Epicardial Connections Between the Pulmonary Veins and Left Atrium: Relevance for Atrial...

149

Epicardial Connections Between the Pulmonary Veins and LeftAtrium: Relevance for Atrial Fibrillation Ablation

NICASIO PEREZ-CASTELLANO, M.D., Ph.D., JULIAN VILLACASTIN, M.D., Ph.D.,JORGE SALINAS, M.D., MERCEDES VEGA, M.D., JAVIER MORENO, M.D., Ph.D.,

MANUEL DOBLADO, M.D., EDUARDO RUIZ, M.D., and CARLOS MACAYA, M.D., Ph.D.

From the Unit of Arrhythmias, Cardiovascular Institute, San Carlos University Hospital, Madrid, Spain

Epicardial Connections Between PVs and the LA. Introduction: Some observations support theexistence of epicardial connections (ECs) between ipsilateral pulmonary veins (vein to vein ECs [VVECs]),and we have observed venoatrial ECs inserted at distance from the pulmonary vein ostium (vein to atriumECs [VAECs]). Our aim was to determine the prevalence of ECs and their relevance for pulmonary veinisolation.

Methods and Results: We studied 100 consecutive patients with drug-refractory atrial fibrillation whounderwent ostial pulmonary vein isolation by cooled radiofrequency catheter ablation. A VVEC wasidentified if pulmonary vein pacing activated the ipsilateral vein before the atrium, requiring ablationof both venous ostia to isolate either pulmonary vein. A VAEC was identified if pacing produced atrialbreakthrough located at distance from the venous ostium, requiring extraostial ablation to isolate thepulmonary vein. Patients with ECs (20%) were younger (P = 0.02) and had a higher prevalence of structuralheart disease (P = 0.01) than patients without ECs. VVECs and VAECs were identified in 32 pulmonaryveins (10%) and VAECs in 10 veins (3%). Veins with ECs had a higher rate of early recurrence of conductionfollowing isolation (29% vs 11%; P = 0.01).

Conclusion: Twenty percent of patients with atrial fibrillation had ECs resistant to ostial ablation in one ormore pulmonary veins. Isolating veins with ECs may require a different ablation approach. These connec-tions are associated with an increased rate of early recurrence of conduction. (J Cardiovasc Electrophysiol,Vol. 22, pp. 149-159, February 2011)

atrial fibrillation, catheter ablation, epicardium, pulmonary vein isolation

Introduction

Atrial fibrillation (AF) may be triggered by ectopic beatsoriginating in sleeves of atrial myocardium entering the pul-monary veins (PVs).1-3 The direct ablation of these foci mayprevent AF recurrence.1-3 However, the ability to locate thesefoci is limited and radiofrequency applications inside the PVsare associated with a risk of PV stenosis.4-8 Consequently,PV isolation was proposed and demonstrated to be more ef-fective and safer than the direct ablation of ectopic foci.9-12

Techniques used to isolate PVs assume that electrical im-pulses arising from a PV arrive at the atrium through theipsilateral PV ostium. Thus, the creation of a barrier of un-excitable tissue at the ostium by consecutive radiofrequencyapplications may block the propagation of ectopic beats tothe atrium and prevent the initiation or maintenance of AFepisodes. However, we have observed in our clinical practicethat electrical impulses arising from a PV might be propa-gated through pathways other than the venoatrial continu-ity at the vein’s own ostium, such as epicardial connections

J. Salinas reports serving as consultant to and/or on the advisory board ofSt. Jude Medical. Other authors: No disclosures.

Address for correspondence: Nicasio Perez-Castellano, M.D., Ph.D.,Unidad de Arritmias, Instituto Cardiovascular, Hospital Clınico San Carlos,C./Profesor Martın Lagos, s/n 28040 Madrid, Spain. Fax: +34-91-3303527;E-mail: [email protected]

Manuscript received 5 August 2009; Revised manuscript received 15 June2010; Accepted for publication 6 July 2010.

doi: 10.1111/j.1540-8167.2010.01873.x

(ECs) with a nearby PV (vein to vein ECs [VVECs]) orepicardial venoatrial connections inserted at distance fromthe PV ostium (vein to atrium ECs [VAECs]). Our aim inthis prospective study was to determine the prevalence ofepicardial electrical connections in the PVs of patients withsymptomatic recurrent AF who underwent PV isolation, andthe relevance of this condition for the management of AF.

Methods

Patients

Participants in the present study were 100 consecutive pa-tients with symptomatic recurrent AF (either paroxysmal orpersistent) refractory to class I or III antiarrhythmic drugs,who were referred to our institution for first AF ablation pro-cedure. The procedures and ablation technique used in thisstudy were approved by our institutional review committee.All patients provided written informed consent.

Procedures

Before the procedure, left atrial thrombus was ruled outby transesophageal echocardiography. A cardiac magneticresonance imaging study was performed, transferred to theCartoMerge R© electroanatomical mapping system (BiosenseWebster Inc., Diamond Bar, CA, USA), and processed toextract a 3D reconstruction of the left atrium and proximalsegments of the PVs.

Procedures were performed with patients in the fastingstate under conscious sedation and analgesia with propofoland remifentanil. Three introducers (6-, 8-, and 11-French)

150 Journal of Cardiovascular Electrophysiology Vol. 22, No. 2, February 2011

were placed into the right femoral vein. A 6-French, 24-pole catheter (Orbiter Large Curve R©, Bard Electrophysiol-ogy Inc., Lowell, MA, USA) was partially introduced into thecoronary sinus for recording and pacing at different sites ofthe right and left atrium as necessary. An 8-French transseptalsheath mounted on a Brockenbrough needle was advanced tothe left atrium through the posterior part of the fossa ovalis.A 10-French, phased array, intracardiac echocardiographycatheter (Acuson AcuNav R© Diagnostic Ultrasound Catheter,Siemens Medical Solutions Inc., Malvern, PA, USA) wasused to guide transseptal puncture.

