This research was presented in an American Heart Association conference: Abstract 17990 AHA 2013. Sponsorship of the Open Access Video was supported in part by Medtronic plc.

Ethical Statement: All methods and procedures performed in these examinations were typical and standard-of-care during this time period of data collection. Informed consent was obtained from all patients, and local institutional review board approval was granted for both studies.
1. Transseptal Access
NOTE: Procedural methods and techniques have now been well described in several publications6-11, and the cryoballoon ablation strategy used here was similar to published descriptions.
<ol>
	<li>Examine patients with a transesophageal echocardiogram on the day of the AF ablation procedure. Use transesophageal echocardiogram imaging to assess the LA for thrombus presence or formation.</li>
	<li>Re-schedule ablation for any patient with LA thrombus present, and correct the patient anticoagulation strategy.</li>
	<li>Establish patient sedation with the use of general anesthesia (with an agent such as intravenous propofol) or conscious sedation (with agents such as intravenous fentanyl and versed). In both sedation methods, do not use a paralytic agent so that phrenic nerve monitoring can be used during the ablation procedure.</li>
	<li>During the AF ablation procedure, use ICE guidance for the transseptal catheterization with a Mullins-type sheath. Use the ICE guidance to position the transseptal needle at the septum, to avoid aortic puncture, and to safeguard against inadvertent LA lateral wall needle-puncture (by examining the needle &#8220;tenting&#8221; distance during transseptal puncture)12. 
	NOTE: In the traditional FO location, the transseptal access point is at the thinnest septal tissue depth near the center of the septum which is evaluated by &#8220;tenting&#8221; the septum with the transseptal needle under ICE imaging (Figure 1).</li>
	<li>For the IL transseptal location, enter approximately one centimeter below the traditional FO site and at an anterior septal location (Figure 1; panels A and B). The IL location is found through evaluation of ICE and fluoroscopy once the FO site is established.
	<ol>
		<li>Use ICE plane imaging to define the entry point in the IL location. Sweep the ICE image anterior towards the plane of the mitral value to define the anterior position of the site.</li>
		<li>The inferior location will be dependent on the IL, which is triangular in cross-section. Place the transseptal needle puncture at the center of this triangular area.</li>
	</ol>
	</li>
	<li>Facilitate the IL puncture by further bending the transseptal needle approximately &#189; inch from this distal tip. Needle bending is customized to the approach angle on LAO view of the inferior vena cava into the right atrium. Use more needle bending when the approach angle is vertical rather than horizontal to the patient&#8217;s body axis.
	<ol>
		<li>Optionally, use a radiofrequency transseptal needle to facilitate the IL position technique; however, only standard transseptal needles were used for this study.</li>
	</ol>
	</li>
	<li>Immediately after transseptal puncture, administer heparin bolus using a patient weight-based protocol and then give supplemental doses of heparin throughout the procedure with the goal of maintaining active clotting time between 350 and 400 sec.</li>
	<li>Establish the transseptal access route with an exchange of the transseptal needle with a guidewire.</li>
</ol>
2. Cryoballoon Ablation
<ol>
	<li>Use the guidewire to introduce the cryoballoon sheath. Then deploy the cryoballoon catheter and the dedicated inner lumen circular mapping catheter into the LA through the cryoballoon sheath.</li>
	<li>During each cryoballoon ablation, inflate the cryoballoon and advance it over the inner lumen circular mapping catheter which is wired towards the PV ostium.</li>
	<li>Inject 5 to 10 ml of radiopaque contrast agent (isovue 300) through the cryoballoon catheter inner lumen.</li>
	<li>Confirm cryoballoon-to-PV occlusion by using the retention of contrast agent after injection at the distal tip of the balloon.
	<ol>
		<li>Additionally (or alternatively), confirm cryoballoon-to-PV occlusion by ICE imaging under color-flow Doppler using the lack of flow around the balloon anterior surface as an indicator of occlusion.</li>
	</ol>
	</li>
	<li>Start the cryoballoon cryoablation once occlusion is established by pressing the &#8220;start&#8221; button on the cryoconsole. This action will push cryorefrigerant into the cryoballoon catheter and initiate cryoablation.</li>
	<li>On right-sided PVs, use a diagnostic catheter in the right atrial/superior vena caval junction and position it to pace the right phrenic nerve.</li>
	<li>Pace the phrenic nerve at 20 mA amplitude and 2.0 msec pulse width, and monitor phrenic nerve function by manual detection of diaphragmatic contractions. Immediately terminate any ablation if phrenic nerve function is diminished, delayed, or lost.</li>
	<li>Deliver a minimum of two freezes, each lasting 120 to 180 sec, while using the inner lumen circular mapping catheter to monitor both real-time and post-ablation PVI through entrance and exit block testing.</li>
	<li>Once entrance and exit block is established at each PV, withdraw the cryoballoon, sheath, and inner lumen circular mapping catheter.</li>
	<li>Use standard medical care to stop bleeding at vascular entry points and discharge patients via hospital protocols, which may include anticoagulation pharmaceutical therapy and guidance on antiarrhythmic drugs.</li>
</ol>

