Supported in part by NHLBI Grants P01-HL039707 and P01-HL087226 and the Leducq Foundation (J.J. and O.B.), by a Spanish Society of Cardiology Fellowship, Fundaci&oacute;n Pedro Barri&eacute; de la Maza and Fundaci&oacute;n Alfonso Mart&iacute;n Escudero (D.F.R.), by F&eacute;d&eacute;ration Fran&ccedil;aise de Cardiologie (R.P.M.), by a Heart Rhythm Society fellowship Award, The Fellowship of Japan Heart Foundation/The Japanese Society of Electrocardiology (M.Y.).

1. Heart removal and Langendorff perfusion
 Sheep weighing 35-40 Kg are anesthetized using 4-6 mg/Kg propofol and 60-100 mg/Kg of sodium pentobarbital. Hearts are removed via thoracotomy and connected to a Langendorff-perfusion system with circulating oxygenated (95% O2, 5% CO2) Tyrode's solution at a constant flow rate of 240-270 ml/min, pH 7.4 and 35.5-37.5 &deg;C. The Tyrode's composition (in mM) is: NaCl 130, KCl 4.0, MgCl2 1, CaCl2 1.8, NaHCO3 24, NaH2PO4 1.2, Glucose 5.6, and Albumin 0.04 g /L. Blebbistatin 10 &mu;M (Enzo Life Science International, INC. Plymouth Meeting, PA, USA) is used to reduce the contractile force.
2. Stretch-induced atrial fibrillation in the Langendorff-perfused sheep heart
 The isolated, coronary perfused heart undergoes an atrial trans-septal puncture to enable equalized intracavitary pressure in both atria. All vein orifices are then sealed, except the inferior vena cava, which is cannulated and connected to a digital sensor (Biopac Systems transducer-TSD104A; Biopac Systems, Inc., Goleta, CA, USA) and to an outflow cannula whose open-ended height above the atria controls the intra-atrial pressure. The pressure is then increased to 12 cm H2O, which leads to a ~30% increase in atrial volume relative to the volume at 6 cm H2O. The pressure is maintained stable throughout the experiment. Prior to sealing the veins tetrapolar electrode catheters (Torq, Medtronic Inc./Minneapolis/MN/USA) are placed in each of the pulmonary veins to record bipolar signals from the two distal electrodes (sampling rate, 1.0 kHz) using a Biopac Systems amplifier (DA100C; Biopac Systems, Inc., Goleta, CA, USA). Two additional custum-made bipolar electrodes are placed on the roof of left atrial appendage (LAA) and the top of right atrial appendage. 
 3. Optical mapping set up
<ol>
<li> Epicardial mapping of the left atrial appendage. A bolus injection of 5 to 10 ml Di-4-ANEPPS (10 mg/mL) (Sigma-Aldrich, St. Louis, MO, USA) and a loading period of 10 min are needed to obtained voltage-sensitive fluorescence upon laser excitation (532 nm) of the epicardial surface. The emitted fluorescence is then transmitted through a 600 nm long pass filter and projected onto LittleJoe CCD video camera (80x80 pixels, SciMeasure Analytical Systems, Inc. Decatur, GA, USA) and acquired at a rate of 800 frames per second (See schematic representation on Figure 1A). Five-second movies are obtained at 2 min intervals during AF. The area of the mapped epicardial surface is ~14 cm2.</li>
<li> Endocardial optical mapping of the PLA of the intact heart. A second LittleJoe CCD camera (80x80 pixels) is synchronized with the epicardial camera. A 10 mm diameter dual-channel rigid borescope (Everest VIT, Inc. Flanders, NJ, USA) with a 90-degree field of view is introduced through the anterior wall of the left ventricle, across the mitral valve and focused on the endocardial surface of the PLA. The optically mapped area on the PLA is ~4 cm2, which allows visualizing the four pulmonary veins and the atrial septo-pulmonary bundle (Figure 1A, B). The borescope is c-mounted to the CCD camera through a custom-made eyepiece adapter. Laser 532 nm light is then delivered to the excitation channel of the borescope through a liquid light-guide (0.2 in core).</li>
</ol>
4. Atrial fibrillation protocol
 Under continuous atrial stretch AF is induced via burst pacing (12 Hz, 5 ms pulses, 2x diastolic threshold) by a pacing electrode located on top of the LAA. AF is allowed to continue for 50 minutes and 5-sec optical movies are acquired at two min intervals. Bipolar recordings are collected continuously. Acquisition of the optical movies triggers simultaneous acquisition of 5-sec segments of the bipolar recordings. 
5. Frequency analysis
 Frequency analysis allows identification of regions with high activation rate during AF, along with frequency gradients between left and right atrium. Dominant frequency (DF) maps are obtained from each optical movie after applying a fast Fourier transform algorithm (FFT) to the time-series fluorescence signal recorded at each pixel.7 FFT is also applied to the 5 second bipolar signals (High-pass filtered at 3 Hz and low-pass filtered at 35 Hz) synchronized with the optical movies.
6. Atrial fibrillation dynamics
<ol>
<li> Generation of phase maps. Analysis of AF dynamics takes advantage of phase movies generated via Hilbert transformation.14 Briefly, the instantaneous phase of the action potential recorded at each pixel is determined by transforming the original time-series signals such that every spectral component is shifted by its corresponding quarter cycle.15 Afterwards, the instantaneous phase of the signal is obtained from the inverse tangent of the ratio of the transformed signal to the original signal. The phase angle, with values between -&pi; and &pi; radians is represented as a continuous color scheme to construct a phase map, in which the continuous spatial phase change reflects the process of excitation, repolarization and recovery.14</li>
<li> Characterization of activation patterns. Various classes of activation patterns can be identified using phase movies (Figure 2), including the following:
<ul> 
	<li>A rotor is identified by the presence of all phases converging on a singularity point lasting more than one rotation (Figure 2A). </li>
	<li>A breakthrough is defined as a wavefront appearing in the field of view and propagating outward (Figure 2B) in a target-like pattern.</li>
	<li>Spatiotemporally organized periodic waves are defined as a minimum of four sequential periodic waves emerging from the same location in the field of view, with similar direction and inter-wave interval (Figure 2C).</li>
</ul>
</li>
</ol>
Further quantification allows spatial correlation of highest frequency domains with the most common pattern of activation obtained from that particular region. The latter highlights the crucial role of mapping the endocardial surface of the PLA, since it commonly represents the region where the highest frequency domains are located during acute AF.
7. Representative Results:
Dominant frequency (DF) gradients from PLA to LAA and RAA are present during acute stretch-induced AF. The highest DF region is localized either at or near one of the pulmonary veins or somewhere in the PLA.11 A representative AF episode is shown in Figure 3, in which the highest DF is localized on the PLA (Right inferior pulmonary vein). The results support the presence of high frequency sources in the PLA driving AF consistent with the left to right DF gradients observed during ablative procedures in paroxysmal human AF.16
Quantification of patterns of activation using phase map movies shows that the highest number of rotors is found at the PLA and the junction between the PLA and the LAA.8 Occasionally it is possible to identify long-lasting rotors whose center of rotation (Singularity point) localizes with the highest frequency domain.10 Since atrial tissue represents a three-dimensional structure, identifying rotors on the mapped endocardial surface of the PLA suggests that the center of rotation of those rotors (filament) is eventually perpendicular to the surface of the mapping area. Figure 4 shows such a rotor recorded from the endocardium of the PLA with simultaneous fibrillatory conduction toward the LAA, which also correlates with a frequency gradient between the PLA and the LAA (9 and 6.4 Hz respectively). The number of rotors is consistently higher at the PLA than the LAA, which suggests an essential role of reentry on the PLA to maintain the arrhythmia in this model. 
Overall, the results support the theory that stable and fast rotors in the left atrium may drive acute stretch-induced AF and emanating waves undergo complex, spatially distributed conduction block patterns as they head toward the right atrium, manifesting as fibrillatory conduction and progressively decreasing dominant frequency.

