of concurrent sympathetic (SNS) and vagus (VNS) nerve stimulation on ventricular fibrillation threshold (VFT) and standard restitution (RT) in an isolated rabbit heart preparation with intact dual autonomic innervation, with and without beta-blockade. Methods and resultsMonophasic action potentials were recorded from left ventricular epicardial surface of dual-innervated isolated heart preparations from New Zealand white rabbits (n = 18). HR, VFT and RT were measured during different stimulation protocols (Protocol 1: VNS-SNS; Protocol 2: SNS-VNS) involving low- and high-frequency stimulations. A sub-study of Protocol 2 was performed in the presence of metoprolol tartrate.In both protocols, HR changes were characterized by vagal-dominant bradycardic component, affirming accentuated antagonism. During concurrent high-frequency VNS (HV), SNS prevails in lowering VFT in a frequency-sensitive manner during low (LS) or high (HS)-frequency stimulations (HV-LS: −2.8 ± 0.8 mA; HV-HS: −4.0 ± 0.9 mA, p < .05 vs. HV), with accompanying steepening of relative RT slope gradients (HV-LS: 223.54 ± 37.41%; HV-HS: 295.20 ± 60.86%, p < .05 vs. HV). In protocol 2, low (LV) and high (HV) vagal stimulations during concurrent HS raised VFT (HS-LV: 1.0 ± 0.4 mA; HS-HV: 3.0 ± 0.6 mA, p < .05 vs HS) with associated flattening of RT slopes (HS-LV: 32.40 ± 4.97%;HS-HV: 38.07 ± 6.37%; p < .05 vs HS). Metoprolol abolished accentuated antagonism in HR changes, reduced VFT and flattened RT globally during SNS-VNS. ConclusionsAccentuated antagonism is absent in ventricular electrophysiological changes during sympatho-vagal interaction with sympathetic effect prevailing, suggesting a different mechanism at the ventricular level from heart rate effects. Metoprolol nullified accentuated antagonism with additional anti-fibrillatory effect beyond adrenergic blockade during sympatho-vagal stimulations.

Characterization of Electrical Activity in Post-myocardial Infarction Scar Tissue in Rat Hearts Using Multiphoton Microscopy.

Background: The origin of electrical behavior in post-myocardial infarction scar tissue is still under debate. This study aims to examine the extent and nature of the residual electrical activity within a stabilized ventricular infarct scar.Methods and Results: An apical infarct was induced in the left ventricle of Wistar rats by coronary artery occlusion. Five weeks post-procedure, hearts were Langendorff-perfused, and optically mapped using di-4-ANEPPS. Widefield imaging of optical action potentials (APs) on the left ventricular epicardial surface revealed uniform areas of electrical activity in both normal zone (NZ) and infarct border zone (BZ), but only limited areas of low-amplitude signals in the infarct zone (IZ). 2-photon (2P) excitation of di-4-ANEPPS and Fura-2/AM at discrete layers in the NZ revealed APs and Ca2+ transients (CaTs) to 500–600 μm below the epicardial surface. 2P imaging in the BZ revealed superficial connective tissue structures lacking APs or CaTs. At depths greater than approximately 300 μm, myocardial structures were evident that supported normal APs and CaTs. In the IZ, although 2P imaging did not reveal clear myocardial structures, low-amplitude AP signals were recorded at discrete layers. No discernible Ca2+ signals could be detected in the IZ. AP rise times in BZ were slower than NZ (3.50 ± 0.50 ms vs. 2.23 ± 0.28 ms) and further slowed in IZ (9.13 ± 0.56 ms). Widefield measurements of activation delay between NZ and BZ showed negligible difference (3.37 ± 1.55 ms), while delay values in IZ showed large variation (11.88 ± 9.43 ms).Conclusion: These AP measurements indicate that BZ consists of an electrically inert scar above relatively normal myocardium. Discrete areas/layers of IZ displayed entrained APs with altered electrophysiology, but the structure of this tissue remains to be elucidated.