<ol>
	<li>Ha&#239;ssaguerre, M., Jais, P., Shah, D. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Spontaneous+initiation+of+atrial+&#64257;brillation+by+ectopic+beats+originating+in+the+pulmonary+veins.">Spontaneous initiation of atrial &#64257;brillation by ectopic beats originating in the pulmonary veins.</a> N Engl J Med. 339 (10), 659-666 (1998).</li><li>Calkins, H., Kuck, K. H., Cappato, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Heart+Rhythm+Society+Task+Force+on+Catheter+and+Surgical+Ablation+of+Atrial+Fibrillation.+2012+HRS/EHRA/ECAS+expert+consensus+statement+on+catheter+and+surgical+ablation+of+atrial+fibrillation:+recommendations+for+patient+selection,+procedural+techniques,+patient+management+and+follow-up,+definitions,+endpoints,+and+research+trial+design:+a+report+of+the+Heart+Rhythm+Society+(HRS)+Task+Force+on+Catheter+and+Surgical+Ablation+of+Atrial+Fibrillation.">Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation.</a> Heart Rhythm. 9 (4), 632-696 (2012).</li><li>Gerstenfeld, E. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=New+technologies+for+catheter+ablation+of+atrial+fibrillation.">New technologies for catheter ablation of atrial fibrillation.</a> Curr Treat Options Cardiovasc Med. 13 (5), 393-401 (2011).</li><li>Packer, D. L., Kowal, R. C., Wheelan, K. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cryoballoon+ablation+of+pulmonary+veins+for+paroxysmal+atrial+fibrillation:+first+results+of+the+North+American+Arctic+Front+(STOP+AF)+pivotal+trial.">Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial.</a> J Am Coll Cardiol. 61 (16), 1713-1723 (2013).</li><li>Chan, N. Y., Choy, C. C., Lau, C. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Persistent+iatrogenic+atrial+septal+defect+after+pulmonary+vein+isolation+by+cryoballoon:+an+under-recognized+complication.">Persistent iatrogenic atrial septal defect after pulmonary vein isolation by cryoballoon: an under-recognized complication.</a> Europace. 13 (10), 1406-1410 (2011).</li><li>Chierchia, G. B., Di Giovanni, G., Ciconte, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Second-generation+cryoballoon+ablation+for+paroxysmal+atrial+fibrillation:+1-year+follow-up.">Second-generation cryoballoon ablation for paroxysmal atrial fibrillation: 1-year follow-up.</a> Europace. 16 (5), 639-644 (2014).</li><li>Straube, F., Dorwarth, U., Schmidt, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+the+first+and+second+cryoballoon:+high-volume+single-center+safety+and+efficacy+analysis.">Comparison of the first and second cryoballoon: high-volume single-center safety and efficacy analysis.</a> Circ Arrhythm Electrophysiol. 7 (2), 293-299 (2014).</li><li>Metzner, A., Reissmann, B., Rausch, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-year+clinical+outcome+after+pulmonary+vein+isolation+using+the+second-generation+28-mm+cryoballoon.">One-year clinical outcome after pulmonary vein isolation using the second-generation 28-mm cryoballoon.</a> Circ Arrhythm Electrophysiol. 7 (2), 288-292 (2014).</li><li>Giovanni, G. D., Wauters, K., Chierchia, G. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-year+follow-up+after+single+procedure+cryoballoon+ablation:+A+comparison+between+the+first+and+second+generation+balloon.">One-year follow-up after single procedure cryoballoon ablation: A comparison between the first and second generation balloon.</a> J Cardiovasc Electrophysiol. 25 (8), 834-839 (2014).</li><li>Bordignon, S., Dugo, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Improved+1-year+clinical+success+rate+of+pulmonary+vein+isolation+with+the+second-generation+cryoballoon+in+patients+with+paroxysmal+atrial+fibrillation.">Improved 1-year clinical success rate of pulmonary vein isolation with the second-generation cryoballoon in patients with paroxysmal atrial fibrillation.</a> J Cardiovasc Electrophysiol. 25 (8), 840-844 (2014).</li><li>Straube, F., Dorwarth, U., Vogt, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Differences+of+two+cryoballoon+generations:+insights+from+the+prospective+multicentre,+multinational+FREEZE+Cohort+Substudy.">Differences of two cryoballoon generations: insights from the prospective multicentre, multinational FREEZE Cohort Substudy.</a> Europace. 16 (10), 1434-1442 (2014).</li><li>Mitchell-Heggs, L., Lellouche, N., Deal, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transseptal+puncture+using+minimally+invasive+echocardiography+during+atrial+fibrillation+ablation.">Transseptal puncture using minimally invasive echocardiography during atrial fibrillation ablation.</a> Europace. 12 (10), 1435-1438 (2010).</li><li>Chun, K. R., Schmidt, B., Metzner, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+'single+big+cryoballoon'+technique+for+acute+pulmonary+vein+isolation+in+patients+with+paroxysmal+atrial+fibrillation:+a+prospective+observational+single+centre+study.">The 'single big cryoballoon' technique for acute pulmonary vein isolation in patients with paroxysmal atrial fibrillation: a prospective observational single centre study.</a> Eur Heart J. 30 (6), 699-709 (2009).</li><li>Chun, K. R., Nuyens, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+conduction+recovery+after+pulmonary+vein+isolation+using+the+'single+big+cryoballoon'+technique.">Characterization of conduction recovery after pulmonary vein isolation using the 'single big cryoballoon' technique.</a> Heart Rhythm. 7 (2), 184-190 (2010).</li><li>Ci&#231;ek&#231;io&#287;lu, H., Diker, E., Aydo&#287;du, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+rare+complication+of+radiofrequency+catheter+ablation+of+left+atrial+tachycardia:+atrial+septal+dissection+and+left+atrial+hematoma+formation.">A rare complication of radiofrequency catheter ablation of left atrial tachycardia: atrial septal dissection and left atrial hematoma formation.</a> Turk Kardiyol Dern Ars. 38 (4), 279-281 (2010).</li></ol>