<img src="/files/ftp_upload/3103/3103fig1.jpg" alt="Figure 1" /> 
Figure 1. Diagrammatic representation of the experimental set up. A: A rigid borescope is introduced through the anterior wall of the left ventricle and the mitral valve orifice and focused on the endocardial surface of the posterior left atrium (PLA). A CCD camera is coupled to the borescope and laser illumination is provided through a laser liquid guide connected to the inferior part of the borescope. Epicardial mapping is performed on the LAA. Bipolar electrodes are placed on right atrium and roof of the left atrium. Additional bipolar signals are obtained from the pulmonary veins. B: Lateral view of the left atrium following opening the lateral wall for illustration purposes. The tip of the borescope illuminates the endocardial surface of the PLA. A bipolar electrode is located on the roof of the left atrium. LAA: left atrial appendage. LV: left ventricle. RA: right atrium. RV: right ventricle. 


<img src="/files/ftp_upload/3103/3103fig2.jpg" alt="Figure 2" /> 
Figure 2.Different patterns of activation identified after the generation of phase movies. A: Sequential snap shots of the left atrial appendage (LAA) show the pivoting of a rotor around its center of rotation (Singularity point). From left to right, one full rotation is completed. B: A sample breakthrough activation pattern on the LAA. The wave appears on the upper right corner of the field of view and propagates outward. C: Four spatiotemporally organized periodic waves (At 0, 182, 352 and 512 ms, respectively) coming from the PLA region toward the LAA. Isochrones are plotted at 10 ms intervals. Bottom, key for the different phases of the action potential is color-coded. 


<img src="/files/ftp_upload/3103/3103fig3.jpg" alt="Figure 3" /> 
Figure 3. Identification of the regions with the highest frequency activity during acute stretch-induced AF in a Langendorff-perfused isolated sheep heart. A: Anatomical view of the left atrial appendage (LAA), right atrial appendage (RAA) and posterior left atrium (PLA). PLA image is an endoscopic view of the mapped region with the four pulmonary veins (PVs). B: DF maps obtained by optical mapping on the LAA and PLA. Frequency value in the RAA was obtained from bipolar electrograms. The highest frequency region is located in the PLA. C: Representative power spectra, in which the maximum DF corresponds to 12.4 Hz at the PLA region of the right PVs. LSPV: left superior pulmonary vein. LIPV: left inferior pulmonary vein. RSPV: right superior pulmonary vein. RIPV: right inferior pulmonary vein. Reproduced from reference 11 (David Filgueiras Rama &amp; Jos&eacute; Jalife. Mechanisms Underlying Atrial Fibrillation. in Basic Science for Clinical Electrophysiologist, Vol. 3 (ed. Charles Antzelevitch) 141-156 (SAUNDERS, 2011).

<img src="/files/ftp_upload/3103/3103fig4.jpg" alt="Figure 4" /> 
Figure 4. Simultaneousphase maps (A, B) and dominant frequency maps (C) from posterior left atrium (PLA) and left atrial appendage (LAA). A: Sequential snap shots from the PLA showing a rotor and the drifting of its singularity point. B: Simultaneous phase snap shots from the LAA. Patterns of activation show propagation waves compatible with fibrillatory conduction. Singularity points are also present in correlation with wavebreaks in the fibrillatory conduction region. (See also video 4) C: Simultaneous dominant frequency maps from the PLA and the LAA. The fastest region is located at the PLA (9 Hz), which correlates with the presence of a rotor in the phase map analysis. The highest frequency at the LAA is 6 Hz, which correlates with fibrillatory conduction. On the right side of panel C, single pixel optical activations from PLA and LAA are shown.