Once transseptal puncture was performed, systemic an-ticoagulation with intravenous heparin was initiated aimingfor an activated clotting time >250 seconds. Selective PVangiograms were obtained during hand injection of 10 mLof contrast (Visipaque R©, Amersham Health, Cork, Ireland)through a 6-French, 145◦ angled, pigtail catheter (Super-torque Plus R©, Cordis Corp., Miami, FL, USA). Then theintracardiac echocardiography catheter was replaced with anopen irrigation ablation catheter (Navistar R© Thermo-cool R©,Biosense Webster Inc.) that was flushed at 2 mL/min andfreely introduced into the left atrium through the transseptalpuncture. This maneuver often required removing the sheathtemporarily from the left atrium, leaving a guidewire in placeto cross the interatrial septum again. A 15-mm diameter cir-cular decapolar catheter (Lasso R©, Biosense Webster) wasadvanced to the left atrium through the transseptal sheath.At this point, patients in AF were cardioverted. Sustainedepisodes of AF occurring later during the ablation were alsocardioverted. Then a shell of the left atrium and proximalportion of the PVs was built on the CartoMerge R© systemand was integrated with the magnetic resonance imaging re-construction. Special care was taken to achieve an accuraterepresentation of the PV ostia.

Ablation

Ablation was done by ostial electrical isolation of all PVs,guided by PV recordings obtained with the Lasso R© catheterand facilitated by simultaneous use of the CartoMerge R© sys-tem, which provided continuous 3D location of the ablationcatheter with reference to the integrated electroanatomicalmap. The Lasso R© catheter was introduced into every targetedPV before ablation. The temperature limit was set at 45◦C andthe power limit was set at 35 W, allowing a 5-W reduction inthe limit for small PVs and a 5-W increase for focal applica-tions at sites resistant to ablation or recurrent gaps. Irrigationwas set at 15 mL/min during radiofrequency delivery. PVswere isolated during sinus rhythm or coronary sinus pacingby delivering radiofrequency energy at ostial sites with theearliest PV potentials. Radiofrequency energy was deliveredas dragging or consecutive point-to-point applications, at theoperator’s discretion, depending on catheter steerability andstability at the site. Ablation tags were manually acquiredevery 15–20 seconds of radiofrequency application in theCartoMerge R© system synchronized with the GE Cardiolab R©IT Electrophysiology Monitoring system (GE Medical Sys-tems Information Technologies GmbH, Freiburg, Germany).Temperature and power limit settings, application duration,and temperature and power reached during every radiofre-quency application were recorded.

The endpoint of ablation was to achieve bidirectional PVconduction block. Entry block was achieved when all PV po-

tentials disappeared during sinus rhythm or left atrial pacing.Then high-output pacing (10 mA, 2-ms pulse width) was per-formed from every dipole of the Lasso catheter positioned atthe proximal part of the PV to assess exit block. The absenceof left atrial capture during pacing was indicative of exitblock. In most cases, a progressive reduction of the pacingoutput decreased pacing artifacts and allowed us to verify PVlocal capture. Bidirectional block was also determined by thepresence of venoatrial dissociation during spontaneous PVectopic activity.

Identification of PV Epicardial Connections

If PV conduction persisted after delivering radiofrequencyenergy at the entire PV ostium, the ablation catheter was in-troduced into the ipsilateral PV and the targeted PV waspaced from the Lasso R© catheter. Pacing was performed justabove the threshold voltage for 2 ms pulse width to avoid dis-tant capture, reduce pacing artifacts and facilitate the recogni-tion of PV local capture. Distant capture of the ipsilateral PVor the adjacent left atrium was ruled out by pacing just abovethe threshold voltage from different dipoles of the Lasso R©catheter, particularly from the ones farthest from these struc-tures (for example, the left inferior PV could be capturedduring high-output pacing at the floor of the left superiorPV, but not during low-output pacing at the roof of the leftsuperior PV), and by the observation of a delay between thepacing artifact and the earliest electrical activation recordedoutside the paced PV.

Three different conditions could be identified: venoatrialconduction through one or multiple gaps in the ablationcircumference, venoatrial conduction through VVECs, andvenoatrial conduction through VAECs inserted at distancefrom the VAECs. The method we used to differentiate amongthese 3 situations is detailed in Figure 1, and real examplesare shown in Figures 2–4.

Monitoring for Recurrence of PV Conduction

After isolation of every PV, the Lasso R© catheter was in-troduced into the previously disconnected PVs to monitor forconduction recurrence. Monitoring lasted at least 10 minutesafter the last PV was isolated. If PV conduction recurred, theconduction gap was located and the PV was isolated again.

Postablation Care and Follow-Up

Oral anticoagulants, subcutaneous enoxaparin (1 mg/kg/12h), and antiplatelet drugs were started 4 hours after abla-tion. Enoxaparin was maintained until the international nor-malized ratio was >2. Previous antiarrhythmic drug therapywas discontinued, except in patients with either persistentAF or structural heart disease. All patients were seen inour outpatient clinic 1 month after ablation and then every3 months. A 24-hour Holter recording was performed be-fore every scheduled follow-up and when there were symp-toms suggestive of AF recurrence. Documented episodes ofsymptomatic or asymptomatic AF, regardless of their dura-tion, were considered AF recurrences. AF episodes occurringwithin the first month after ablation were blanked for anal-ysis. Magnetic resonance imaging was done 3 months afterablation to search for PV stenosis.

Perez-Castellano et al. Epicardial Connections Between PVs and the LA 151

Figure 1. Use of PV pacing to identify the reason for persistent PV conduc-tion despite ostial PV ablation. A Lasso R© and an ablation catheter wereintroduced into the targeted PV and the ipsilateral PV, respectively. Ideally,these catheters should be placed near the PV ostia to record PV and atrialpotentials simultaneously. Panels A, B, and C represent 3 hypothetical sit-uations that may be responsible for persistent PV conduction despite ostialablation. These situations are arbitrarily illustrated in the left superior (tar-geted) PV and left inferior (ipsilateral) PV. Panel A: Conduction throughone or multiple gaps in the ablation circumference. In this case, when thetargeted PV is paced, local PV potentials (1) are followed by atrial poten-tials recorded at the conduction gap (2) located somewhere on the ablationcircumference. Then electrical activation is propagated to atrial tissue sur-rounding the ipsilateral PV (3), and finally to the ipsilateral PV (4). ThePV can be isolated by mapping the ablation circumference and ablating theconduction gaps. Panel B: Direct epicardial connection between ipsilateralPVs. In this situation, ipsilateral PVs directly activate each other, and thetargeted PV may remain electrically connected to the left atrium despiteachieving local conduction block all around its ostium. When the targeted

Statistical Methods

Continuous variables did not follow a normal distributionaccording to the Shapiro-Wilk test, so they are presentedas medians (25th–75th percentile) and were compared withnonparametric tests. The Fisher exact test was used to com-pare categorical variables between 2 groups with expectedvalues <5. Otherwise, categorical variables were comparedwith the chi-squared test. Multiple stepwise logistic regres-sion was used to analyze the independent effect of baselinecharacteristics on the existence of ECs. PV conduction andAF recurrences were analyzed by Kaplan and Meier sur-vival analysis, and the significance level was calculated withthe Wilcoxon test. All results were analyzed with a 2-sidedsignificance level of 0.05. Data analyses were done withJMP R© software (version 5.0.1.2, SAS Institute Inc., Cary,NC, USA).