Conflicts of interest: Michael Rich &#8211; none; Andrew Tseng &#8211; none; Hae Lim- an employee of Medtronic plc; Paul Wang &#8211; none; Wilbur Su &#8211; research and honorarium; Medtronic, AtriCure, St. Jude Medical.

This study observed that using the anterior and inferior transseptal site approach resulted in 93% of the patients not requiring an additional focal ablation with an adjunctive focal ablation catheter to achieve acute procedural PVI. By comparison, the STOP AF trial reported a rate of 83% acute procedural PVI when only the cryoballoon catheter was used4. A rate of 97.6% acute procedural PVI was obtained when adjunctive focal ablation catheters were used during STOP AF4, and a typical transseptal needle puncture during the STOP AF study was located in the FO position. However, more recently, higher rates of acute PVI have been reported when using the second-generation cryoballoon catheter, which does not require perfect cryoballoon-to-PV axial alignment to achieve PVI6-11.
The observation (that the use of an IL site transseptal puncture resulted in a smaller angle between the cryoballoon and the PV) may explain the high degree of success since the puncture site is more likely to be at the same level as the inferior PVs. This smaller angle of cryoballoon catheter and sheath deflection results in a more direct path for the positioning of cryoballoon-to-PV ostium which facilitates the ease of occlusion. In contrast, a larger angle between the cryoballoon and the PV typically makes occlusion of the PV more difficult to achieve and therefore results in reduced PVI. Consequently, prior studies (with the first generation cryoballoon catheter) have described the use of a &#8220;hockey stick&#8221; approach configuration of the cryoballoon when the transseptal site is above the level of the inferior PVs13,14. This procedural movement (hockey stick) is not necessary with the second-generation cryoballoon when an IL transseptal site is employed.
In a virtual intracardiac reconstruction (Figure 4), the cryoballoon catheter takes a sharp turn to reach the right-sided PVs from the FO transseptal location. With the traditional FO puncture site, the cryoballoon-to-PV angles needed to achieve complete occlusion are 131&#176;, 32&#176;, 206&#176;, and 329&#176; for the right superior PV (RSPV), left superior PV (LSPV), right inferior PV (RIPV), and left inferior PV (LIPV), respectively. By comparison, the lower IL transseptal site allows the cryoballoon-to-PV occlusion angles to achieve complete occlusion at 121&#176;, 45&#176;, 182&#176;, and 349&#176;, respectively. When comparing the angles needed to achieve cryoballoon occlusion, the mechanical advantage of the anterior and inferior transseptal site becomes apparent.
Additionally, by direct comparison, this study demonstrated that the IL position was statistically better than the FO transseptal site at preventing acute IASD as monitored by Doppler flow on ICE. Acute left-to-right shunts were detected in 100% of the patients given a FO transseptal puncture while it was reduced to a 33% rate when examining patients with an IL puncture site. A seemingly apparent explanation is that the thicker and more muscular septum, in an anterior and inferior approach, allows for compaction and minimization of the tissue disruption. By comparison the thin-walled FO does not have enough tissue to establish closure by tissue contact once the 15 Fr septal portal has been established. However, further follow-up examination will be necessary to determine the longer-term persistence of transseptal access-induced IASDs. By systematically examining transseptal access locations, this study was able to demonstrate an advantage of using an anterior and inferior approach near the IL.
This current study only examined the acute instance of IASD via Doppler flow ICE imaging. Longer-term and persistent left-to-right atrial shunts are more relevant to the overall health of patients. It is possible (and likely) that most (if not all) patients show no detrimental cardiac symptomology in longer-term follow-up care. Also, while the IL transseptal puncture did have certain advantageous in this study, it is important to clarify that many other cryoballoon using physicians have successful ablation procedures utilizing the FO transseptal position, and that the ultimate point of transseptal entrance should be selected at the physician&#8217;s medical discretion. This study represents the clinical results from a single center retrospective examination, and thus the reproducibility and utility of the technique may rely heavily on physician-user experience.
When choosing to use the IL position, ICE imaging is a required recommendation. The more anterior and inferior location of the IL transseptal puncture may predispose the patient to a higher risk of atrial perforation and/or aortic puncture. ICE imaging is critical to maintain safety during the transseptal puncture and importantly, it can be used to determine a location that is well posterior to the aortic root. In the anterior direction, ICE imaging will ensure that the transseptal puncture is not too anterior and not near the Kock triangle anatomically, which will avoid any potential AV node injury. While using ICE during all 373 procedures reported in this study, there were no complications related to transseptal puncture, and there were no instances of atrial septal dissection and left atrial hematoma formation which have been previously noted during the usage of radiofrequency focal-tip ablation catheters15.
By locating the transseptal access site to approximately one centimeter below the typical level of the FO, there were several benefits that were introduced during the operation of a cryoballoon catheter for AF ablation. The improved angle between the transseptal puncture site and each of the four PVs resulted in a better alignment and a mechanical advantage between the cryoballoon and PV ostium. As an immediate result, the rate of &#8220;balloon-only&#8221; PVI was robust. Additionally, the lower puncture site (at the thicker septum) decreased the incidence of acute IASDs, which may have further implications in longer-term patient care.
Lastly, the study physicians in this examination qualitatively observed that it was easier to push a 15 Fr sheath through the IL position compared to the FO location. The mechanical advantage (of pushing through a more central and rigid cardiac structure) facilitated large sheath pushing during entry and more controlled motion during passage. By comparison, the FO position was prone to &#8220;hanging&#8221; because of a thinner (and compliant) septum during the &#8220;step-up&#8221; entry of the 15 Fr sheath.

