Left atrial pressure and dominant frequency of atrial fibrillationin humansKentaro Yoshida, MD,* Magnus Ulfarsson, PhD,† Hakan Oral, MD,* Thomas Crawford, MD,*ric Good, DO,* Krit Jongnarangsin, MD,* Frank Bogun, MD,* Frank Pelosi, MD,* Jose Jalife, MD,‡
Fred Morady, MD,* Aman Chugh, MD*
From the *Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan, †Department of Electricalnd Computer Engineering, University of Iceland, Reykjavik, Iceland, and ‡Center for Arrhythmia Research, University of
Michigan.
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BACKGROUND Atrial stretch is thought to play a role in thedevelopment of atrial fibrillation (AF). However, the precise mech-anism by which stretch contributes to AF maintenance in humansis unknown.
OBJECTIVE The purpose of this study was to determine the im-pact of left atrial (LA) pressure on AF frequency in patientsundergoing catheter ablation of AF.
METHODS The subjects of this study were 58 consecutive patientswith persistent AF (n � 40) or paroxysmal AF (n � 18) undergoingA ablation. LA pressure was measured before ablation. Both atriand the coronary sinus were mapped, and regional dominantrequency (DF) was determined.
ESULTS Mean LA pressure in the persistent AF group was sig-ificantly higher than in the paroxysmal AF group (18 � 5 vs 10 �mmHg, P �.0001). Mean DF in the persistent AF group was alsoigher than in the paroxysmal AF group (6.36 � 0.51 Hz and
5.83 � 0.54 Hz, P � .0006). In patients with persistent AF, thereas a significant correlation between LA pressure and DF at the LA
ppendage region in 24 (60%) of the 40 patients with persistentF (P � .0006). In multivariate analysis, LA pressure was the onlyndependent predictor of DFmax in the LA appendage (P � .04,dds ratio 1.41, 95% confidence interval 1.02–1.94).
ONCLUSION Higher LA pressure in patients with persistent AFmplies that these patients are more vulnerable to stretch-relatedemodeling than are patients with paroxysmal AF. The DF of AF wasirectly related to LA pressure in patients with persistent AF. Thisnding suggests that atrial stretch may contribute to the main-enance of AF in humans by stabilizing high-frequency sources.
ppendage (r � 0.55, P � .0002). DFmax was found at the LA rights reserved.
IntroductionAtrial stretch has long been implicated in the pathogenesisof atrial fibrillation (AF).1 A prior study showed that atrialtretch, imparted by elevated left atrial (LA) pressure, in-reased the rate of AF drivers in an animal model.2 In
humans, stretch is thought to play a role in the developmentof AF in patients with hypertension, mitral valve disease,and heart failure.3 However, the electrophysiologic mecha-nism by which stretch contributes to the fibrillatory processin humans has not been clarified. The aim of the study wasto determine the impact of LA pressure on AF frequency inpatients undergoing catheter ablation of AF.
Supported in part by a grant from the Leducq Transatlantic Network.Drs. Oral and Morady are co-founders of Ablation Frontiers. Addressreprint requests and correspondence: Dr. Aman Chugh, CardiovascularCenter, SPC 5853, 1500 East Medical Center Drive, Ann Arbor, Michigan48109-5853. E-mail address: [email protected]. (Received July 21,
MethodsStudy subjectsThe subjects of this study were 40 consecutive patients withpersistent AF4 undergoing left atrial ablation. Thirty (75%)f the 40 patients had longstanding persistent AF.4 Theuration of continuous AF was estimated from a combina-ion of records from the referring cardiologist and the his-ory obtained from the patient. If a patient underwent trans-horacic cardioversion and AF recurred thereafter, theuration of continuous AF was defined as the time periodxtending from the date of recurrence to the date of theblation procedure.
Patients with paroxysmal AF4 who presented to the lab-oratory in AF served as a comparison group (N � 18).Patients who had undergone a prior ablation procedure andthose with structural heart disease, history of heart failure,or currently taking diuretic medications were excluded fromthe study. These patients were excluded because these con-
ditions may be associated with increased LA pressure. The
clinical characteristics of the study subjects are listed inTable 1.