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	<li>Kannel, W. B., Wolf, P. A., Benjamin, E. J., Levy, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prevalence,+incidence,+prognosis,+and+predisposing+conditions+for+atrial+fibrillation:+population-based+estimates.">Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates.</a> Am J Cardiol. 82, (1998).</li><li>Wolf, P. A., Abbott, R. D., Kannel, W. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Atrial+fibrillation+as+an+independent+risk+factor+for+stroke:+the+Framingham+Study.">Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.</a> Stroke. 22, 983-988 (1991).</li><li>Miyasaka, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Secular+trends+in+incidence+of+atrial+fibrillation+in+Olmsted+County,+Minnesota,+1980+to+2000,+and+implications+on+the+projections+for+future+prevalence.">Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.</a> Circulation. 114, 119-125 (1980).</li><li>Ravelli, F., Allessie, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+atrial+dilatation+on+refractory+period+and+vulnerability+to+atrial+fibrillation+in+the+isolated+Langendorff-perfused+rabbit+heart.">Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart.</a> Circulation. 96, 1686-1695 (1997).</li><li>Gray, R. A., Pertsov, A. M., Jalife, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Spatial+and+temporal+organization+during+cardiac+fibrillation.">Spatial and temporal organization during cardiac fibrillation.</a> Nature. 392, 75-78 (1998).</li><li>Gray, R. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanisms+of+cardiac+fibrillation.">Mechanisms of cardiac fibrillation.</a> Science. 270, 1222-1225 (1995).</li><li>Samie, F. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rectification+of+the+background+potassium+current:+a+determinant+of+rotor+dynamics+in+ventricular+fibrillation.">Rectification of the background potassium current: a determinant of rotor dynamics in ventricular fibrillation.</a> Circ Res. 89, 1216-1223 (2001).</li><li>Kalifa, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intra-atrial+pressure+increases+rate+and+organization+of+waves+emanating+from+the+superior+pulmonary+veins+during+atrial+fibrillation.">Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation.</a> Circulation. 108, 668-671 (2003).</li><li>Mandapati, R., Skanes, A., Chen, J., Berenfeld, O., Jalife, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stable+microreentrant+sources+as+a+mechanism+of+atrial+fibrillation+in+the+isolated+sheep+heart.">Stable microreentrant sources as a mechanism of atrial fibrillation in the isolated sheep heart.</a> Circulation. 101, 194-199 (2000).</li><li>Yamazaki, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanisms+of+stretch-induced+atrial+fibrillation+in+the+presence+and+the+absence+of+adrenocholinergic+stimulation:+interplay+between+rotors+and+focal+discharges.">Mechanisms of stretch-induced atrial fibrillation in the presence and the absence of adrenocholinergic stimulation: interplay between rotors and focal discharges.</a> Heart Rhythm. 6, 1009-1017 (2009).</li><li>Rama, D. F., Jalife, J., Antzelevitch, C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanisms+Underlying+Atrial+Fibrillation.">Mechanisms Underlying Atrial Fibrillation.</a> Basic Science for Clinical Electrophysiologist. 3, 141-156 (2011).</li><li>Berenfeld, O., Zaitsev, A. V., Mironov, S. F., Pertsov, A. 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No conflicts of interest declared.

The characteristics of acute stretch-induced AF in the isolated sheep heart resemble some of the properties of human paroxysmal AF. An acute increase in intra-atrial pressure in the sheep heart allows the maintenance of AF for long periods of time, similar to a higher risk of AF observed in patients with atrial dilatation.1 The presence of left-to-right DF gradients in the sheep atria is also similar to those registered in human electrophysiological studies.16 Therefore, understanding the mechanism ...