Ha&#239;ssaguerre et al. originally described the muscular sleeves surround pulmonary veins (PVs) that are arrhythmogenic and initiate the maintenance of atrial fibrillation (AF) symptoms1. Since the initial description, pulmonary vein isolation (PVI) has become a cornerstone of the catheter ablation strategy in the treatment of AF2. Subsequently, catheter ablation devices have been built to facilitate PVI with a variety of energy sources3, and these purpose-built PVI catheters have been sometimes referred to as &#8220;single-shot&#8221; ablation catheters. Currently, the cryoballoon is the only FDA approved single-shot catheter, which is approved for the treatment of drug-refractory, recurrent, and symptomatic paroxysmal AF4. Uniquely, the cryoballoon system allows for a simplified approach to PVI with a favorable safety profile. In the pivotal STOP AF IDE trial, 69.9% of subjects were free of AF at one year4.
Delivery of the cryoballoon catheter to the PVs requires a transseptal catheterization with a 15 French (Fr) outer diameter steerable sheath. A typical transseptal puncture is performed at the fossa ovalis (FO), which is the thinnest part of the septum, and the FO can be an easy point of access into the left atrium (LA) because of the sparsity (or reduction) of septal tissue depth. The cryoballoon system uses guidewire delivery of an inflated balloon catheter, and guidewires can be a traditional J-tip design or a propose-built (multi-polar circular inner-balloon-lumen) mapping catheter for the cryoballoon catheter system. However, different from focal ablation catheters, the cryoballoon catheter uses the anterior balloon surface to push against the atrial tissue surrounding the PV ostium which results in simultaneous delivery of cryothermal energy to the contacting atrial tissue and ultimately the formation of a lesion. Therefore, a cryoballoon catheter approach angle that is more anterior and inferior (near the inferior limbus (IL)) may facilitate a mechanical advantage with regard to push force vectors particularly when ablating the inferior PVs. Also, the IL transseptal position may potentially reduce the occurrence of iatrogenic atrial septal defects (IASD) post-cryoballoon procedure5.
In this study, the primary hypothesis was that the location of transseptal puncture could affect the frequency of acute IASD that is detected immediately post-ablation via transseptal Doppler flow while utilizing intracardiac echocardiography (ICE) examination. Additionally, a secondary objective was to assess the acute rate of PVI achieved with the cryoballoon system while using an anterior and inferior transseptal approach angle (IL location). By examining two alternate transseptal puncture locations (FO versus IL), this study attempted to determine which approach was most beneficial when using the cryoballoon system for the treatment of AF via PVI.
CASE STUDY
From August 2012 to August 2013, this study reviewed 200 consecutive patients who were referred for a cryoballoon AF ablation procedure at a single specialized cardiac-care center. All of the above patients were given a cryoballoon AF ablation, where the transseptal puncture location was near the IL. By retrospective review, these patient charts were examined to determine the rate of acute PVI that was achievable through a singular usage of the cryoballoon ablation catheter without the usage of adjunctive AF ablation catheters. This chart review examination was a single-arm, single-center, data collection. Additionally during the same collection period, 173 patients were examined in a prospective investigation that compared the site of transseptal puncture (FO versus IL) via acute post-procedural ICE imaging of Doppler flow dynamics. This comparison analysis was a double-arm, 3:1 collection (IL to FO transseptal site, respectively), single-center prospective examination. In both evaluations, all patients were symptomatic and drug refractory with a history of AF.
PATIENT SELECTION
In both evaluations, the inclusion criteria for all patients was a documented clinical history of symptomatic AF, a medication refractory treatment of AF by one class I or class III antiarrhythmic drug, and an AF ablation treatment strategy that included a cryoballoon catheter PVI as the primary PV ablation method. Exclusion criteria were patients under 18 years old, patients older than 90 years of age, patients who have had a previous LA ablation, patients who have had a previous transseptal puncture entry, patients who required a double transseptal approach for AF ablation, or patients with permanent AF. All the cryoballoon ablation procedures were conducted at a single experienced cardiac-care center with well over 600 cryoballoon procedures done at this hospital, and all patients were treated with the second generation cryoballoon catheter.