Left ventricular access point determination for a coaxial approach to the mitral annular landing zone in transcatheter mitral valve replacement

IntroductionTo facilitate coaxial device deployment in transcatheter mitral valve replacement (TMVR), a coaxial approach to the mitral annular plane is needed. We sought to establish a method to determine an ‘orthogonal’ left ventricular (LV) access point for transapical TMVR and to quantitatively characterize its location in patients with severe mitral regurgitation using cardiac computed tomography. MethodsCardiac CT data sets of 54 patients with moderate-severe mitral regurgitation evaluated for potential TMVR were analyzed. The D-shaped mitral annular contour was segmented and a 2-dimensional annular plane was derived, allowing for subsequent definition of the perpendicularly oriented mitral annular trajectory. The ‘orthogonal’ LV access point was defined as the transection point of mitral trajectory with the LV epicardial surface. The location of the access point was quantified by its epicardial distance from the true apex and by the rotational offset from a 3-chamber view. ResultsLV access points orthogonal to the mitral annular plane were most frequently located in the anterolateral (n = 22, 40.7%) and anterior (n = 16, 29.6%), less frequently anteroseptal (n = 6, 11.1%) and inferolateral (n = 5, 9.3%) ventricular segment; none inferior or inferoseptal. The mean distance to the LV apex was 17.6 ± 7.7 mm. The mean forward rotational offset from the 3-chamber view was 96.4 ± 43.4°, relating to a mean forward rotational offset of 6.4 ± 43.4° in regard to a hypothetical, secondary 90° x-plane view. No significant difference between patients with degenerative mitral valve disease or functional mitral regurgitation was observed. ConclusionThe location of the LV access point that provides an orthogonal trajectory to the mitral annular plane exhibits relevant inter-individual variability. It is commonly not identical with the true apex, and frequently localized in the anterolateral or anterior ventricular segments.

On the efficiency and accuracy of the single equivalent moving dipole method to identify sites of cardiac electrical activation.

We have proposed an algorithm to guide radiofrequency catheter ablation procedures. This algorithm employs the single equivalent moving dipole (SEMD) to model cardiac electrical activity. The aim of this study is to investigate the optimal time instant during the cardiac cycle as well as the number of beats needed to accurately estimate the location of a pacing site. We have evaluated this algorithm by pacing the ventricular epicardial surface and inversely estimating the locations of pacing electrodes from the recorded body surface potentials. Two pacing electrode arrays were sutured on the right and left ventricular epicardial surfaces in swine. The hearts were paced by the electrodes sequentially at multiple rates (120-220bpm), and body surface ECG signals from 64 leads were recorded for the SEMD estimation. We evaluated the combined error of the estimated interelectrode distance and SEMD direction at each time instant during the cardiac cycle, and found the error was minimum when the normalized root mean square (RMS n ) value of body surface ECG signals reached 15% of its maximum value. The beat-to-beat variation of the SEMD locations was significantly reduced (p<0.001) when estimated at 15% RMS n compared to the earliest activation time (EAT). In addition, the 5-95% interval of the estimated interelectrode distance error decreased exponentially as the number of beats used to estimate a median beat increased. When the number of beats was 4 or larger, the 5-95% interval was smaller than 3.5mm (the diameter of a commonly used catheter). In conclusion, the optimal time for the SEMD estimation is at 15% of RMS n , and at that time instant a median beat estimated from 4 beats is associated with a beat-to-beat variability of the SEMD location that is appropriate for catheter ablation procedures.

3D Fusion of LV Venous Anatomy on Fluoroscopy Venograms With Epicardial Surface on SPECT Myocardial Perfusion Images for Guiding CRT LV Lead Placement