<table border="1">
<tbody>
<tr>
<td>
Material Name
</td>
<td>
Company		
</td>
<td>
Catalogue Number
</td>
</tr>
<tr>
<td>
Euthanasia
</td>
<td>&nbsp;</td>
<td>&nbsp;</td>
</tr>
<tr>
<td>
Heparin
</td>
<td>
Sigma
</td>
<td>
H3393
</td>
</tr>
<tr>
<td>
Propofol
</td>
<td>
Abbott
</td>
<td>
5206-04-03
</td>
</tr>
<tr>
<td>
Pentobarbital
</td>
<td>
Lundbeck Inc
</td>
<td>
NDC 67386-501-55
</td>
</tr>
<tr>
<td>
Introducer 18 Gauge
</td>
<td>
Terumo
</td>
<td>
SS*FF1832
</td>
</tr>
<tr>
<td>
Cuffed endotracheal tube (9 mm)
</td>
<td>
DRE Veterinary
</td>
<td>
#9440
</td>
</tr>
<tr>
<td>
Fiber Optic Laryngoscope Case
</td>
<td>
DRE Veterinary
</td>
<td>
#991
</td>
</tr>
<tr>
<td>
Fiber Optic Blade
</td>
<td>
DRE Veterinary
</td>
<td>
#984
</td>
</tr>
<tr>
<td>
Operating Scissors
</td>
<td>
DRE Veterinary
</td>
<td>
#9702
#1944
</td>
</tr>
<tr>
<td>
Scalpel Handle #3 Solid 4&quot;
</td>
<td>
Roboz Surgical Instrument Co., Inc.
</td>
<td>
RS-9843
</td>
</tr>
<tr>
<td>
Sterile Scalpel Blades
</td>
<td>
Roboz Surgical Instrument Co., Inc.
</td>
<td>
RS-9801-10
</td>
</tr>
<tr>
<td>
Ventilation bag
</td>
<td>
Westmed
</td>
<td>
562013
</td>
</tr>
<tr>
<td>
Sims Scissors Curved Sharp/Blunt
</td>
<td>
Roboz Surgical Instrument Co., Inc.
</td>
<td>
RS-7035
</td>
</tr>
<tr>
<td>
Tissue Forceps (&times;2)
</td>
<td>
DRE Veterinary
</td>
<td>
#1895
</td>
</tr>
<tr>
<td>
KANTROWITZ Thoracic Forceps, 11&quot;&nbsp;
</td>
<td>
Biomedical Research Instruments, Inc.
</td>
<td>
34-1980
</td>
</tr>
<tr>
<td>
Finochietto Large Chest Spreader
</td>
<td>
Kapp Surgical Instrument Inc.
</td>
<td>
KS-7301
</td>
</tr>
<tr>
<td>
Thoracotomy shears
</td>
<td>
Rostfrei Solingen
</td>
<td>&nbsp;</td>
</tr>
<tr>
<td>
Plastic tray
</td>
<td>
Nalgene
</td>
<td>
Fischer
</td>
</tr>
<tr>
<td>
Optical mapping
</td>
<td>&nbsp;</td>
<td>&nbsp;</td>
</tr>
<tr>
<td>
Bonn Scissors (&times;2)
</td>
<td>
Roboz Surgical Instrument Co., Inc
</td>
<td>
RS-5840SC
</td>
</tr>
<tr>
<td>
Surgical silk
</td>
<td>
Fischer
</td>
<td>
50-900-04214
</td>
</tr>
<tr>
<td>
Micro Dissecting Forceps
</td>
<td>
Roboz Surgical Instrument Co., Inc
</td>
<td>
RS-5130
</td>
</tr>
<tr>
<td>
Tetrapolar electrode catheters (Torq) (&times;4)
</td>
<td>
Medtronic Inc.
</td>
<td>
05580SP
</td>
</tr>
<tr>
<td>
Digital sensor. Biopac Systems transducer
</td>
<td>
Biopac Systems, Inc.
</td>
<td>
RX104A
</td>
</tr>
<tr>
<td>
Biopac Systems amplifier
</td>
<td>
Biopac Systems, Inc.
</td>
<td>
DA-100C
</td>
</tr>
<tr>
<td>
Di-4-ANEPPS
</td>
<td>
Sigma-Aldrich, St.
</td>
<td>
D8604-5mg
</td>
</tr>
<tr>
<td>
Blebbistatin
</td>
<td>
Enzo Life Science International, INC.
</td>
<td>
BML-E1315-0025
</td>
</tr>
<tr>
<td>
LittleJoe CCD video camera(&times;2)
</td>
<td>
SciMeasure Analytical Systems, Inc.
</td>
<td>&nbsp;</td>
</tr>
<tr>
<td>
Dual-channel rigid borescope
</td>
<td>
Everest VIT, Inc.
</td>
<td>
R10-25-0-90
</td>
</tr>
<tr>
<td>
Perfusion pumps (&times;2)
</td>
<td>
Cole Parmer
</td>
<td>
GK-77920-30
</td>
</tr>
<tr>
<td>
Temperature probe
</td>
<td>
Cole Parmer
</td>
<td>
R-08491-02
</td>
</tr>
<tr>
<td>
pH meter
</td>
<td>
Fischer
</td>
<td>
01-913-806
</td>
</tr>
<tr>
<td>
Digital temperature gauge
</td>
<td>
Cole Parmer
</td>
<td>
GK89000-10
</td>
</tr>
<tr>
<td>
Oxygenator filters
</td>
<td>
Sorin
</td>
<td>
05318
</td>
</tr>
<tr>
<td>
Silicon perfusion tubes (L/S 15)
</td>
<td>
MasterFlex
</td>
<td>
96410-15
</td>
</tr>
<tr>
<td>
Laser light guides (&times;6)
</td>
<td>
Oriel Corporation
</td>
<td>
77536
</td>
</tr>
<tr>
<td>
Liquid light-guide (0.2 in core)
</td>
<td>
Newport Corporation
</td>
<td>
77556
</td>
</tr>
<tr>
<td>
Laser generator (1 watt) 

(&times;1)
</td>
<td>
Shanghai Dream Lsaer Tecchnology
</td>
<td>
SDL-532-1000T
</td>
</tr>
<tr>
<td>
Laser generator (5 watt)
 (&times;1)
</td>
<td>
Spectra Physics Lasers
</td>
<td>
MILL 5sJ
</td>
</tr>
</tbody>
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high-resolution endocardial and epicardial optical mapping in a sheep model of stretch-induced atrial fibrillation