Transthoracic echocardiography was performed beforethe ablation procedure, and LA volume was measured off-line using the prolate ellipsoid model V � �D2L/6, whereD is the minor axis (width) and L is the major axis (length)of the LA as measured in the apical four-chamber view. Allpatients with persistent AF underwent transesophagealechocardiography (Phillips iE33, Andover, MD, USA) torule out the presence of thrombus prior to the ablationprocedure.
Measurements of LA pressure and electroanatomicmappingThe study protocol was approved by the Institutional Re-view Board, and all patients provided informed writtenconsent. Rhythm- and rate-controlling medications werediscontinued four to five half-lives before the procedure,except for amiodarone, which was discontinued at least 8weeks before the procedure. Vascular access was obtainedthrough a femoral vein. A steerable decapolar catheter (Bio-sense Webster, Diamond Bar, CA, USA) was positioned inthe coronary sinus. LA pressure was defined as the height ofthe v wave during AF (normal range 6–21 mmHg)5 andmeasured just after transseptal puncture using a long sheath
Table 1 Patient characteristics
ParoxysmalAF group(N � 18)
PersistentAF group(N � 40) P
Age (years) 58 � 8 59 � 10 .71ender (M/F) 14/5 33/7 .44ody mass index (kg/m2) 27 � 3 32 � 5 .0001leep apnea syndrome 3 (17%) 7 (18%) .94ypertension 6 (32%) 25 (63%) .03iabetes 1 (6%) 2 (5%) .93eriod from first diagnosis
Data are given as mean � SD.ACE � angiotensin-converting enzyme; AF � atrial fibrillation; ARB �
angiotensin II receptor blocker; LA � left atrium.
(SL0, St. Jude Medical, Inc., Minnetonka, MN, USA) con-
nected to a pressure transducer (Transpac, Hospira, LakeForest, IL, USA). After transseptal puncture, systemic an-ticoagulation was achieved with intravenous heparin tomaintain an activated clotting time of 300 to 350 seconds.An open-irrigation, 3.5-mm-tip deflectable catheter (Ther-moCool, Biosense Webster) was used for mapping andablation. Bipolar electrograms were displayed and recordedat filter settings of 30 to 500 Hz during the procedure(EPMed Systems, West Berlin, NJ, USA).
All patients underwent electroanatomic mapping duringAF before ablation. Endocardial contact was ensured byfluoroscopy, electrogram stability, and the three-dimen-sional navigation system. Electrograms were recorded fromthe following 16 biatrial regions in patients with persistentAF and 12 left atrial regions in patients with paroxysmalAF: (1) right pulmonary vein (PV) antrum, (2) left PVantrum, (3) posterior wall, (4) anterior wall, (5) roof, (6)septum, (7) mitral isthmus, (8) inferior wall, (9) LA append-age, (10) base of appendage, (11) ridge between left PV andLA appendage, (12) coronary sinus, (13) right atrial (RA)appendage, (14) RA septum, (15) cavotricuspid isthmus,and (16) RA lateral wall. Three sites per region were sam-pled for �5 seconds in order to obtain the mean dominantfrequency (DF) and atrial voltage for each region.
Digital signal processing and data analysisThe details regarding spectral analysis have been describedpreviously.6 Briefly, bipolar electrograms recorded for 5seconds were processed offline in the MatLab environment(MathWorks, Inc., Natick, MA, USA) during AF. Electro-gram voltage was defined as the mean of 10 of the largestelectrograms in a sampling window of 5,000 ms and mea-sured using custom software (Figure 1). In the spectralanalysis, preprocessing steps included bandpass filteringwith cutoffs at 40 and 250 Hz, rectification, and low-passfiltering with a 20-Hz cutoff.7 DF was defined as the fre-quency of the highest peak of the periodogram in the inter-val from 0.5 to 20 Hz using fast Fourier transformation.Points demonstrating an organization index less than 0.2were excluded (4%) in subsequent analysis to control forambiguity in DF detection related to poor signal-to-noiseratio. The organization index was defined as the ratio of thetotal area of the spectrum under the first five harmonic peaksto the total area of the spectrum from 0 to 60 Hz.8
Statistical analysisContinuous variables are expressed as mean � 1 SD andwere compared using Student’s t-test or paired t-test, asappropriate. Categorical variables were compared by Chi-square analysis or with the Fisher exact test, as appropriate.One-way analysis of variance (ANOVA) was used to com-pare continuous variables among multiple groups, and posthoc analysis was performed using the Scheffe test. To de-termine the relationship between LA pressure and DF, anindependent Pearson correlation coefficient was calculatedfor each of the 11 LA sites sampled. To account for these
multiple comparisons, P values were corrected using the
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183Yoshida et al Atrial Pressure and Dominant Frequency of AF
Bonferroni correction. The relationship was deemed signif-icant at the .05 level if P �.0045 (i.e., 0.05/11). Multivariateregression analysis was performed to identify the predictorsof the region with the highest DF. P �.05 was consideredsignificant in this case.