ObjectivesThe aim of this study was to develop a 3-dimensional (3D) fusion tool kit to integrate left ventricular (LV) venous anatomy on fluoroscopy venograms with LV epicardial surface on single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for guiding cardiac resynchronization therapy (CRT) LV lead placement. BackgroundLV lead position is important for CRT response. For LV lead placement into viable regions with late activation, it is important to visualize both LV venous anatomy and myocardium. MethodsMajor LV veins were manually identified on fluoroscopic venograms and automatically reconstructed into a 3D anatomy. 3D LV epicardial surface was extracted from SPECT MPI. SPECT-vein fusion that consisted of geometric alignment, landmark-based registration, and vessel-surface overlay was developed to fuse the 3D venous anatomy with the epicardial surface. The accuracy of this tool was evaluated using computed tomography (CT) venograms. LV epicardial surfaces and veins were manually identified on the CT images and registered with the SPECT image by an independent operator. The locations of the fluoroscopic and CT veins on the SPECT epicardial surfaces were compared using absolute distances on SPECT short-axis slice and the 17-segment model. ResultsTen CRT patients were enrolled. The distance between the corresponding fluoroscopic and CT veins on the short-axis epicardial surfaces was 4.6 ± 3.6 mm (range 0 to 16.9 mm). The presence of the corresponding fluoroscopic and CT veins in the 17-segment model agreed well with a kappa value of 0.87 (95% confidence interval: 0.82 to 0.93). The tool kit was used to guide LV lead placement in a catheter laboratory and showed clinical feasibility and benefit to the patient. ConclusionsA tool kit has been developed to reconstruct 3D LV venous anatomy from dual-view fluoroscopic venograms and to fuse it with LV epicardial surface on SPECT MPI. It is technically accurate for guiding LV lead placement by the 17-segment model and is feasible for clinical use in the catheterization laboratory.

Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts

Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity. The purpose of this study was to define the influence of selective block of INa-L on EAD- and DAD-mediated triggered ventricular tachycardia (VT) and ventricular fibrillation (VF) in intact hearts using (GS967), a selective and potent (IC50 = 0.13 ± 0.01 μM) blocker of INa-L. VT/VF were induced either by local aconitine injection (50 μg) in the left ventricular muscle of adult (3-4 months) male rats (N = 21) or by arterial perfusion of 0.1 mM hydrogen peroxide (H2O2) in aged male rats (24-26 months, N = 16). The left ventricular epicardial surface of the isolated-perfused hearts was optically mapped using fluorescent voltage-sensitive dye, and microelectrode recordings of action potentials were made adjacent to the aconitine injection site. The suppressive and preventive effects of GS967 (1 μM) against EAD/DAD-mediated VT/VF were then determined. Aconitine induced VT in all 13 hearts studied. Activation map (N = 6) showed that the VT was initiated by a focal activity arising from the aconitine injection site (cycle length [CL] 84 ± 12) that degenerated to VF (CL 52 ± 8 ms) within a few seconds. VF was maintained by multifocal activity with occasional incomplete reentrant wavefronts. Administration of GS967 suppressed the VT/VF in 10 of 13 hearts (P < .001). Preexposure to GS967 for 15 minutes before aconitine injection prevented initiation of VT/VF in 5 of 8 additional hearts (P < .02). VF reoccurred within 10 minutes on washout of GS967. Microelectrode recordings (N = 7) showed that VT/VF was initiated by EAD- and DAD-mediated triggered activity at CL of 86 ± 14 ms (NS from VT CL) that preceded the VF. GS967 shortened APD, flattened the slope of the dynamic APD restitution curve, and reduced APD dispersion from 42 ± 12 ms to 8 ± 3 ms (P < .01). H2O2 perfusion in eight fibrotic aged hearts promoted EAD-mediated focal VT/VF, which was suppressed by GS967 in five hearts (P < .02). The selective INa-L blocker GS967 effectively suppresses and prevents aconitine and oxidative stress-induced EADs, DADs, and focal VT/VF. Suppression of EADs, DADs, and reduction of APD dispersion make GS967 a potentially useful antiarrhythmic drug in conditions of enhanced INa-L.