Results

One hundred consecutive patients referred for a first AFablation procedure were included in this study. Medianage of the study population was 55 years (25th–75th per-centile = 45–62 years). Seventy-seven patients were men,34 had hypertension, and 25 patients had structural heart dis-ease. Median anteroposterior left atrial diameter was 42 mm(25th–75th percentile = 40–45 mm). AF was paroxysmal in72 patients and persistent in 28 patients.

Prevalence of Epicardial Connections

A total of 366 PVs were identified in the study population.Three hundred and thirty-eight PVs (85 right superior, 81right inferior, 4 right middle, 8 right common, 67 left superior,63 left inferior, and 30 left common PVs) were individuallytargeted by ostial electrical isolation. The remaining 28 PVs(7.6%) were not targeted due to the absence of clear PVpotentials inside, and were excluded from analysis.

Among the 338 targeted PVs, 301 (89%) were success-fully isolated by delivering radiofrequency applications attheir ostia. The remaining 37 PVs (11%) were resistant toostial ablation. The cause for persistent conduction despiteostial ablation was the existence of VVECs in 32 PVs (9.5%)and VAECs in 10 PVs (3%). Five PVs (1.5%) had both typesof EC.

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−PV is paced, local PV potentials (1) are followed by ipsilateral PV poten-tials (2), and the atrial breakthrough is located somewhere on the ipsilateralPV ostium (3). From here, the wavefront is propagated to the atrial tissuesurrounding the targeted PV ostium (4) and the rest of left atrium. PV isola-tion requires the ablation of both PV ostia. Panel C: Epicardial venoatrialconnection. In this case, when the targeted PV is paced, the atrial break-through is located at distance from its ostium. Thus, paced PV potentials (1)are followed by atrial electrograms recorded by other mapping catheterssuch as a CS catheter (2), and activation of the atrial tissue surroundingthe targeted PV ostium occurs later (3). If the atrial breakthrough is locatednear the ostium of the ipsilateral PV, a direct epicardial connection betweenipsilateral PVs should be ruled out before making the diagnosis of epicar-dial venoatrial connection. This type of connection is better identified bythe construction of left atrial activation maps on electroanatomical mappingsystems during pacing from the targeted PV. These PVs may be disconnectedremotely from the ostium by delivering radiofrequency energy to the atrialbreakthrough. CS = coronary sinus; LIPV = left inferior PV; LSPV = leftsuperior PV; PV = pulmonary vein; RF = radiofrequency.


Figure 2. Persistence of conduction in a RSPV after ostial ablation, due to the existence of an epicardial connection with an ipsilateral PV (RMPV). Eachtracing panel shows, from top to bottom, surface lead I and recordings from an ablation catheter introduced into the RMPV, a decapolar Lasso R© catheterintroduced into the RSPV (5 dipoles), and 3 dipoles of a multipolar catheter introduced into the CS (9–10 at the CS ostium). The ablation catheter recordsRMPV potentials (labeled in red). The Lasso R© catheter records RSPV potentials and the surrounding atrial potentials (labeled in blue). Stimulus artifactsare labeled as S. All tracing panels are at the same paper speed (100 ms between large ticks), except B (200 ms between large ticks). Panel A: Baselinerecordings. Two sinus beats enter the RMPV and RSPV. Panel B: Recordings obtained after full circumference ablation at the RSPV ostium. Entry block hasnot been achieved yet, although RSVP activation has been delayed. Compared to baseline recordings in panel A, the P–RSPV interval (time from P waveonset to the earliest RSPV potential) increased from 50 ms to 100 ms. RSPV pacing was used to distinguish between slow conduction through gaps at theRSPV ostium and conduction through epicardial connections. Panel C: RSPV pacing (dipole 3–4 of the Lasso R© catheter) after full circumference ablationat the RSPV ostium. There is constant capture of RSPV potentials (PV) and the RMPV is activated (PV′) earlier than the atrial tissue surrounding the ostiumof the RSPV (A). Note that RMPV potentials (PV′) are also earlier than P wave onset. This response strongly supported the existence of a direct epicardialconnection between these 2 veins. Thus, the RMPV was targeted instead of delivering more radiofrequency applications at the RSPV. Panel D: Occurrenceof entry block of the RSPV (3rd and 4th beats) during ostial ablation of the RMPV. It further supports that full local conduction block had been createdaround the RSPV ostium and that this PV was activated via an epicardial connection with the RMPV. Panels E and F: CartoMerge R© maps obtained aftercomplete isolation of the right PVs. Panel E is an outer view of the right PVs (cranial-right anterior oblique projection). Panel F is an inner view of theright PV ostia (left lateral projection). Both panels show the 3 independent ablation circumferences (white ovals) for the RSPV, RMPV, and RIPV. Red tagsare ablation sites. Flags are RSPV ostium landmarks that were used, together with left PV ostia landmarks and atrial wall anatomical points (white dots),to merge the anatomical map with the patient’s cardiac magnetic resonance imaging. The blue tag is an anatomical landmark of the RSPV posterior wall,slightly distal to the ablation level. Panel G: Exit block during pacing from the RSPV (dipole 5–6). Local capture of the RSPV is clearly appreciated (PV).Note that electrical activation is propagated to the RMPV (PV′) in the presence of venoatrial dissociation, which demonstrates the existence of the epicardial


VVECs were more frequent in left PVs (13.8%) than inright PVs (5.6%, P = 0.01). VAECs were found only incommon trunks or superior PVs, and were also more frequentin left PVs (5%) than in right PVs (1.1%, P = 0.05).