Atrial fibrillation (AF) is a complex cardiac arrhythmia with high morbidity and mortality.1,2 It is the most common sustained cardiac rhythm disturbance seen in clinical practice and its prevalence is expected to increase in the coming years.3 Increased intra-atrial pressure and dilatation have been long recognized to lead to AF,1,4 which highlights the relevance of using animal models and stretch to study AF dynamics. Understanding the mechanisms underlying AF requires visualization of the cardiac electrical waves with high spatial and temporal resolution. While high-temporal resolution can be achieved by conventional electrical mapping traditionally used in human electrophysiological studies, the small number of intra-atrial electrodes that can be used simultaneously limits the spatial resolution and precludes any detailed tracking of the electrical waves during the arrhythmia. The introduction of optical mapping in the early 90's enabled wide-field characterization of fibrillatory activity together with sub-millimeter spatial resolution in animal models5,6 and led to the identification of rapidly spinning electrical wave patterns (rotors) as the sources of the fibrillatory activity that may occur in the ventricles or the atria.7-9 Using combined time- and frequency-domain analyses of optical mapping it is possible to demonstrate discrete sites of high frequency periodic activity during AF, along with frequency gradients between left and right atrium. The region with fastest rotors activates at the highest frequency and drives the overall arrhythmia.10,11 The waves emanating from such rotor interact with either functional or anatomic obstacles in their path, resulting in the phenomenon of fibrillatory conduction.12 Mapping the endocardial surface of the posterior left atrium (PLA) allows the tracking of AF wave dynamics in the region with the highest rotor frequency. Importantly, the PLA is the region where intracavitary catheter-based ablative procedures are most successful terminating AF in patients,13 which underscores the relevance of studying AF dynamics from the interior of the left atrium. Here we describe a sheep model of acute stretch-induced AF, which resembles some of the characteristics of human paroxysmal AF. Epicardial mapping on the left atrium is complemented with endocardial mapping of the PLA using a dual-channel rigid borescope c-mounted to a CCD camera, which represents the most direct approach to visualize the patterns of activation in the most relevant region for AF maintenance.

Watch this Scientific Journal Video about High-Resolution Endocardial and Epicardial Optical Mapping in a Sheep Model of Stretch-Induced Atrial Fibrillation at JoVE.com

High-Resolution Endocardial and Epicardial Optical Mapping in a Sheep Model of Stretch-Induced Atrial Fibrillation

This report provides a detailed description of the methodology and results of simultaneous endocardial and epicardial optical mapping of electrical excitation in the intact left atrium of a Langendorff-perfused sheep heart during stretch-induced atrial fibrillation.

 Atrial fibrillation (AF) is a complex cardiac arrhythmia with high morbidity and mortality.1,2 It is the most common sustained cardiac rhythm disturbance ...

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14.7K Views.  University of Michigan. В настоящем докладе содержится подробное описание методологии и результатов одновременных эндокарда и эпикарда оптических отображение электрического возбуждения в интактном левое предсердие из Langendorff-перфузии овец сердца во время стретч-индуцированной ф?...

Video: High-Resolution Endocardial and Epicardial Optical Mapping in a Sheep Model of Stretch-Induced Atrial Fibrillation

The WATCHMAN Left Atrial Appendage Closure Device for Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 6 million people in the United States 1. Since AF affects primarily elderly people, its prevalence increases parallel with age. As such, it is expected that 15.9 million Americans will be affected by the year 2050 2. Ischemic stroke occurs in 5% of non-anticoagulated AF patients each year. Current treatments for AF include rate control, rhythm control and prevention of stroke 3.
The American College of Cardiology, American Heart Association, and European Society of Cardiology currently recommended rate control as the first course of therapy for AF 3. Rate control is achieved by administration of pharmacological agents, such as &beta;-blockers, that lower the heart rate until it reaches a less symptomatic state 3. Rhythm control aims to return the heart to its normal sinus rhythm and is typically achieved through administration of antiarrhythmic drugs such as amiodarone, electrical cardioversion or ablation therapy. Rhythm control methods, however, have not been demonstrated to be superior to rate-control methods 4-6. In fact, certain antiarrhythmic drugs have been shown to be associated with higher hospitalization rates, serious adverse effects 3, or even increases in mortality in patients with structural heart defects 7. Thus, treatment with antiarrhythmics is more often used when rate-control drugs are ineffective or contraindicated. Rate-control and antiarrhythmic agents relieve the symptoms of AF, including palpitations, shortness of breath, and fatigue 8, but don't reliably prevent thromboembolic events 6.
Treatment with the anticoagulant drug warfarin significantly reduces the rate of stroke or embolism 9,10. However, because of problems associated with its use, fewer than 50% of patients are treated with it. The therapeutic dose is affected by drug, dietary, and metabolic interactions, and thus requires detailed monitoring. In addition, warfarin has the potential to cause severe, sometimes lethal, bleeding 2. As an alternative, aspirin is commonly prescribed. While aspirin is typically well tolerated, it is far less effective at preventing stroke 10. Other alternatives to warfarin, such as dabigatran 11 or rivaroxaban 12 demonstrate non-inferiority to warfarin with respect to thromboembolic events (in fact, dabigatran given as a high dose of 150 mg twice a day has shown superiority). While these drugs have the advantage of eliminating dietary concerns and eliminating the need for regular blood monitoring, major bleeding and associated complications, while somewhat less so than with warfarin, remain an issue 13-15.
Since 90% of AF-associated strokes result from emboli that arise from the left atrial appendage (LAA) 2, one alternative approach to warfarin therapy has been to exclude the LAA using an implanted device to trap blood clots before they exit. Here, we demonstrate a procedure for implanting the WATCHMAN Left Atrial Appendage Closure Device. A transseptal cannula is inserted through the femoral vein, and under fluoroscopic guidance, inter-atrial septum is crossed. Once access to the left atrium has been achieved, a guidewire is placed in the upper pulmonary vein and the WATCHMAN Access Sheath and dilator are advanced over the wire into the left atrium. The guidewire is removed, and the access sheath is carefully advanced into the distal portion of the LAA over a pigtail catheter. The WATCHMAN Delivery System is prepped, inserted into the access sheath, and slowly advanced. The WATCHMAN device is then deployed into the LAA. The device release criteria are confirmed via fluoroscopy and transesophageal echocardiography (TEE) and the device is released.

The accompanying video describes a procedure for percutaneous placement of the WATCHMAN Left Atrial Appendage (LAA) Device. The WATCHMAN is a nitinol device designed to be permanently implanted at, or slightly distal to, the opening of the left atrial appendage (LAA) to trap blood clots before they exit the LAA, preventing thromboembolic stroke.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 6 million people in the United States 1. Since AF affects primarily ...