A Geometrical Approach for Automatic Shape Restoration of the Left Ventricle

This paper describes an automatic algorithm that uses a geometry-driven optimization approach to restore the shape of three-dimensional (3D) left ventricular (LV) models created from magnetic resonance imaging (MRI) data. The basic premise is to restore the LV shape such that the LV epicardial surface is smooth after the restoration and that the general shape characteristic of the LV is not altered. The Maximum Principle Curvature () and the Minimum Principle Curvature () of the LV epicardial surface are used to construct a shape-based optimization objective function to restore the shape of a motion-affected LV via a dual-resolution semi-rigid deformation process and a free-form geometric deformation process. A limited memory quasi-Newton algorithm, L-BFGS-B, is then used to solve the optimization problem. The goal of the optimization is to achieve a smooth epicardial shape by iterative in-plane and through-plane translation of vertices in the LV model. We tested our algorithm on 30 sets of LV models with simulated motion artifact generated from a very smooth patient sample, and 20 in vivo patient-specific models which contain significant motion artifacts. In the 30 simulated samples, the Hausdorff distances with respect to the Ground Truth are significantly reduced after restoration, signifying that the algorithm can restore geometrical accuracy of motion-affected LV models. In the 20 in vivo patient-specific models, the results show that our method is able to restore the shape of LV models without altering the general shape of the model. The magnitudes of in-plane translations are also consistent with existing registration techniques and experimental findings.

Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells

Mesenchymal stem cells (MSCs) have been shown to improve cardiac electrophysiology when administered in the setting of acute myocardial infarction. However, the electrophysiological phenotype of MSCs in situ is not clear. We hypothesize that MSCs delivered intramyocardially to cryoinjured myocardium can engraft, but will not actively generate, action potentials. Cryoinjury-induced scar was created on the left ventricular epicardial surface of adult rat hearts. Within 30 min, hearts were injected with saline (sham, n = 11) or bone marrow-derived MSCs (2 × 10(6)) labeled with 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarbocyanine percholate (DiI; n = 16). At 3 wk, optical mapping and cell isolation were used to measure optical action potentials and calcium transients, respectively. Histological analysis confirmed subepicardial scar thickness and the presence of DiI-positive cells that express connexin-43. Optical action potential amplitude within the scar at MSC-positive sites (53.8 ± 14.3%) was larger compared with sites devoid of MSCs (35.3 ± 14.2%, P < 0.05) and sites within the scar of shams (33.5 ± 6.9%, P < 0.05). Evidence of simultaneous action potential upstroke, the loss of action potential activity following ablation of adjacent viable myocardium, and no rapid calcium transient response in isolated DiI+ cells suggest that the electrophysiological influence of engrafted MSCs is electrotonic. MSCs can engraft when directly injected into a cryoinjury and are associated with evidence of action potential activity. However, our results suggest that this activity is not due to generation of action potentials, but rather passive influence coupled from neighboring viable myocardium.

153 Ventricular pacing along individual branches of the coronary sinus using a quadripolar LV pacing lead

IntroductionCardiac resynchronisation therapy (CRT) usually involves placing the left ventricular (LV) pacing lead in the postero-lateral or lateral region of the LV epicardial surface as this is thought likely to...

Suppression of Re-Entrant and Multifocal Ventricular Fibrillation by the Late Sodium Current Blocker Ranolazine

The purpose of this study was to test the hypothesis that the late Na current blocker ranolazine suppresses re-entrant and multifocal ventricular fibrillation (VF). VF can be caused by either re-entrant or focal mechanism. Simultaneous voltage and intracellular Ca(+)² optical mapping of the left ventricular epicardial surface along with microelectrode recordings was performed in 24 isolated-perfused aged rat hearts. Re-entrant VF was induced by rapid pacing and multifocal VF by exposure to oxidative stress with 0.1 mM hydrogen peroxide (H₂O₂). Rapid pacing induced sustained VF in 7 of 8 aged rat hearts, characterized by 2 to 4 broad propagating wavefronts. Ranolazine significantly (p < 0.05) reduced the maximum slope of action potential duration restitution curve and converted sustained to nonsustained VF lasting 24 ± 8 s in all 7 hearts. Exposure to H₂O₂ initiated early afterdepolarization (EAD)-mediated triggered activity that led to sustained VF in 8 out of 8 aged hearts. VF was characterized by multiple foci, appearing at an average of 6.8 ± 3.2 every 100 ms, which remained confined to a small area averaging 2.8 ± 0.85 mm² and became extinct after a mean of 43 ± 16 ms. Ranolazine prevented (when given before H₂O₂) and suppressed H₂O₂-mediated EADs by reducing the number of foci, causing VF to terminate in 8 out of 8 hearts. Simulations in 2-dimensional tissue with EAD-mediated multifocal VF showed progressive reduction in the number of foci and VF termination by blocking the late Na current. Late Na current blockade with ranolazine is effective at suppressing both pacing-induced re-entrant VF and EAD-mediated multifocal VF.