ResultsBaseline characteristicsAge (58 � 8 years vs 59 � 10 years, P � .71) and timerom first diagnosis of AF (54 � 38 months vs 53 � 47onths, P � .96) were similar between patients with par-
xysmal AF and those with persistent AF (Table 1). LAiameter was significantly larger in patients with persistentF than in those with paroxysmal AF (48 � 6 mm vs 38 �mm, P �.0001). Left ventricular systolic function was
reserved in all patients (ejection fraction �50%). Hyper-ension (63% vs 32%, P � .03) and obesity indicated byody mass index (32 � 5 kg/m2 vs 27 � 3 kg/m2, P �0001) were more prevalent in patients with persistent AF.
LA pressure in paroxysmal and persistent AFLA pressure was significantly higher in patients with per-sistent AF compared to those with paroxysmal AF (18 � 5vs 10 � 4 mmHg, P �.0001). The distribution of LApressure in the paroxysmal AF group was too narrow toevaluate a relationship between atrial pressure and DF.Therefore, such a relationship was investigated only in the
Figure 1 Measurement of atrial voltage and dominant frequency (DF).A: Electrogram voltage was defined as the mean of 10 of the largestelectrograms in a sampling window of 5,000 ms and measured by customsoftware in the MatLab environment. Open green circles indicate detectionof peak electrogram amplitude. Red lines indicate the amplitude in thisrecoding period (0.28 mV). B: Periodogram of the same recording periodhown in A. DF was 7.60 Hz.
persistent AF group.
Regional DF in persistent AFMean DF of the LA and RA was 6.4 � 0.7 Hz and 6.3 �.8 Hz, respectively (P � .17). DF at the LA appendage6.8 � 0.6 Hz), base of LA appendage (6.6 � 0.7 Hz), ridgeetween appendage and left PVs (6.7 � 0.6 Hz), and RAppendage (6.7 � 0.8 Hz) was significantly higher than inhe other regions (e.g., posterior wall and inferior walls ofA, and the CS, P �.0001; Figure 2). Among the LA sites,
he LA appendage region (including the base and ridge)ad the highest DF (DFmax) in 24 (60%) of the 40 patients.
In the remainder, DFmax was found at the left PV antrum in(13%), mitral isthmus in 3 (8%), anterior wall in 2 (5%),
nferior wall in 2 (5%), posterior wall in 2 (5%), roof in 12%), right PV antrum in 1 (2%), and septum in none of theatients (P � .0006). The coefficient of variation (COV �D/mean � 100%) for DF in the LA among patients withersistent AF was 6.7% � 1.6%. There was no significantifference in regional DF in the LA in patients with parox-smal AF (P � .9; Figure 2).
LA pressurePatients with persistent AF were divided into two groups:a low-pressure group with LA pressure �18 mmHg,which was the mean and median LA pressure in thepersistent AF group; and a high-pressure group with LApressure �18 mmHg (Table 2). There was a borderlinesignificant difference in the prevalence of sleep apneasyndrome, which was higher in the high-pressure groupversus the low-pressure group (29% vs 5%, respectively,P � .05).
Figure 2 Mean dominant frequency (DF) at each region in persistent(blue) and paroxysmal (red) atrial fibrillation (AF). In patients with per-sistent AF, mean DFs at 11 regions in the left atrium (LA), at four regionsin the right atrium (RA), and in the coronary sinus (CS) are shown. Therewas a significant difference in the mean DF across the regions (P �.0001,analysis of variance [ANOVA]). ‡P �.05 vs DF at LAA; §P �.05 vs DFat ridge; †P �.05 vs DF at base of LAA; ¶P �.05 vs DF at RA appendage.In patients with paroxysmal AF, there was no difference in regional DF (P �.9). CTI � cavotricuspid isthmus; LAA � left atrial appendage; PVA �
pulmonary vein antrum.