Electrophysiological Diagnosis of EpicardialConnections

In a patient-based analysis, 20 individuals (20%) had atleast 1 PV with ECs. Table 1 shows electrophysiological datasupporting the diagnosis of ECs in these patients. In all cases,the existence of ECs was considered when complete ostial ab-lation failed to disconnect a PV. When a diagnosis of VVECwas made, the interval between the onset of the sinus P waveand the earliest PV potential recorded inside the targeted PV(P-PV interval) was increased by a median of 53 ms (25th–75th percentile = 46–60 ms) over baseline. The shortestinterval between atrial and PV potentials at the targeted PV(A–P interval) was 75 ms (25th–75th percentile = 61–85 ms).When the targeted PV was paced, there was also a prolongedinterval between the pacing artifact and local atrial potentials(median SA interval of 108 ms [25th–75th percentile = 95–120 ms]), and the ipsilateral PV was activated a median of63 ms (25th–75th percentile = 51–65 ms) before the atrialtissue next to the targeted PV. This was the main indicatorof the existence of a VVEC (negative A–PV′ intervals).

In 11 of 16 cases of VVECs, the targeted PV was blockedafter ostial ablation of the ipsilateral PV. In the remaining 5cases, ablation of the ipsilateral PV produced an additionalincrease in the P–PV interval (median 25 ms [25th–75th per-centile = 20–35 ms]), and the A–PV interval increased to105 ms (25th–75th percentile = 88–108 ms). At this point,when the first targeted PV was paced, the S–A interval in-creased to 120 ms (25th–75th percentile = 113–125 ms) andthe earliest atrial activation site was recorded remotely fromthe targeted PV ostium. This supported the additional pres-ence of a VAEC. Five additional PVs had single VAECs.Three of them were in the left common PV trunks. In theremaining 2 cases, when the targeted PV was paced, the ip-silateral PV was activated 55 and 65 ms after the local atrialpotentials surrounding the targeted PV ostium (positive A–PV′ intervals), and ostial isolation of the ipsilateral PV hadno effect on venoatrial conduction in the first PV. When the10 PVs with VAECs were paced, the earliest atrial activationsite was recorded 38 ms (25th–75th percentile = 34–40 ms)before the local atrial potentials surrounding the targeted PV.Ablation at the earliest activation site was successful in 7of 10 cases. The sites of successful ablation were located amean of 17 mm (25th–75th percentile = 15–20 mm) fromthe targeted PV ostium.

Baseline Characteristics Associated with EpicardialConnections

Patients with ECs in their PVs were younger and hada higher prevalence of structural heart disease. There were

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−connection between the RSPV and the RMPV. Panel H: Exit block during pacing from the RMPV. Note that when the RMPV is paced (S), the impulses arealso propagated to the RSPV (PV′) in the presence of venoatrial dissociation, which proves the existence of a bidirectional epicardial connection betweenthese veins. Panel I: During RSPV pacing at 200 ms cycle length there was constant capture of the RSPV (PV) with failure of one-to-one activation of theRMPV (PV′) in the presence of venoatrial dissociation. Conduction time from the RSPV to the RMPV was variable between blocked impulses, sometimessuggestive of a Wenckebach phenomenon. A = atrium; RIPV = right inferior PV; RMPV = right middle PV; RSPV = right superior PV. Other abbreviationsas in Figure 1.

no significant differences in other baseline characteristics(Table 2). After adjustment for gender, hypertension, leftatrial diameter, and type of AF, the effect of age (OR 0.94[95% confidence interval = 0.89–0.98] per year increase;P = 0.02) and structural heart disease (OR 5.2 [95% confi-dence interval = 1.4–19]; P = 0.01) remained significant.

ECs were not associated with the temperature or thepower of the radiofrequency applications delivered beforetheir identification (Table 3).

Difficulty of PV Isolation

In the absence of associated VAECs, VVECs did not makePV isolation more difficult other than the need to identifythis situation and target both PVs to disconnect either one.The time and amount of radiofrequency energy needed todisconnect 2 ipsilateral PVs were the same whether they weredirectly connected or not. All such PVs were successfullyisolated.

In contrast, PVs with VAECs were very hard to isolate.Disconnecting these PVs required much more time and ra-diofrequency energy than the remaining PVs (Table 4). Fur-thermore, isolation was achieved in only 7 of 10 PVs withVAECs (70%) whereas all PVs without VAECs were suc-cessfully disconnected (P < 0.01).

PV Conduction Recurrence

PV conduction was monitored for a median of 35 min-utes (25th–75th percentile = 14–60 minutes) after completeisolation. Monitoring time was similar in PVs with and with-out ECs (36 [25th–75th percentile = 20–71] minutes vs 35[25th–75th percentile = 13–60] minutes; P = NS). Conduc-tion recurrence was detected in 10 of 35 PVs (28.6%) withECs and 33 of 292 PVs (11.3%) without ECs (P = 0.01).Figure 5 shows the incidence of early conduction recurrencein both groups according to Kaplan-Meier analysis. Bidi-rectional block was achieved again with a median numberof 4 (25th–75th percentile = 3–7) radiofrequency applica-tions in PVs with ECs and 5 (25th–75th percentile = 3–8)applications in PVs without such connections (P = NS).

Follow-up

All patients were followed up for a minimum of 1 yearafter ablation (21 [25th–75th percentile = 16–29] monthsin patients with ECs vs 21 [25th–75th percentile = 15–27]months in patients without ECs; P = NS). There was nosignificant difference in AF-free survival rate between the2 groups of patients (75% vs 68%, respectively; P = NS).Magnetic resonance imaging was performed 3 months afterablation in 94 patients. No PV developed significant stenosisafter ablation.