003 Gap junctional uncoupling with carbenoxolone slows conduction and increases vulnerability to ventricular arrhythmias in structurally normal hearts: an optical mapping study

<h3>Background</h3> Gap junctional uncoupling is thought to contribute to arrhythmogenesis through its effects on conduction slowing and creation of heterogeneities, often in the context of action potential or structural abnormalities. However, it is uncertain as to whether moderate conduction slowing through gap junctional uncoupling on its own, in the absence of action potential or structural changes, is sufficient to be pro-arrhythmic. We used optical mapping: (1) to study the effects of carbenoxolone, a gap junction uncoupler, on conduction velocity and action potential duration, and (2) to assess the effects of moderate conduction slowing and gap junctional uncoupling on arrhythmia vulnerability in structurally normal hearts. <h3>Methods</h3> Normal rat hearts (n=12) were isolated and perfused with Krebs-Henseleit solution, then loaded with a voltage-sensitive dye (RH237) and perfused with an excitation-contraction uncoupler (10 μM blebbistatin) to eliminate motion artefact. Transmembrane voltage (V_m) transients were recorded using a 256-photodiode array and epicardial activation was mapped across the anterolateral left ventricle during ventricular pacing (stimulus 1 mA, cycle length 180 ms). Hearts were then perfused with 30 μM carbenoxolone (CBX; n=6) or control (n=6) for 30 min and epicardial activation mapped every 2 min. Subsequently, hearts were subjected to programmed ventricular stimulation with up to three extrastimuli and assigned an Inducibility Quotient depending on ease of arrhythmia inducibility. <h3>Results</h3> Carbenoxolone significantly slowed conduction across the left ventricular epicardial surface (Conduction velocity index: Baseline 100%, CBX 70% ± 2%, p&lt;0.01) whereas there was no change in conduction velocity in control hearts after 30 min (Baseline 100%, Controls 98%±3%, p=NS). Carbenoxolone did not affect action potential duration (Baseline: APD50: 52±2 ms, APD75: 70±3 ms, APD90: 90±3 ms; CBX: APD50: 54±4 ms; APD75: 74±6 ms; APD90: 94±5 ms; all p=NS). Inducibility of ventricular arrhythmias was significantly increased in CBX hearts compared with control hearts during programmed stimulation (Inducibility quotient: CBX: 5.0±1.0; Control: 2.5±1.0; p&lt;0.05). <h3>Conclusions</h3> Gap junctional uncoupling with carbenoxolone produced a 30% reduction in conduction velocity without changes in action potential duration, and resulted in increased arrhythmia vulnerability in structurally normal hearts. These results suggest that moderate conduction slowing produced by gap junctional uncoupling in isolation, that is, in the absence of changes in action potential duration or structural abnormalities, is sufficient to increase susceptibility to ventricular arrhythmias, and therefore highlight the importance of gap junctional uncoupling in ventricular arrhythmogenesis.

Successful catheter ablation of epicardial ventricular tachycardia worsened by cardiac resynchronization therapy

Soon after an upgrade from a single-chamber implantable cardioverter-defibrillator (ICD) to cardiac resynchronization therapy (CRT) with an ICD, a 64-year-old man with non-ischaemic cardiomyopathy began to have increasingly frequent ICD shocks for slow ventricular tachycardia (VT). At electrophysiological study, no clinical VT was induced by endocardial right ventricular pacing, but was easily induced by epicardial left ventricular (LV) pacing via a subxiphoid pericardial approach. The VT was successfully ablated on the LV epicardial surface. This case suggests that epicardial catheter ablation may be an alternative for managing CRT-induced proarrhythmias without the inactivation of LV pacing.