<table border="0" cellpadding="0" cellspacing="0" style="border-collapse:
 collapse;width:429pt">
	<tbody>
		<tr>
			<td class="xl63">Arctic Front Advance Cardiac CryoAblation Catheter</td>
			<td class="xl63">Medtronic, Inc.</td>
			<td class="xl63">2AF284</td>
			<td class="xl64">28mm Cryoballoon catheter</td>
		</tr>
	</tbody>
</table>

reduction of iatrogenic atrial septal defects with an anterior and inferior transseptal puncture site when operating the cryoballoon ablation catheter

The cryoballoon catheter ablates atrial fibrillation (AF) triggers in the left atrium (LA) and pulmonary veins (PVs) via transseptal access. The typical transseptal puncture site is the fossa ovalis (FO) &#8211; the atrial septum&#8217;s thinnest section. A potentially beneficial transseptal site, for the cryoballoon, is near the inferior limbus (IL). This study examines an alternative transseptal site near the IL, which may decrease the frequency of acute iatrogenic atrial septal defect (IASD). Also, the study evaluates the acute pulmonary vein isolation (PVI) success rate utilizing the IL location. 200 patients were evaluated by retrospective chart review for acute PVI success rate with an IL transseptal site. An additional 128 IL transseptal patients were compared to 45 FO transseptal patients by performing Doppler intracardiac echocardiography (ICE) post-ablation to assess transseptal flow after removal of the transseptal sheath. After sheath removal and by Doppler ICE imaging, 42 of 128 (33%) IL transseptal patients demonstrated acute transseptal flow, while 45 of 45 (100%) FO transseptal puncture patients had acute transseptal flow. The difference in acute transseptal flow detection between FO and IL sites was statistically significant (P &#60;0.0001). Furthermore, 186 of 200 patients (with an IL transseptal puncture) did not need additional ablation(s) and had achieved an acute PVI by a &#8220;cryoballoon only&#8221; technique. An IL transseptal puncture site for cryoballoon AF ablations is an effective location to mediate PVI at all four PVs. Additionally, an IL transseptal location can lower the incidence of acute transseptal flow by Doppler ICE when compared to the FO. Potentially, the IL transseptal site may reduce later IASD complications post-cryoballoon procedures.