Catheter Ablation in Combination With Left Atrial Appendage Closure for Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting millions of individuals worldwide 1-3. The rapid, irregular, and disordered electrical activity in the atria gives rise to palpitations, fatigue, dyspnea, chest pain and dizziness with or without syncope 4, 5. Patients with AF have a five-fold higher risk of stroke 6.
Oral anticoagulation (OAC) with warfarin is commonly used for stroke prevention in patients with AF and has been shown to reduce the risk of stroke by 64% 7. Warfarin therapy has several major disadvantages, however, including bleeding, non-tolerance, interactions with other medications and foods, non-compliance and a narrow therapeutic range 8-11. These issues, together with poor appreciation of the risk-benefit ratio, unawareness of guidelines, or absence of an OAC monitoring outpatient clinic may explain why only 30-60% of patients with AF are prescribed this drug 8.
The problems associated with warfarin, combined with the limited efficacy and/or serious side effects associated with other medications used for AF 12,13, highlight the need for effective non-pharmacological approaches to treatment. One such approach is catheter ablation (CA), a procedure in which a radiofrequency electrical current is applied to regions of the heart to create small ablation lesions that electrically isolate potential AF triggers 4. CA is a well-established treatment for AF symptoms 14, 15, that may also decrease the risk of stroke. Recent data showed a significant decrease in the relative risk of stroke and transient ischemic attack events among patients who underwent ablation compared with those undergoing antiarrhythmic drug therapy 16.
Since the left atrial appendage (LAA) is the source of thrombi in more than 90% of patients with non-valvular atrial fibrillation 17, another approach to stroke prevention is to physically block clots from exiting the LAA. One method for occluding the LAA is via percutaneous placement of the WATCHMAN LAA closure device. The WATCHMAN device resembles a small parachute. It consists of a nitinol frame covered by fabric polyethyl terephthalate that prevents emboli, but not blood, from exiting during the healing process. Fixation anchors around the perimeter secure the device in the LAA (Figure 1). To date, the WATCHMAN is the only implanted percutaneous device for which a randomized clinical trial has been reported. In this study, implantation of the WATCHMAN was found to be at least as effective as warfarin in preventing stroke (all-causes) and death (all-causes) 18. This device received the Conformit&eacute; Europ&eacute;enne (CE) mark for use in the European Union for warfarin eligible patients and in those who have a contraindication to anticoagulation therapy 19.
Given the proven effectiveness of CA to alleviate AF symptoms and the promising data with regard to reduction of thromboembolic events with both CA and WATCHMAN implantation, combining the two procedures is hoped to further reduce the incidence of stroke in high-risk patients while simultaneously relieving symptoms. The combined procedure may eventually enable patients to undergo implantation of the WATCHMAN device without subsequent warfarin treatment, since the CA procedure itself reduces thromboembolic events. This would present an avenue of treatment previously unavailable to patients ineligible for warfarin treatment because of recurrent bleeding 20 or other warfarin-associated problems.
The combined procedure is performed under general anesthesia with biplane fluoroscopy and TEE guidance. Catheter ablation is followed by implantation of the WATCHMAN LAA closure device. Data from a non-randomized trial with 10 patients demonstrates that this procedure can be safely performed in patients with a CHADS2 score of greater than 1 21. Further studies to examine the effectiveness of the combined procedure in reducing symptoms from AF and associated stroke are therefore warranted.

Catheter ablation is combined with placement of the WATCHMAN Left Atrial Appendage Closure Device to prevent ischemic stroke in a patient with non-valvular atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting millions of individuals worldwide 1-3. The rapid, irregular, and ...

A Rat Model of Ventricular Fibrillation and Resuscitation by Conventional Closed-chest Technique

A rat model of electrically-induced ventricular fibrillation followed by cardiac resuscitation using a closed chest technique that incorporates the basic components of cardiopulmonary resuscitation in humans is herein described. The model was developed in 1988 and has been used in approximately 70 peer-reviewed publications examining a myriad of resuscitation aspects including its physiology and pathophysiology, determinants of resuscitability, pharmacologic interventions, and even the effects of cell therapies. The model featured in this presentation includes: (1) vascular catheterization to measure aortic and right atrial pressures, to measure cardiac output by thermodilution, and to electrically induce ventricular fibrillation; and (2) tracheal intubation for positive pressure ventilation with oxygen enriched gas and assessment of the end-tidal CO2. A typical sequence of intervention entails: (1) electrical induction of ventricular fibrillation, (2) chest compression using a mechanical piston device concomitantly with positive pressure ventilation delivering oxygen-enriched gas, (3) electrical shocks to terminate ventricular fibrillation and reestablish cardiac activity, (4) assessment of post-resuscitation hemodynamic and metabolic function, and (5) assessment of survival and recovery of organ function. A robust inventory of measurements is available that includes &#8211; but is not limited to &#8211; hemodynamic, metabolic, and tissue measurements. The model has been highly effective in developing new resuscitation concepts and examining novel therapeutic interventions before their testing in larger and translationally more relevant animal models of cardiac arrest and resuscitation.

This article describes a rat model of electrically-induced ventricular fibrillation and resuscitation by chest compression, ventilation, and delivery of electrical shocks that simulates an episode of sudden cardiac arrest and conventional cardiopulmonary resuscitation. The model enables gathering insights on the pathophysiology of cardiac arrest and exploration of new resuscitation strategies.

A rat model of electrically-induced ventricular fibrillation followed by cardiac resuscitation using a closed chest technique that incorporates the basic ...