Ventricular Restraint Prevents Infarct Expansion and Improves Borderzone Function After Myocardial Infarction: A Study Using Magnetic Resonance Imaging, Three-Dimensional Surface Modeling, and Myocardial Tagging

Infarct expansion is associated with impaired borderzone function, adverse remodeling, and poor long-term prognosis. We hypothesized that left ventricular restraint early after myocardial infarction limits infarct expansion, preserves borderzone function, and reduces remodeling. We used an ovine model as well as high spatial and temporal resolution cardiac magnetic resonance imaging to quantify total and infarcted left ventricular epicardial surface area at baseline and 1 week and 12 weeks after anterior wall infarction in 10 animals. Five animals were randomly assigned to treatment with left ventricular restraint (Acorn cardiac support device) 1 week after infarction. Five animals were untreated controls. Total left ventricular surface area was measured by importing the end-diastolic magnetic resonance imaging-derived epicardial contours into custom software, which creates a three-dimensional surface from the two-dimensional magnetic resonance imaging contours. Infarct area was calculated from magnetic resonance imaging-detectable titanium markers placed at the infarct border. Borderzone radial and circumferential strains during systole were also assessed using myocardial tagging techniques as a measure of contractile function. The infarct area 1 week after infarction was 1,177 +/- 386 mm(2) in the control group and 1,124 +/- 427 mm(2) in the cardiac support device group. After 12 weeks, infarct area was 3,666 +/- 1,013 mm(2) in the control group and 1,227 +/- 301 mm(2) in the cardiac support device group. Borderzone systolic radial strain decreased from 12.6% +/- 0.77% to 3.6% +/- 0.3% after infarction in the control group and 13.7% +/- 0.87% to 4.7% +/- 0.3% in the cardiac support device group. At 12 weeks after infarction, radial strain was 3.4% +/- 0.5% in the control group and 6.7% +/- 0.4% in the cardiac support device group. Early postinfarction left ventricular restraint limits infarct expansion and improves borderzone contractile function.

Remote Magnetic Navigation to Guide Endocardial and Epicardial Catheter Mapping of Scar-Related Ventricular Tachycardia

The present study examines the safety and feasibility of using a remote magnetic navigation system to perform endocardial and epicardial substrate-based mapping and radiofrequency ablation in patients with scar-related ventricular tachycardia (VT). Using the magnetic navigation system, we performed 27 procedures on 24 consecutive patients with a history of VT related to myocardial infarction, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, or sarcoidosis. Electroanatomic mapping of the left ventricular, right ventricular, and ventricular epicardial surfaces was constructed in 24, 10, and 12 patients, respectively. Complete-chamber VT activation maps were created in 4 patients. A total of 77 VTs were inducible, of which 21 were targeted during VT with the remotely navigated radiofrequency ablation catheter alone. With a combination of entrainment and activation mapping, 17 of 21 VTs (81%) were successfully terminated in a mean of 8.4+/-8.2 seconds; for the remainder, irrigated radiofrequency ablation was necessary. The mean fluoroscopy times for endocardial and epicardial mapping were 27+/-23 seconds (range, 0 to 105 seconds) and 18+/-18 seconds (range, 0 to 49 seconds), respectively. In concert with a manually navigated irrigated ablation catheter, 75 of 77 VTs (97%) were ultimately ablated. Four patients underwent a second procedure for recurrent VT, 3 with the magnetic navigation system. After 1.2 procedures per patient, VT did not recur during a mean follow-up of 7+/-3 months (range, 2 to 12 months). The present study demonstrates the safety and feasibility of remote catheter navigation to perform substrate mapping of scar-related VT in a wide range of disease states with a minimal amount of fluoroscopy exposure.

Direct measurements of membrane time constant during defibrillation strength shocks