The 200 consecutive patients that underwent retrospective chart review were all given a transseptal puncture near the IL position. Examination of the equipment list and ablation records are used to established the proportion of patients that achieved PVI with a singular usage of the cryoballoon catheter. An additional group of 173 patients were assessed and tested for the differential usage of transseptal entry location. The data is collected in a 3:1 manner, whereby 128 patients are examined with an IL transseptal location and compared to 45 patients who had a FO transseptal site. Acute IASD rates for FO versus IL transseptal locations are assessed by Doppler ICE imaging and later compared by Fisher&#8217;s exact statistical testing. In this study, statistical significance is set at P &#60;0.05.
In the group of 200 patients undergoing an IL site transseptal puncture, 186 patients (93%) did not require the usage of an additional focal radiofrequency ablation catheter. Representative fluoroscopy images of each of the four PVs during cryoballoon ablation are illustrated in Figure 2A-D. Examination of Figure 2 demonstrates that the cryoballoon catheter and steerable sheath were not required to use full catheter and sheath deflection to achieve PVI at the inferior PVs. Furthermore, analyses of catheter and sheath deflection angles during inferior PV cryoablation via IL transseptal puncture in all 328 patients shows that full cryoballoon catheter and sheath deflection were never necessary to achieve a cryoballoon-to-PV occlusion.
Analysis of the ICE Doppler flow acutely after removal of the ablation sheath revealed that all 45 patients who had a FO puncture site had evidence of atrial septal flow consistent with a small atrial septal defect with left-to-right atrial fluid movement (Qp&#8212;Qs ratio greater than 1). By contrast, 42 of the 128 patients (32.8%) with the IL puncture site demonstrated acute Doppler ICE flow after removal of the transseptal sheath (Figure 3). The difference in acute Doppler flow detection between the IL and FO transseptal puncture site was statistically significant by Fisher&#8217;s Exact testing (P &#60;0.0001).
Lastly, during the entire examination of 373 patients, no patient experienced a pericardial effusion or tamponade. Also, neither septal dissections nor hematoma formations were observed for either FO or IL transseptal techniques. A combination of ICE and fluoroscopy imaging during all procedures demonstrated qualitatively that the IL position often had ample distance at a lower entry position from collateral tissue puncture. In the IL position, the transseptal needle would point towards the mitral valve rather than the left atrial appendage or left atrial roof. Both of the latter two left atrial lateral structures required more imaging attention when utilizing the FO transseptal approach.
Figure 1 demonstrates that &#8220;tenting&#8221; of the FO can help to determine an inferior and anterior transseptal location near the IL. This anterior and inferior transseptal location can allow the cryoballoon catheter to be used with minimal catheter and/or sheath deflection. Specifically, with ablations in the lower PVs, the IL transseptal location allows for a &#8220;more direct&#8221; alignment between the cryoballoon catheter and the tubular section of each PV. As demonstrated in Figure 2, this alignment between the PV and cryoballoon catheter allows for the most direct transfer of occlusion force that is necessary to ensure that a complete and circumferential lesion is created surrounding each PV during the cryoballoon ablation procedure. Incomplete cryoballoon lesion sets are created when there are gaps between the cryoballoon and PV contact, which results in reduced transfer of cold between the balloon and tissue.
Figure 3 illustrates another acute advantage of using the IL location during a cryoballoon ablation procedure. When the FO location is used, immediate withdrawal of the cryoballoon and sheath will often leave an acute left-to-right blood-shunt at the transseptal puncture location, which can be observed with color-flow Doppler imaging. Alternatively the IL location for a transseptal puncture is typically in a thicker part of the septum. Consequently, when the cryoballoon and sheath are removed from the LA, there is less left-to-right shunting of blood, and in some cases there is no detectable blood shunting when viewed by color-flow Doppler imaging.
<img alt="Figure 1" src="/files/ftp_upload/52811/52811fig1highres.jpg" width="700" /> 
Figure 1: ICE images of FO and IL transseptal puncture. (A) The traditional placement of transseptal entry at the fossa ovalis will demonstrate &#8220;tenting&#8221; of the septum tissue due to the sparsity of tissue when viewed by fluoroscopy. (B) An inferior and anterior transseptal approach at the inferior limbus will provided a mechanical advantage when using the cryoballoon catheter. Yellow arrows indicate the transseptal puncture locations. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/52811/52811fig1highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" src="/files/ftp_upload/52811/52811fig2highres.jpg" width="700" /> 
Figure 2: Cryoablation at the PVs. Cryoballoon placement at four pulmonary vein (PV) locations with antral balloon positioning at each vein as view by fluoroscopy. All PV are viewed in LAO positioning with an inferior and anterior transseptal entry position (IL location). (A) The left superior PV is an almost straight-on approach from the transseptal entry, and it is typically the first PV that is ablated because of the ease of guidewire approach. (B) The left inferior PV will use sheath deflection to achieve proper PV-to-balloon occlusion. (C and D) Phrenic nerve pacing will be used to monitor nerve function during right-sided ablations. Both PVs will use sheath deflection, and the right inferior PV (RIPV) will typical use the highest degree of deflection. However, note that with an inferior and anterior approach, the RIPV ablation does not require the maximal deflection capability that is provided in the cryoballoon system. Yellow brackets are the cryoballoon and blue brackets are the steerable sheath. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/52811/52811fig2highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" src="/files/ftp_upload/52811/52811fig3highres.jpg" width="700" /> 
Figure 3: ICE imaging with color-flow Doppler. Doppler images from intracardiac echocardiography. Notice the amount of Doppler flow that is present after catheter removal at the septum when comparing the fossa ovalis transseptal position (A) compared to the inferior limbus position (B). Yellow arrows indicate the transseptal puncture location. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/52811/52811fig3highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" src="/files/ftp_upload/52811/52811fig4highres.jpg" width="500" /> 
Figure 4: Angles of cryoballoon approach into PVs. A virtual reconstruction of FO versus IL transseptal locations. The FO puncture site achieved complete occlusion at the following deflection angles: 131&#176;, 32&#176;, 206&#176;, and 329&#176;. By comparison, the IL transseptal site achieved occlusion with the following deflection angles: 121&#176;, 45&#176;, 182&#176;, and 349&#176;. Note that less catheter deflection is needed in the inferior PVs for the IL location. Green lines are representative of the cryoballoon catheter direction from a FO site, and red lines denote the cryoballoon direction from an IL site. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/52811/52811fig4highres.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Reduction of Iatrogenic Atrial Septal Defects with an Anterior and Inferior Transseptal Puncture Site when Operating the Cryoballoon Ablation Catheter at JoVE