Discussion

This study provides evidence of electrical impulse con-duction pathways between the PVs and the left atrium other


Figure 3. Persistence of conduction in a LSPV despite ostial ablation, due to the existence of epicardial connections between the left PVs and between theLSPV and the left atrium. Each tracing panel shows, from top to bottom, surface lead I, III, and V1, and recordings from an ablation catheter introducedinto the LIPV, a decapolar Lasso R© catheter introduced into the LSPV (5 dipoles), and 3 dipoles of a multipolar catheter introduced into the coronarysinus (9–10 at the CS ostium). Top, middle, and bottom panels were obtained at baseline, after LSPV ostial ablation, and after LIPV ostial ablation,respectively. Left and right panels were obtained during sinus rhythm and during left superior PV pacing at 500 ms cycle length, respectively. Duringsinus rhythm, calipers indicate P-LSPV intervals (time from P wave onset to the earliest LSPV potential). During LSPV pacing, calipers indicate P–Aintervals (time from P wave onset to the earliest atrial potential surrounding the LSPV ostium recorded with the Lasso R© catheter). Stimulus artifactsare labeled as S. All tracing panels are at the same paper speed (100 ms between large ticks). Panel A: At baseline, atrial and PV potentials are fusedduring sinus rhythm in both left PVs. The P–LSPV interval is difficult to measure; however, maximum value is 110 ms. Panel B: During LSPV pacing, Pwave onset appears 45 ms later than the stimulus artifact. Atrial potentials surrounding the LSPV ostium (A) can be observed 15 ms before P wave onset


Figure 4. Top panel: Left atrial activa-tion map integrated with 3D magneticresonance (CartoMerge R©, Biosense-Webster) performed during LSPV pacing,in a patient who had an epicardial con-nection between the LSPV and the pos-terior wall of the left atrium. Ostial ab-lation of the left PVs had already beenperformed, but only the LIPV had beendisconnected. During LSPV pacing, theatrial breakthrough was located on theposterior wall of the left atrium, 20 mmaway from the LSPV ostium. Focal abla-tion at this site disconnected the LSPV.On the right, from top to bottom, surfaceleads I, II, III, and V1, and intracardiacrecordings from the ablation catheter po-sitioned at the earliest activation site, adecapolar Lasso R© catheter introducedinto the LSPV (5 dipoles), and a mul-tipolar catheter introduced into the CS(4 dipoles). The LSPV is paced from theLasso R© catheter (dipole 1–2). The stim-ulus artifact (S) is followed by tiny lo-cal LSPV potentials (dipoles 7–8 and 9–10). Careful mapping with the ablationcatheter failed to disclose the atrial break-through surrounding the LSPV ostium. Infact, activation of the atrial tissue adja-cent to the LSPV ostium, recorded fromthe Lasso R© catheter (A), occurred 45 mslater than P wave onset and was precededby atrial potentials recorded at more dis-tant sites (A′) such as the successful ab-lation site (50 ms earlier, asterisk) andthe distal CS (20 ms earlier). This tracingis at double paper speed (50 ms betweenlarge ticks). Bottom panel: Tracings ob-tained after ablation of the earliest acti-vation site (100 ms between large ticks).During sinus rhythm LSPV ectopic beatsoccur dissociated from atrial activation.During LSPV pacing, constant capture oflocal potentials (PV) and venoatrial dis-sociation are evident. Abbreviations as inFigure 1.

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−(P–A interval–15 ms). Panel C: LSPV ostial ablation has not produced entry block, although LSPV activation has been delayed. Now the P–LSPV intervalis 150 ms (at least 40 ms longer than at baseline). LSPV pacing was used to distinguish between slow conduction through gaps at the LSPV ostium andconduction through epicardial connections. Panel D: During LSPV pacing, the earliest atrial potential surrounding the LSPV ostium (A) now appears 25 mslater than P wave onset (increase of 40 ms over baseline), suggesting an atrial breakthrough distant from the LSPV ostium. In fact, the earliest electricalactivation is recorded in the LIPV. LIPV potentials (PV′) are followed by atrial potentials surrounding the LIPV (A′) and later by atrial potentials surroundingthe LSPV (A). This strongly supports the existence of an epicardial connection between the left PVs and local conduction block at the LSPV ostium. Thus,the LIPV was targeted instead of delivering additional radiofrequency applications to the LSPV. Panel E: Ostial ablation of the LIPV produced entry blockat the LIPV (note the disappearance of PV′ potentials observed in panel C) and an additional delay of 40 ms in P–LSPV interval. The delay between local Apotentials and LSPV potentials is 105 ms. The additional delay in the activation of the LSPV after LIPV isolation suggests an additional propagation pathwaybetween the left atrium and the LSPV. The connection between the left PVs was probably damage during LIPV ablation, which made LIPV disconnectionpossible. Panel F: During LSPV pacing, atrial potentials surrounding the LSPV ostium (A) appear at least 45 ms later than P wave onset. The P–A intervalhas increased by 20 ms. There is a long isoelectric segment between the pacing artifact and the A potentials surrounding the LSPV ostium. Morphologicalchanges in the paced P wave are evident (compared to panels B and D). These observations suggest a shift in the exit site. An epicardial venoatrial connectionbetween the LSPV and a distant atrial site was suspected, and left atrial activation mapping done during LSPV pacing located the atrial breakthrough onthe posterior wall of the left atrium. Ablation at this site disconnected the LSPV (Figure 4). Abbreviations as in Figure 1.


TA

BL

E1

Ele

ctro

phys

iolo

gica

lDat

aSu

ppor

ting

the

Dia

gnos

isan

dL

ocat

ion

ofth

eE

pica

rdia

lCon

nect

ions

Foun

din

the

Stud

yPo

pula

tion

Aft

erO

stia

lAbl

atio

nA

fter

Ost

ialA

blat

ion

ofth

eTa

rget

edP

Vof

the

Ipsi

late

ralP

VD

iagn

osis

Sinu

sR

hyth

mTa

rget

edP

VP

acin

gSi

nus

Rhy

thm

Targ

eted

PV

Pac

ing

Site

ofP

VP

VTa

rget

edV

VV

AD

isco

nnec

tion

IDP

atte

rnP

V�

P–P

VA

–PV

S–A

A–P

V′

A–A

′�

P–P

VA

–PV

S–A

A–A

′E

CE

C(m

mfr

omO

stiu

m)

EC

14

PVs

LSP

V45

5590

–45

–40

2080

110

–40

++

No

disc

onne

ctio

nE

C2

4PV

sL

SPV

5570

105

–65

–40

Bid

irec

tiona

lblo

ckin

both

PVs

+–

LIP

Vos

tium

EC

34

PVs

LSP

V40

5090

55–3

00

5090

–30

–+

No

disc

onne

ctio

nE

C4

4PV

sL

SPV

5065

100

–60

–40

Bid

irec

tiona

lblo

ckin

both

PVs

+–

LIP

Vos

tium

RSP

V60

9012

565

–40

090

125

–40

–+

LA

roof

(22)