Robotic Ablation of Atrial Fibrillation

Background: Pulmonary vein isolation (PVI) is an established treatment for atrial fibrillation (AF). During PVI an electrical conduction block between pulmonary vein (PV) and left atrium (LA) is created. This conduction block prevents AF, which is triggered by irregular electric activity originating from the PV. However, transmural atrial lesions are required which can be challenging. Re-conduction and AF recurrence occur in 20 - 40% of the cases. Robotic catheter systems aim to improve catheter steerability. Here, a procedure with a new remote catheter system (RCS), is presented. Objective of this article is to show feasibility of robotic AF ablation with a novel system. Materials and Methods: After interatrial trans-septal puncture is performed using a long sheath and needle under fluoroscopic guidance. The needle is removed and a guide wire is placed in the left superior PV. Then an ablation catheter is positioned in the LA, using the sheath and wire as guide to the LA. LA angiography is performed over the sheath. A circular mapping catheter is positioned via the long sheath into the LA and a three-dimensional (3-D) anatomical reconstruction of the LA is performed. The handle of the ablation catheter is positioned in the robotic arm of the Amigo system and the ablation procedure begins. During the ablation procedure, the operator manipulates the ablation catheter via the robotic arm with the use of a remote control. The ablation is performed by creating point-by-point lesions around the left and right PV ostia. Contact force is measured at the catheter tip to provide feedback of catheter-tissue contact. Conduction block is confirmed by recording the PV potentials on the circular mapping catheter and by pacing maneuvers. The operator stays out of the radiationfield during ablation. Conclusion: The novel catheter system allows ablation with high stability on low operator fluoroscopy exposure.

Pulmonary vein isolation (PVI) with an ablation catheter is a curative treatment for atrial fibrillation (AF). Robotic catheter systems aim to improve catheter steerability. Here, a procedure with a new robotic catheter system is presented. The goal of the procedure is electrical block between pulmonary vein and left atrium.

Background: Pulmonary vein isolation (PVI) is an established treatment for atrial fibrillation (AF). During PVI an electrical conduction block between ...

Electrophysiological Assessment of Murine Atria with High-Resolution Optical Mapping

Recent genome-wide association studies targeting atrial fibrillation (AF) have indicated a strong association between the genotype and electrophysiological phenotype in the atria. That encourages us to utilize a genetically-engineered mouse model to elucidate the mechanism of AF. However, it is difficult to evaluate the electrophysiological properties in murine atria due to their small size. This protocol describes the electrophysiological evaluation of atria using an optical mapping system with a high temporal and spatial resolution in Langendorff perfused murine hearts. The optical mapping system is assembled with dual high-speed complementary metal oxide semiconductor cameras and high magnification objective lenses, to detect the fluorescence of a voltage-sensitive dye and Ca2+ indicator. To focus on the assessment of murine atria, optical mapping is performed with an area of 2 mm &#215; 2 mm or 10 mm x 10 mm, with a 100 &#215; 100 resolution (20 &#181;m/pixel or 100 &#181;m/pixel) and sampling rate of up to 10 kHz (0.1 ms) at maximum. A 1-French size quadripolar electrode pacing catheter is placed into the right atrium through the superior vena cava avoiding any mechanical damage to the atrium, and pacing stimulation is delivered through the catheter. An electrophysiological study is performed with programmed stimulation including constant pacing, burst pacing, and up to triple extrastimuli pacing. Under a spontaneous or pacing rhythm, the optical mapping recorded the action potential duration, activation map, conduction velocity, and Ca2+ transient individually in the right and left atria. In addition, the programmed stimulation also determines the inducibility of atrial tachyarrhythmias. Precise activation mapping is performed to identify the propagation of the excitation in the atrium during an induced atrial tachyarrhythmia. Optical mapping with a specialized setting enables a thorough electrophysiological evaluation of the atrium in murine pathological models.

This protocol describes the electrophysiological evaluation of murine atria utilizing an optical mapping system with a high temporal and spatial resolution, including dual recordings of the membrane voltage and Ca2+ transient under programmed stimulation through a specialized electrode catheter.

Recent genome-wide association studies targeting atrial fibrillation (AF) have indicated a strong association between the genotype and ...

High-Throughput Analysis of Optical Mapping Data Using ElectroMap

Optical mapping is an established technique for high spatio-temporal resolution study of cardiac electrophysiology in multi-cellular preparations. Here we present, in a step-by-step guide, the use of ElectroMap for analysis, quantification, and mapping of high-resolution voltage and calcium datasets acquired by optical mapping. ElectroMap analysis options cover a wide variety of key electrophysiological parameters, and the graphical user interface allows straightforward modification of pre-processing and parameter definitions, making ElectroMap applicable to a wide range of experimental models. We show how built-in pacing frequency detection and signal segmentation allows high-throughput analysis of entire experimental recordings, acute responses, and single beat-to-beat variability. Additionally, ElectroMap incorporates automated multi-beat averaging to improve signal quality of noisy datasets, and here we demonstrate how this feature can help elucidate electrophysiological changes that might otherwise go undetected when using single beat analysis. Custom modules are included within the software for detailed investigation of conduction, single file analysis, and alternans, as demonstrated here. This software platform can be used to enable and accelerate the processing, analysis, and mapping of complex cardiac electrophysiology.

This protocol describes the setup and use of ElectroMap, a MATLAB-based open-source software platform for analysis of cardiac optical mapping data. ElectroMap provides a versatile high-throughput tool for analysis of optical mapping voltage and calcium datasets across a wide range of cardiac experimental models.

Optical mapping is an established technique for high spatio-temporal resolution study of cardiac electrophysiology in multi-cellular preparations. Here we ...