Reduction of Iatrogenic Atrial Septal Defects with an Anterior and Inferior Transseptal Puncture Site when Operating the Cryoballoon Ablation Catheter

The goal of this study is to demonstrate the preferential location of transseptal puncture during a cryoballoon catheter ablation procedure for the treatment of atrial fibrillation.

The cryoballoon catheter ablates atrial fibrillation (AF) triggers in the left atrium (LA) and pulmonary veins (PVs) via transseptal access. The typical ...

reduction-iatrogenic-atrial-septal-defects-with-an-anterior-inferior

Nanyang Technological University

Research

JoVE Journal

Medicine

13.7K Views.  Banner-University Medical Center. The goal of this study is to demonstrate the preferential location of transseptal puncture during a cryoballoon catheter ablation procedure for the treatment of atrial fibrillation.

Video: Reduction of Iatrogenic Atrial Septal Defects with an Anterior and Inferior Transseptal Puncture Site when Operating the Cryoballoon Ablation Catheter

Remote Magnetic Navigation for Accurate, Real-time Catheter Positioning and Ablation in Cardiac Electrophysiology Procedures

New remote navigation systems have been developed to improve current limitations of conventional manually guided catheter ablation in complex cardiac substrates such as left atrial flutter. This protocol describes all the clinical and invasive interventional steps performed during a human electrophysiological study and ablation to assess the accuracy, safety and real-time navigation of the Catheter Guidance, Control and Imaging (CGCI) system. Patients who underwent ablation of a right or left atrium flutter substrate were included. Specifically, data from three left atrial flutter and two counterclockwise right atrial flutter procedures are shown in this report. One representative left atrial flutter procedure is shown in the movie. This system is based on eight coil-core electromagnets, which generate a dynamic magnetic field focused on the heart. Remote navigation by rapid changes (msec) in the magnetic field magnitude and a very flexible magnetized catheter allow real-time closed-loop integration and accurate, stable positioning and ablation of the arrhythmogenic substrate.

This report provides a detailed description of a new remote navigation system based on magnetic driven forces, which has been recently introduced as a new robotic tool for human cardiac electrophysiology procedures.

New remote navigation systems have been developed to improve current limitations of conventional manually guided catheter ablation in complex cardiac ...

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 ...

Direct Pressure Monitoring Accurately Predicts Pulmonary Vein Occlusion During Cryoballoon Ablation

Cryoballoon ablation (CBA) is an established therapy for atrial fibrillation (AF). Pulmonary vein (PV) occlusion is essential for achieving antral contact and PV isolation and is typically assessed by contrast injection. We present a novel method of direct pressure monitoring for assessment of PV occlusion.
Transcatheter pressure is monitored during balloon advancement to the PV antrum. Pressure is recorded via a single pressure transducer connected to the inner lumen of the cryoballoon. Pressure curve characteristics are used to assess occlusion in conjunction with fluoroscopic or intracardiac echocardiography (ICE) guidance. PV occlusion is confirmed when loss of typical left atrial (LA) pressure waveform is observed with recordings of PA pressure characteristics (no A wave and rapid V wave upstroke). Complete pulmonary vein occlusion as assessed with this technique has been confirmed with concurrent contrast utilization during the initial testing of the technique and has been shown to be highly accurate and readily reproducible.
We evaluated the efficacy of this novel technique in 35 patients. A total of 128 veins were assessed for occlusion with the cryoballoon utilizing the pressure monitoring technique; occlusive pressure was demonstrated in 113 veins with resultant successful pulmonary vein isolation in 111 veins (98.2%). Occlusion was confirmed with subsequent contrast injection during the initial ten procedures, after which contrast utilization was rapidly reduced or eliminated given the highly accurate identification of occlusive pressure waveform with limited initial training.
Verification of PV occlusive pressure during CBA is a novel approach to assessing effective PV occlusion and it accurately predicts electrical isolation. Utilization of this method results in significant decrease in fluoroscopy time and volume of contrast.