EC

54

PVs

LSP

V45

5595

–50

–35

Bid

irec

tiona

lblo

ckin

both

PVs

+–

LIP

Vos

tium

EC

6L

CPV

LC

PV40

5090

–30

The

reis

noip

sila

tera

lPV

–+

No

disc

onne

ctio

nE

C7

4PV

sR

SPV

5085

95–5

5–4

020

105

120

–40

++

Post

erio

rL

A(1

5)E

C8

4PV

sL

SPV

6080

115

–70

–45

Bid

irec

tiona

lblo

ckin

both

PVs

+–

LIP

Vos

tium

EC

9L

CPV

LC

PV40

5085

–35

The

reis

noip

sila

tera

lPV

–+

VO

Mar

ea(1

9)E

C10

RM

PVR

SPV

5090

130

–70

–40

Bid

irec

tiona

lblo

ckin

both

PVs

+–

RM

PVos

tium

EC

114

PVs

LSP

V50

6595

–50

–35

2595

115

–35

++

VO

Mar

ea(1

5)E

C12

4PV

sR

SPV

6070

110

–60

–40

Bid

irec

tiona

lblo

ckin

both

PVs

+–

RIP

Vos

tium

EC

13L

CPV

LC

PV55

7511

5–3

5T

here

isno

ipsi

late

ralP

V–

+Po

ster

ior

LA

(17)

EC

144

PVs

LSP

V65

8513

0–6

5–4

5B

idir

ectio

nalb

lock

inbo

thPV

s+

–L

IPV

ostiu

mE

C15

4PV

sL

SPV

6080

95–6

5–4

030

110

120

–40

++

VO

Mar

ea(1

7)E

C16

4PV

sL

SPV

8095

140

–85

–55

Bid

irec

tiona

lblo

ckin

both

PVs

+–

LIP

Vos

tium

EC

174

PVs

LSP

V60

8512

0–6

5–4

5B

idir

ectio

nalb

lock

inbo

thPV

s+

–L

IPV

ostiu

mE

C18

4PV

sR

SPV

6090

120

–60

–45

Bid

irec

tiona

lblo

ckin

both

PVs

+–

RIP

Vos

tium

EC

19R

MPV

RIP

V45

5095

–45

–25

Bid

irec

tiona

lblo

ckin

both

PVs

+–

RM

PVos

tium

EC

204

PVs

LSP

V40

6011

0–6

5–5

040

105

130

–50

++

Post

erio

rL

A(2

0)

The

tabl

esh

ows

the

patie

ntid

entifi

catio

nnu

mbe

r,th

ePV

anat

omic

alpa

ttern

,th

eta

rget

edPV

,PV

cond

uctio

ntim

ein

terv

als

duri

ngsi

nus

rhyt

hman

ddu

ring

paci

ngfr

omth

eta

rget

edPV

afte

ros

tial

isol

atio

n,PV

cond

uctio

ntim

ein

terv

als

duri

ngsi

nus

rhyt

hman

ddu

ring

paci

ngfr

omth

eta

rget

edPV

afte

ros

tiali

sola

tion

ofth

eip

sila

tera

lPV

,typ

eof

epic

ardi

alco

nnec

tion,

and

site

ofsu

cces

sful

PVdi

scon

nect

ion

(dis

tanc

efr

omPV

ostiu

m).

Ana

tom

ical

patte

rn:4

PVs=

4si

ngle

PVos

tia;L

CPV

=le

ftco

mm

onPV

ostiu

m;R

MPV

=ri

ghtm

iddl

ein

depe

nden

tPV

ostiu

m.D

urin

gsi

nus

rhyt

hm,(

1)�

P–PV

inte

rval

indi

cate

sth

ein

crea

sein

the

time

elap

sed

from

Pw

ave

onse

tto

the

earl

iest

PVpo

tent

ialr

ecor

ded

inth

eta

rget

edPV

afte

ros

tiala

blat

ion;

(2)

A–P

Vin

terv

alin

dica

tes

the

shor

test

inte

rval

obse

rved

betw

een

atri

alan

dPV

pote

ntia

lsre

cord

edin

the

targ

eted

PVaf

ter

ostia

lab

latio

n.W

hen

the

targ

eted

PVw

aspa

ced,

(1)

S–A

inte

rval

indi

cate

sth

etim

eel

apse

dbe

twee

nth

est

imul

usar

tifac

tand

the

earl

iest

atri

alel

ectr

ogra

mre

cord

edfr

omth

eta

rget

edPV

ostiu

m;

(2)

A–P

V′ i

nter

vali

ndic

ates

the

time

elap

sed

betw

een

the

earl

iest

atri

alel

ectr

ogra

mre

cord

edfr

omth

eta

rget

edPV

and

the

activ

atio

nof

the

ipsi

late

ralP

V(n

egat

ive

valu

esin

dica

teth

atth

eip

sila

tera

lPV

isac

tivat

edbe

fore

the

atri

umsu

rrou

ndin

gth

eta

rget

edPV

,and

vice

vers

a);

(3)

A–A

′ int

erva

lin

dica

tes

the

time

elap

sed

betw

een

the

earl

iest

atri

alel

ectr

ogra

mre

cord

edfr

omth

eta

rget

edPV

and

the

earl

iest

atri

alel

ectr

ogra

mre

cord

edat

othe

rdi

stan

tsite

s(n

egat

ive

valu

esin

dica

teth

atth

eat

rial

brea

kthr

ough

isno

tloc

ated

arou

ndth

eta

rget

edPV

).


TABLE 2

Baseline Characteristics of Study Patients

Patients PatientsWithout With ECs

ECs (n = 80) (n = 20) P

Age (years) 56 (48–63) 44 (35–59) 0.01Male gender 60 (75%) 17 (85%) NSHypertension 28 (35%) 6 (30%) NSStructural heart disease 6 (8%) 6 (30%) 0.01Left atrial diameter† (mm) 42 (40–45) 42 (40–50) NSPersistent atrial fibrillation 22 (28%) 6 (30%) NS

Quantitative data are presented as median (25th–75th percentile).†The left atrial anteroposterior diameter was estimated by transthoracicechocardiography (long axis parasternal view). ECs = epicardial connec-tions.

than the venoatrial continuity of the PV ostia. These alter-native pathways, which can be either direct connections be-tween ipsilateral PVs or venoatrial connections attached atdistance from the PV ostia, may maintain electrical con-duction between a PV and the left atrium in spite of full-circumference local conduction block at the PV ostium. Thus,they probably have an epicardial course.