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184 Heart Rhythm, Vol 8, No 2, February 2011
LA pressure and DFThere was a direct relationship between LA pressure and theDF of AF at the LA appendage (P � .0002, r � 0.55; Figure3) and the LA septum (P � .003, r � 0.46).
Continuous AF and DFMean DF in patients with paroxysmal AF and those withpersistent AF was 5.8 � 0.5 Hz and 6.4 � 0.5 Hz, respec-tively (P � .0006). There was no correlation between thetime from first diagnosis of AF and mean DF in the parox-ysmal AF group (P � .5, r � 0.18) and in the persistent AFroup (P � .14, r � 0.24). However, the duration of con-inuous (uninterrupted) AF in the persistent AF group wasirectly related to the mean DF of both LA and RA (P �0009, r � 0.51; Figure 4). The correlation between LAressure and duration of continuous AF was weaker than theorrelation between LA pressure and mean DF (P � .04,� 0.33).
Table 2 Characteristics of patients with normal and high LApressure
Persistent AF group (N � 40)
P
Low LApressure group(�18 mmHg,n � 19)
High LApressure group(�18 mmHg,n � 21)
Age 60 � 9 57 � 11 .44Gender (M/F) 17/2 16/5 .27Body mass index (kg/m2) 33 � 5 31 � 4 .19leep apnea syndrome 1 6 .05ypertension 10 15 .22uration of continuousAF (months)
22 � 19 28 � 18 .32
A diameter (mm) 47 � 5 48 � 7 .53
AF � atrial fibrillation; LA � left atrium.
Figure 3 Relationship between left atrial (LA) pressure and dominantfrequency (DF) at the LA appendage. *Significant at the .05 level if
P �.0045 by Bonferroni correction.
Atrial voltageMean LA voltage was significantly lower than mean RAvoltage (0.45 � 0.36 mV vs 0.92 � 0.53 mV, P �.0001) inatients with persistent AF. Mean LA voltage was signifi-antly lower in patients with persistent AF than in thoseith paroxysmal AF (0.45 � 0.36 mV vs 0.64 � 0.39 mV,�.0001). Regional atrial voltage was significantly lower
t every LA site, except the appendage, in patients withersistent AF than in those with paroxysmal AF (Figure 5).lthough voltage at the LA appendage was also lower inatients with persistent versus paroxysmal AF (1.12 � 0.56V vs 1.43 � 0.67 mV), this difference did not reach
tatistical significance (P � 0.08). There were also signifi-ant regional differences in LA voltage in patients with botharoxysmal and persistent AF (Figure 5). Among patientsith persistent AF, mean voltage at the LA appendage andA posterior wall was 1.12 � 0.56 mV and 0.28 � 0.12
Figure 4 Relationship between duration of continuous atrial fibrillation(AF) and mean dominant frequency (DF).
Figure 5 Regional left atrial (LA) voltage in patients with persistent(blue) and paroxysmal (red) atrial fibrillation. There were significant dif-ferences in mean voltage across regions (P �.0001, analysis of variance).‡P �.05; §P �.01; †P �.001; ¶P �.0001. CS � coronary sinus; LAA �
left atrial appendage; PVA � pulmonary vein antrum.
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mV, respectively (P �.0001). In patients with paroxysmalAF, mean voltage at the LA appendage and posterior wallwas 1.43 � 0.67 mV and 0.58 � 0.36 mV, respectivelyP � .0009). COV for LA voltage in patients with persistentnd paroxysmal AF was 65% � 19% and 53% � 17%,
respectively (P � .02).