Effective pulmonary vein isolation utilizing a cryoballoon depends on complete pulmonary vein occlusion. The point of occlusion can be effectively predicted by direct analysis of pulmonary vein pressure waveform analysis during balloon inflation using a simple and reproducible technique.

Cryoballoon  ablation (CBA) is an established therapy for atrial fibrillation (AF).  Pulmonary vein (PV) occlusion is essential for achieving antral ...

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 ...

Non-fluoroscopic Catheter Tracking for Fluoroscopy Reduction in Interventional Electrophysiology

A technological platform (MediGuide) has been recently introduced for non-fluoroscopic catheter tracking. In several studies, we have demonstrated that the application of this non-fluoroscopic catheter visualization system (NFCV) reduces fluoroscopy time and dose by 90-95% in a variety of electrophysiology (EP) procedures. This can be of relevance not only to the patients, but also to the nurses and physicians working in the EP lab. Furthermore, in a subset of indications such as supraventricular tachycardias, NFCV enables a fully non-fluoroscopic procedure and allows the lab staff to work without wearing lead aprons. With this protocol, we demonstrate that even complex procedures such as ablations of atrial fibrillation, that are typically associated with fluoroscopy times of &#62;30 min in conventional settings, can safely be performed with a reduction of &#62;90% in fluoroscopy exposure by the additional use of NFCV.

Radiation exposure is an underestimated risk in complex ablation procedures. Here, we describe a protocol to significantly decrease fluoroscopy time and dosage for both the patient and the lab staff by using a novel non-fluoroscopic catheter visualization system.

A technological platform (MediGuide) has been recently introduced for non-fluoroscopic catheter tracking. In several studies, we have demonstrated that ...

Endoscopic Septoplasty with Limited Two-line Resection: Minimally Invasive Surgery for Septal Deviation

Endoscopic septoplasty is a surgical procedure in otolaryngology that is commonly performed to treat nasal airway obstruction caused by nasal septal deviation. It has a long history with multiple variations. In this article, a modified endoscopic septoplasty procedure using the limited two-line resection (2LoRs) technique at the posterior and inferior junction of the cartilaginous and bony septum is presented based on embryologic and anatomic knowledge of the nasal septum and the biomechanics of cartilaginous behavior. With this procedure, the quadrangular cartilage can be preserved as much as possible, which is helpful in retaining the supporting framework and rigidness of the septum. 2LoRs has been proven effective and sound for the correction of nasal septal deviation with rare complications. This modified procedure can be applied to correct the deviated nasal septum in the absence of any external nasal deformity to improve nasal patency or to improve access to the middle meatus or to the axillary region of the middle turbinate. It may also be used to expand the indications of septoplasty to children and adolescents because of its minimally invasive approach.

Endoscopic septoplasty is a time-honored surgical procedure with multiple variations. This paper focuses on a step-by-step surgical approach to perform a modified septoplasty procedure known as limited two-line resection. This surgical technique can be applied to correct a deviated nasal septum in the absence of an external nasal deformity.

Endoscopic septoplasty is a surgical procedure in otolaryngology that is commonly performed to treat nasal airway obstruction caused by nasal septal ...

Subclavian Vein Puncture As an Alternative Method of Blood Sample Collection in Rats

Blood collection with enough blood volume is essential in animal experiments. Blood collection from the tail vein of rats is popular and less stressful compared to other more aggressive methods such as retro-orbital plexus sample collection. However, this blood collection method is sometimes limited by an unsatisfactory success rate. Here, we introduce a method for blood collection through the subclavian vein puncture. The subclavian vein is located just under the clavicle and this vein is large enough to fulfill the volume requirements of blood collection. Our results show that this method is safe and applicable for blood collection sampling with the required blood volume. Blood collection through the subclavian vein puncture could serve as an alternative blood collection method in case of failed tail vein blood sampling in rats.

Here, we present a protocol to collect blood samples from the rat subclavian vein.

Blood collection with enough blood volume is essential in animal experiments. Blood collection from the tail vein of rats is popular and less stressful ...

Blood Collection Through Subclavian Vein Puncture in Mice

The mouse is the foremost mammalian model for studying human disease and human health. However, blood sample collection from mice is challenging in research work. Tail blood collection is a popular method when a small amount of blood sample is needed. Orbital artery could be considered if a large amount of blood is needed but this blood collection method has ethical issues. Formerly, we demonstrated the feasibility and safety of blood sample collection through subclavian vein puncture in rats, and here we investigate whether this method could be used in mice. We report that this method is safe and practical for blood collection in mice. Blood collection through the subclavian vein puncture in mice can be a convenient method in daily research works.

Here, we present a protocol to take blood samples from the subclavian vein of mice.

The mouse is the foremost mammalian model for studying human disease and human health. However, blood sample collection from mice is challenging in ...

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 ...

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. ...