Little is known about this type of electrical connectionin the PVs. Only 2 publications have reported a total of 8patients with electrical connections between left PVs.13,14

There are no data in the literature on the existence of electri-cal connections between right PVs and epicardial venoatrialconnections. However, this study shows that ECs are not un-usual. They can be found in 11% of PVs and 20% of patientsundergoing ostial PV isolation. The lack of information re-garding these ECs and the need for a specific methodologyto identify them may explain why they have remained unde-tected.

It is important to recognize the presence of ECs to achievecomplete PV isolation and avoid unnecessary and potentiallyharmful applications. In addition, PVs with ECs deserve spe-cial attention following isolation because they are vulnerableto an increased rate of early conduction recurrence. In a smallpreliminary series from our center, when PV conduction wasnot regularly monitored following isolation, patients withECs had a higher rate of AF recurrence than patients withoutECs (33% vs 5%), a difference that approached significance(P = 0.1).15 The different clinical course might be explainedby the higher rate of early conduction recurrence of PVswith ECs, because in the present study, when PVs with early

TABLE 3

Ablation Parameters Settings and Readings

PVs Without PVs WithECs (n = 301) ECs (n = 37) P

Maximum power setting (W) 35 (35–40) 35 (35–40) NSMean power delivered (W) 35 (34–36) 35 (35–36) NSMaximum temperature 45 (45–45) 45 (45–45) NS

setting (◦C)Mean temperature reached (◦C) 39 (38–40) 39 (38–41) NSMaximum impedance (Ω) 126 (117–140) 130 (120–135) NSMean impedance (Ω) 119 (111–131) 118 (114–125) NS

Data are presented as median (25th–75th percentile). ECs = epicardialconnections; PVs = pulmonary veins.

TABLE 4

Difficulty of PV Isolation

PVs With PVs WithPVs Without VVEC VAECEC (n = 301) (n = 27) (n = 10)

Bidirectional 301 (100%) 27 (100%) 7 (70%)block (n %)

Time to bidirectional 9.3 (5.2–16.4) 9.4 (5.3–11.5) 42.7 (12.1–90)block (minutes)

Number of applications 6 (4–10) 6 (4.8–10.3) 17.5 (9–30)Total duration of 5.5 (3.6–8.3) 4.4 (3.4–6.9) 13.0 (5.5–35.8)

applications(minutes)

Total energy 11.8 (7.4–17.5) 9.2 (7.3–14.3) 31.1 (11.7–49.7)delivered (kJ)

Quantitative data are presented as median (25th–75th percentile) pertargeted PV. The group of PVs with VAEC was significantly different tothe other 2 groups in every variable shown (P < 0.01 for all comparisons).PVs = pulmonary veins; VAEC = venoatrial epicardial connections;VVEC = vein to vein epicardial connections (after excluding PVs that alsohad VAEC).

conduction recurrence were re-isolated, AF-free survival wassimilar in patients with and without ECs.

Anatomical Correlates

The notion of EC presented in this study is purelyfunctional, since we have no pathological correlates. Hy-pothetically, the anatomical basis of ECs might be eitherepicardial fibers surviving endocardial radiofrequency appli-cations when the venoatrial junction is particularly thick,especially if edema develops after initial applications, ordistinctive accessory pathway-like myocardial bundles in-sulated from the venoatrial wall by fibrofatty tissue (Fig. 6).Anatomical studies of normal human hearts support bothhypotheses.16-18

PV myocardial sleeves are composed mainly of a layerof circularly or spirally oriented bundles of myocytes.3,16

Longitudinal myocardial fibers can also be found within thislayer, and they may become discrete endocardial or epicar-dial muscle bundles surrounded by fibrous tissue and fat thatbecome particularly broad at the venoatrial junction.3,16 In

Figure 5. Incidence of early conduction recurrence following electricalisolation of pulmonary veins with (green) and without (red) epicardialconnections.


Figure 6. Hypotheses explaining the structural basis of pulmonary veinepicardial connections. Possible connections are arbitrarily illustrated atthe LSPV (targeted PV) and LIPV (ipsilateral PV). Left, electrical stimuli (S)travel from the targeted PV to the left atrium through epicardial fibers sur-viving endocardial radiofrequency applications (black dots) in cases whenthe venoatrial junction is particularly thick, especially if edema developsafter initial applications. Right, electrical stimuli (S) travel from the targetedPV to the left atrium through distinctive accessory pathway-like myocardialbundles insulated from the venoatrial wall by fibrofatty tissue.

some cases, 3 or more muscular layers can be found at thevenoatrial junction.3,16 The thickness of the venoatrial junc-tion may be over 4.5 mm at the interpulmonary isthmus.17 Inthis area, epicardial myocardial strands can be found linkingsuperior and inferior PVs.17 In addition, myocardial bridgescrossing the fibrofatty intervenous space to connect ipsilat-eral PVs directly can be observed in 40% of normal hearts.17

Experimental and clinical studies support the existence ofepicardial electrical connections between the left superiorPV and the vein of Marshall that bypass the venoatrial junc-tion.18 In 6 of the 10 VAECs identified in the present study,the earliest atrial activation during pacing inside the LSPVor the left common PV trunk was recorded anteriorly to theleft PVs, below the left atrial appendage, where the vein ofMarshall is usually located.

The thickness, length, and circumferential extension ofmyocardial sleeves are greater in the left PVs than in the rightPVs, and greater in the superior PVs than in the inferior PVs.The most developed myocardial sleeves are usually seen inthe left superior PV.3,16 These regional differences were re-produced in our study according to the frequency distributionof ECs. VVECs and VAECs were more frequently observedin the left PVs, and VAECs were found only in superior PVsor common trunks. The greatest prevalence of ECs was ob-served in the left superior PV. In addition, data from our studysupport an association between myocardial sleeve size andECs resistant to ostial ablation. Age was inversely associatedwith the prevalence of ECs, which may be explained by age-related amyloid degeneration and scarring of PV myocardialsleeves.19 Structural heart disease was another independentpredictor of the presence of ECs, an association that mightbe related to hypertrophy of the left atrium and PV myocar-dial sleeves.20,21 Hypothetically, an increase in the thicknessof the venoatrial junction may protect epicardial myocardialstrands and accessory pathway-like myocardial bridges fromradiofrequency applications. In fact, ECs might be even moreprevalent than we report in the present study, since some ofthem may have been destroyed by PV ostial ablation.