Cooling or Warming the Esophagus to Reduce Esophageal Injury During Left Atrial Ablation in the Treatment of Atrial Fibrillation

Ablation of the left atrium using either radiofrequency (RF) or cryothermal energy is an effective treatment for atrial fibrillation (AF) and is the most frequent type of cardiac ablation procedure performed. Although generally safe, collateral injury to surrounding structures, particularly the esophagus, remains a concern. Cooling or warming the esophagus to counteract the heat from RF ablation, or the cold from cryoablation, is a method that is used to reduce thermal esophageal injury, and there are increasing data to support this approach. This protocol describes the use of a commercially available esophageal temperature management device to cool or warm the esophagus to reduce esophageal injury during left atrial ablation. The temperature management device is powered by standard water-blanket heat exchangers, and is shaped like a standard orogastric tube placed for gastric suctioning and decompression. Water circulates through the device in a closed-loop circuit, transferring heat across the silicone walls of the device, through the esophageal wall. Placement of the device is analogous to the placement of a typical orogastric tube, and temperature is adjusted via the external heat-exchanger console.

The goal of this protocol is to describe the use of esophageal temperature modulation to counteract esophageal thermal injury from left atrial ablation for the treatment of atrial fibrillation.

Ablation of the left atrium using either radiofrequency (RF) or cryothermal energy is an effective treatment for atrial fibrillation (AF) and is the most ...

Sterile Pericarditis in Aachener Minipigs As a Model for Atrial Myopathy and Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia caused by structural remodeling of the atria, also called atrial myopathy. Current therapies only target the electrical abnormalities and not the underlying atrial myopathy. For the development of novel therapies, a reproducible large animal model of atrial myopathy is necessary. This paper presents a model of sterile pericarditis-induced atrial myopathy in Aachener minipigs. Sterile pericarditis was induced by spraying sterile talcum and leaving a layer of sterile gauze over the atrial epicardial surface. This led to inflammation and fibrosis, two crucial components of the pathophysiology of atrial myopathy, making the atria susceptible to the induction of AF. Two pacemaker electrodes were positioned epicardially on each atrium and connected to two pacemakers from different manufacturers. This strategy allowed for repeated non-invasive atrial programmed stimulation to determine the inducibility of AF at specified time points after surgery. Different protocols to test AF inducibility were used. The advantages of this model are its clinical relevance, with AF inducibility and the rapid induction of inflammation and fibrosis-both present in atrial myopathy-and its reproducibility. The model will be useful in the development of novel therapies targeting atrial myopathy and AF.

We describe a sterile pericarditis model in minipigs to study atrial myopathy and atrial fibrillation (AF). We present surgical and anesthetic techniques, strategies for vascular access, and a protocol to study the inducibility of AF.

Atrial fibrillation (AF) is the most common arrhythmia caused by structural remodeling of the atria, also called atrial myopathy. Current therapies only ...

High-Resolution Three-Dimensional Imaging of the Footpad Vasculature in a Murine Hindlimb Gangrene Model

Peripheral arterial disease (PAD) is a significant cause of morbidity resulting from chronic exposure to atherosclerotic risk factors. Patients suffering from its most severe form, chronic limb-threatening ischemia (CLTI), face substantial impairments to daily living, including chronic pain, limited walking distance without pain, and nonhealing wounds. Preclinical models have been developed in various animals to study PAD, but mouse hindlimb ischemia remains the most widely used. There can be significant variation in response to ischemic insult in these models depending on the mouse strain used and the site, number, and means of arterial disruption. This protocol describes a unique method combining femoral artery and vein electrocoagulation with the administration of a nitric oxide synthase (NOS) inhibitor to reliably induce footpad gangrene in Friend Virus B (FVB) mice that resembles the tissue loss of CLTI. While traditional means of assessing reperfusion such as laser Doppler perfusion imaging (LDPI) are still recommended, intracardiac perfusion of the lipophilic dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) is used to label the vasculature. Subsequent whole-mount confocal laser scanning microscopy allows for high-resolution, three-dimensional (3D) reconstruction of footpad vascular networks that complements traditional means of assessing reperfusion in hindlimb ischemia models.

The present protocol describes a unique, clinically relevant model of peripheral arterial disease that combines femoral artery and vein electrocoagulation with the administration of a nitric oxide synthase inhibitor to induce hindlimb gangrene in FVB mice. Intracardiac DiI perfusion is then used for high-resolution, three-dimensional imaging of the footpad vasculature.

Peripheral arterial disease (PAD) is a significant cause of morbidity resulting from chronic exposure to atherosclerotic risk factors. Patients suffering ...

Transesophageal Atrial Burst Pacing for Atrial Fibrillation Induction in Rats

Animal studies have brought important insights into our understanding regarding atrial fibrillation (AF) pathophysiology and therapeutic management. Reentry, one of the main mechanisms involved in AF pathogenesis, requires a certain mass of myocardial tissue in order to occur. Due to the small size of the atria, rodents have long been considered 'resistant' to AF. Although spontaneous AF has been shown to occur in rats, long-term follow-up (up to 50 weeks) is required for the arrhythmia to occur in those models. The present work describes an experimental protocol of transesophageal atrial burst pacing for rapid and efficient induction of AF in rats. The protocol can be successfully used in rats with healthy or remodeled hearts, in the presence of a wide variety of risk factors, allowing the study of AF pathophysiology, identification of novel therapeutic targets, and evaluation of novel prophylactic and/or therapeutic strategies.

The present work describes an experimental protocol of transesophageal atrial burst pacing for efficient induction of atrial fibrillation (AF) in rats. The protocol can be used in rats with healthy or remodeled hearts, allowing the study of AF pathophysiology, identification of novel therapeutic targets, and evaluation of new therapeutic strategies.

Animal studies have brought important insights into our understanding regarding atrial fibrillation (AF) pathophysiology and therapeutic management. ...