Determinants of DF in the LA appendageBy univariate analysis, patients with DFmax in the LA ap-pendage compared to those with DFmax elsewhere had asignificantly higher LA pressure (21 � 3 mmHg vs 17 � 5mmHg, P � .009), lower age (52 � 9 years vs 61 � 9 years,P � .009), and higher voltage in the LA appendage (1.61 �0.45 mV vs 0.95 � 0.50 mV, P � .0006). There was noignificant difference in gender (8/2 vs 25/5, P � .81),uration of continuous AF (22 � 14 months vs 27 � 20onths, P � .41), and LA diameter (45 � 7 mm vs 49 �
5 mm, P � .14). In a multivariate analysis using age,ender, LA pressure, duration of continuous AF, voltage inA appendage, and LA diameter, the only independentredictor for DFmax in the LA appendage was LA pressure
(odds ratio [OR] 1.41, 95% confidence interval [CI] 1.01–1.96, P � .04). There were no predictors of DFmax at otheregions.
DiscussionMain findingsThis study demonstrates that (1) DF of AF is directly relatedto LA pressure in patients with persistent AF; (2) DF of AFis directly related to duration of continuous AF in patientswith persistent AF; (3) LA pressure is higher in patients
ith persistent AF and is an independent predictor of DFmax
in the LA appendage; and (4) regional LA voltage is lowerin patients with persistent AF than in those with paroxysmalAF.
LA pressure and DFA stretch-related mechanism of AF has been proposed in anumber of clinical conditions, such as mitral valve diseaseand heart failure. It is thought that stretch may contribute toAF by evoking triggers9,10 and/or promoting AF mainte-nance related to shortening of the atrial effective refractoryperiod (ERP).11 Abbreviation of atrial ERP would allow for
higher activation frequency. A prior animal study showedhat an acute increase in LA pressure resulted in an increasen DF, which is closely related to atrial ERP.12,13 To the bestf our knowledge, this is the first human study to suggesthat stretch imparted by elevated LA pressure may contrib-te to the maintenance of AF by stabilizing high-frequencyources.
Several therapeutic options may be helpful in minimiz-ng the detrimental consequences of stretch. For example,ngiotensin receptor blockers may have a favorable effecty preventing stretch-induced electrical remodeling.14
Atrial stretch has also been implicated in the pathogenesisof AF related to sleep apnea,15 underscoring the importance
of treating this condition. An animal study demonstrated t
that as LA pressure was lowered, AF sources became slowand unstable.2 Therefore, the role of diuretic therapy, evenin the absence of heart failure, in reducing LA pressure andstretch should be explored. Also, specific inhibitors ofstretch-activated channels would be a welcome addition tothe armamentarium of antiarrhythmic medications. Al-though catheter ablation can eliminate persistent AF, it doesnot directly address elevated LA pressure and stretch. In-terventions that have the potential to attenuate atrial stretchand/or its consequences may serve as adjuvant therapy aftersuccessful ablation to minimize the risk of late recurrenceof AF.
Duration of persistent AF and DFPatients with persistent AF of long duration do not respondas well to medical therapy or to surgical16 or catheter abla-ion.17 The results of the current study suggest that patientsith a longer duration of continuous AF tend to have aigher AF frequency, consistent with more extensive elec-rical remodeling. Experimental studies have demonstratedhat longer-lasting AF is associated with shortening of atrialRP, which then further perpetuates AF.13 It seems that AFlso begets AF in humans by a similar mechanism.
Paroxysmal versus persistent AFThe factors that result in self-limited episodes in patientswith paroxysmal AF as opposed to continuous, uninter-rupted episodes in patients with persistent AF are not wellunderstood. It is possible that the higher LA pressure inpatients with persistent AF results in a greater degree ofstretch-related electrical remodeling, resulting in a higherAF frequency. Indeed, prior studies18 as well as the currentstudy have found that DF in patients with persistent AF ishigher than in patients with paroxysmal AF. Thus, a higheratrial activation rate in patients with persistent AF, related toa greater degree of stretch, may stabilize the arrhythmia,making it less likely to spontaneously terminate.2
DFmax in the LA appendageThe DFmax site in the majority of patients with persistent AFin this study was found at the region of the LA appendage.This observation may provide the rationale for ablation ofcomplex electrograms around the LA appendage, which hasbeen shown to be critical during the stepwise approach inacutely terminating AF.19 Also, ligation or excision of the
A appendage during a surgical ablation procedure for AFot only may help reduce the risk of thromboembolism butlso may directly eliminate a high-frequency source respon-ible for maintaining AF.