Conclusion

Twenty percent of patients with AF have ECs resistant toostial ablation in one or more PVs. PVs with ECs may re-

quire a different disconnection approach. These connectionsare associated with an increased rate of early recurrence ofconduction.

References

1. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, QuiniouG, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J: Sponta-neous initiation of atrial fibrillation by ectopic beats originating in thepulmonary veins. N Engl J Med 1998;339:659-666.

2. Chen SA, Hsieh MH, Tai CT, Tsai CF, Prakash VS, Yu WC, HsuTL, Ding YA, Chang MS: Initiation of atrial fibrillation by ectopicbeats originating from the pulmonary veins: Electrophysiological char-acteristics, pharmacological responses, and effects of radiofrequencyablation. Circulation 1999;100:1879-1886.

3. Ho SY, Sanchez-Quintana D, Cabrera JA, Anderson RH: Anatomyof the left atrium: Implications for radiofrequency ablationof atrial fibrillation. J Cardiovasc Electrophysiol 1999;10:1525-1533.

4. Isa-Param R, Perez-Castellano N, Villacastin J, Moreno J, Salinas J,Alonso R, Ruiz E, Doblado M, Morales R, Macaya C: Inducibility ofatrial arrhythmias after adenosine and isoproterenol infusion in patientsreferred for atrial fibrillation ablation. Rev Esp Cardiol 2006;59:559-566.

5. Robbins IM, Colvin EV, Doyle TP, Kemp WE, Loyd JE, McMahonWS, Kay GN: Pulmonary vein stenosis after catheter ablation of atrialfibrillation. Circulation 1998;98:1769-1775.

6. Taylor GW, Kay GN, Zheng X, Bishop S, Ideker RE: Pathological ef-fects of extensive radiofrequency energy applications in the pulmonaryveins in dogs. Circulation 2000;101:1736-1742.

7. Arentz T, Jander N, von Rosenthal J, Blum T, Furmaier R, GornandtL, Josef Neumann F, Kalusche D: Incidence of pulmonary vein steno-sis 2 years after radiofrequency catheter ablation of refractory atrialfibrillation. Eur Heart J 2003;24:963-969.

8. Kok LC, Everett TH 4th, Akar JG, Haines DE: Effect of heating onpulmonary veins: How to avoid pulmonary vein stenosis. J CardiovascElectrophysiol 2003;14:250-254.

9. Haıssaguerre M, Jaıs P, Shah DC, Garrigue S, Takahashi A, LavergneT, Hocini M, Peng JT, Roudaut R, Clementy J: Electrophysiolog-ical end point for catheter ablation of atrial fibrillation initiatedfrom multiple pulmonary venous foci. Circulation 2000;101:1409-1417.

10. Haissaguerre M, Shah DC, Jais P, Hocini M, Yamane T, DeisenhoferI, Chauvin M, Garrigue S, Clementy J: Electrophysiological break-throughs from the left atrium to the pulmonary veins. Circulation2000;102:2463-2465.

11. Pappone C, Rosanio S, Oreto G, Tocchi M, Gugliotta F, VicedominiG, Salvati A, Dicandia C, Mazzone P, Santinelli V, Gulletta S, Chier-chia S: Circumferential radiofrequency ablation of pulmonary vein os-tia: A new anatomic approach for curing atrial fibrillation. Circulation2000;102:2619-2628.

12. Marchlinski FE, Callans D, Dixit S, Gerstenfeld EP, Rho R, Ren JF,Zado E: Efficacy and safety of targeted focal ablation versus PV iso-lation assisted by magnetic electroanatomic mapping. J CardiovascElectrophysiol 2003;14:358-365.

13. Tritto M, De Ponti R, Zardini M, Spadacini G, Oliveira M, Salerno-Uriarte JA: Electrical connections between pulmonary veins in humans:Evidence after radiofrequency ablation of the venoatrial junction. Cir-culation 2001;104:E30-E31.

14. Takahashi A, Iesaka Y, Takahashi Y, Takahashi R, Kobayashi K, Tak-agi K, Kuboyama O, Nishimori T, Takei H, Amemiya H, Fujiwara H,Hiraoka M: Electrical connections between pulmonary veins: Implica-tion for ostial ablation of pulmonary veins in patients with paroxysmalatrial fibrillation. Circulation 2002;105:2998-3003.

15. Perez-Castellano N, Perez-Villacastin J, Moreno Planas J, Salinas ArceJ, Vega Olvera M, Doblado M, Ruiz E, Isa Param R, Macaya C:Prospective identification of anomalous veno-atrial connections com-plicating pulmonary vein isolation. Eur Heart J 2007;28(Abstract Sup-plement):129.

16. Ho SY, Cabrera JA, Tran VH, Farre J, Anderson RH, Sanchez-QuintanaD: Architecture of the pulmonary veins: Relevance to radiofrequencyablation. Heart 2001;86:265-270.

17. Cabrera JA, Ho SY, Climent V, Fuertes B, Murillo M, Sanchez-Quintana D: Morphological evidence of muscular connections be-tween contiguous pulmonary venous orifices: Relevance of the


interpulmonary isthmus for catheter ablation in atrial fibrillation. HeartRhythm 2009;6:1192-1198.

18. Tan AY, Chou CC, Zhou S, Nihei M, Hwang C, Peter CT, Fishbein MC,Chen PS: Electrical connections between left superior pulmonary vein,left atrium, and ligament of Marshall: Implications for mechanisms ofatrial fibrillation. Am J Physiol Heart Circ Physiol 2006;290:H312-H322.

19. Steiner I, Hajkova P, Kvasnicka J, Kholova I: Myocardial sleeves of

pulmonary veins and atrial fibrillation: A postmortem histopathologicalstudy of 100 subjects. Virchows Arch 2006;449:88-95.

20. Smith DM, Sugden PH: Stimulation of left-atrial protein-synthesis ratesby increased left-atrial filling pressures in the perfused working rat heartin vitro. Biochem J 1983;216:537-542.

21. Benedek I, Hintea T, Toganel R: Myocardial fibres in pulmonaryveins—possible compensatory factor in dilated cardiomyopathy. RomJ Intern Med 1998;36:175-181.

Date post:	22-Feb-2023
Category:	Documents
Upload:	independent
View:	0 times
Download:	0 times

Epicardial Connections Between the Pulmonary Veins and Left Atrium: Relevance for Atrial...

Documents