Defibrillation shocks impose significant energy demand on implantable cardioverter-defibrillators (ICDs). Several modeling studies have been devoted to optimizing shock parameters, and a large number of these studies treat the heart as a simplified lumped network. The time constant of membrane polarization (tau(m)) is a key variable for such modeling efforts. The purpose of this study was to perform direct measurements of transmembrane potential (V(m)) during defibrillation strength shocks and estimate tau(m) of membrane polarization. A portion of the left ventricular epicardial surface of Langendorff-perfused rabbit hearts was stimulated using uniform electric fields produced by two parallel line electrodes. The V(m)s were recorded from di-4-ANEPPS-stained hearts using a multisite optical mapping system. The hearts were paced with 20 S1 pulses from the apex, and shocks (S2: 5, 10, 20 V/cm) were applied via the line electrodes during the action potential of the 20th S1 at two different coupling intervals (S1S2: 120 and 180 ms). Residual responses were obtained by subtracting responses to the 19th S1 from the responses to the 20th S1S2 pair and used for time-constant analysis by fitting a monoexponential function. tau(m) exhibited a large variation and ranged from approximately 1 to 30 ms. Furthermore, tau(m) varied with electric field strength, S1S2 interval, position of the tissue from stimulating electrodes, and polarity of the response. To a large extent, the effects of all these factors were captured in a single parameter-the change in transmembrane voltage (DeltaV(m)) in response to the applied field (E). tau(m) showed a monotonically decreasing trend with DeltaV(m) for all Es and S1S2s. Time constant of membrane polarization varies significantly during defibrillation strength shocks and shows a strong dependence on DeltaV(m).

Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in ΔKPQ Scn5a Mice

Gain-of-function mutations within Scn5a, including the DeltaKPQ 1505-1507 deletion in the inactivation domain compromising myocardial repolarization, are implicated in human long QT 3 syndrome (LQT3), associated with ventricular arrhythmogenesis and sudden death. Patch clamp studies on isolated ventricular Scn5a+/Delta myocytes from DeltaKPQ mice produced by homologous recombination in embryonic stem (ES) cells confirmed such altered electrophysiological properties of the mutant channel. Programmed electrical stimulation (PES) with decremental pacing from the basal right ventricular epicardial surface and paced electrogram fractionation analysis (PEFA) of electrograms recorded from the basal left ventricular epicardial surface of Langendorff-perfused whole heart preparations demonstrated ventricular tachycardia (VT) in 8 of 9 Scn5a+/Delta mutant (but no Scn5a+/+ (wild-type (WT)) controls; n = 17), with increased electrogram durations (EGD) and more dispersed conduction curves. Isoproterenol (100 nM) was without effect on tachycardic Scn5a+/Delta hearts (n = 9) yet propranolol (1 microM) prevented VT in all isoproterenol-infused WT control (n = 4) but no Scn5a+/Delta hearts (n = 4). Furthermore propranolol itself increased EGD and dispersion in Scn5a+/Delta hearts. In contrast, mexiletine (10 microM) suppressed VTs in 4 of 5 Scn5a+/Delta hearts without altering EGD or dispersion. Beta-adrenoreceptor blockade does not confer an antiarrhythmic effect and may even enhance arrhythmogenesis by increasing reentrant substrate in Scn5a+/Delta hearts while mexiletine protects against VT without modifying conduction characteristics. Together these findings permit a scheme where VT in LQT3 is initiated by triggered mechanisms but propagated by reentry.

Voltage-sensitive dye mapping of activation and conduction in adult mouse hearts.

A custom-made apparatus based on a charge-coupled-device camera has been used to monitor changes in fluorescence from Langendorff-perfused adult mouse hearts stained with a voltage-sensitive dye, di-4-ANEPPS. With this approach it is possible to monitor activation of the ventricles at high temporal (375 micros/frame) and spatial resolution (72 x 78 pixels, 100 x 100 microm/pixel). In sinus rhythm, activation occurred with a complicated breakthrough pattern on both ventricles, and a total activation time of 3.51+/-0.16 ms (32 degrees C). A stimulus applied near the apex of the left ventricle resulted in a single activation wave front with a total activation time of 8.18+/-0.25 ms. Pacing from a site near the middle of the left ventricular epicardial surface revealed anisotropic conduction, indicating that conduction occurs preferentially in the direction of the predominant fiber orientation. The total activation time in this configuration was 5.44+/-0.24 ms. The difference in total activation time between sinus rhythm and epicardial stimulation suggests an important role for transmural conduction (the Purkinje system) in the mouse heart. These findings provide much of the necessary background needed for studying conduction abnormalities in genetically altered mice and suggest that the comparison of sinus rhythm and epicardial pacing can be used to reveal transmural conduction abnormalities.