LA pressure was found to be an independent predictor ofFmax in the LA appendage. This implies that the LA
appendage may be more vulnerable to stretch-related elec-trical remodeling than other parts of the LA. It has beenshown in an animal model that the LA appendage is morecompliant than the body of the LA.20 That is, for a givenressure, the LA appendage undergoes more distension than
he LA body, which may render the former more susceptible
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186 Heart Rhythm, Vol 8, No 2, February 2011
to stretch-induced changes. In pathologic states in which theLA pressure is elevated, the relative blood flow to the LAappendage increases, consistent with its “reservoir func-tion.”21 However, the results of the current study suggestthat such compensation may actually be maladaptive be-cause it may contribute to stretch-related remodeling of theLA appendage.
Regional differences in LA voltageThis study found significant differences in regional LAvoltage in paroxysmal and persistent AF. For example, inpatients with persistent AF, mean voltage at the LA append-age was more than four times larger than at the posteriorwall of the LA. These results are consistent with those froman anatomic study, which reported that patients with AF hada significantly higher prevalence of interstitial fibrosis in theposterior wall than in the LA appendage.22 Several expla-ations may help explain why the LA appendage seems toe relatively spared from structural remodeling in patientsith AF. First, owing to their disparate embryologic ori-ins,23 the response of the LA posterior wall and appendageo various stimuli (e.g., LA pressure) may be different.nother possibility may be related to wall tension.22 Ac-
cording to Laplace’s law, wall tension is directly related topressure and radius and is indirectly related to wall thick-ness. Although the posterior LA and the LA appendage aresubject to the same pressure, the former would be expectedto endure higher wall stress due to its larger radius andthinner myocardium. These mechanisms may help explainthe substantial heterogeneity in regional LA voltage in bothparoxysmal and persistent AF.
Regional differences in DFIn an animal model, dispersion of atrial refractoriness wasshown to be critical in the initiation and maintenance ofAF.24 However, in the present study, the COV of DF wasnly about 6% to 7% compared with animal studies inhich the COV of ERP was reported to be about 21%.here may be several explanations for this discordance.irst, the animals underwent electrophysiology study afternly 24 hours of rapid atrial pacing compared to the patientsn this study, who were studied after more than 1 year ofninterrupted AF. It is possible that early in the course ofF, there is a large degree of ERP heterogeneity. However,
s AF persists, the atria likely undergo global ERP remod-ling, making it less likely to find marked differences inegional refractoriness. It is also possible that in the rela-ively short time frame in which the animal studies areonducted, structural changes, which have been shown tonterfere with electrical remodeling,25 may not have yetccurred. Finally, because AF frequencies are considerablyigher in animal models than in patients with AF,26 theegree of fibrillatory conduction and the magnitude of fre-uency gradients are likely to be lower among the latter.27
Prior studiesPrior studies examining the impact of stretch on atrial re-
fractoriness in humans have reached disparate conclusions.
Some suggested that refractoriness was prolonged with in-creasing pressure,28,29 whereas others found either the op-osite or no difference.30,31 These studies were limited by aack of LA mapping and the fact that atrial pressure wasssessed during nonphysiologic conditions such as simulta-eous atrioventricular pacing. To our knowledge, the cur-ent study is the first to analyze the relationship betweentrial pressure and AF frequency at multiple biatrial sites inumans without any intervention to increase atrial pressure.ore recent clinical studies have examined the impact of
tretch in patients with mitral stenosis undergoing balloonommissurotomy. One study reported an increase in RARP at 3 months,32 whereas another found a decrease at 6onths after commissurotomy.33 These differences may be
ue to the fact that the former study included patients withF, whereas the latter examined the atrial substrate only inatients with sinus rhythm.
Study limitationsThe results of the current study suggest that there is anassociation between LA pressure and AF frequency. A pro-spective clinical study using saline infusion, as in animalstudies, may be necessary to definitively demonstrate cau-sation. However, acute instillation of saline, apart frombeing nonphysiologic, may not be able to replicate theimpact of chronic elevation in LA pressure. Another limi-tation of the study is that DF was determined by sequentialas opposed to simultaneous atrial mapping. Also, atrialvoltage was measured during AF as opposed to sinusrhythm. Finally, the impact of the intrinsic cardiac auto-nomic system, one of the determinants of DF, was notanalyzed.
ConclusionLA pressure is significantly higher in patients with persis-tent AF, which implies that these patients may be moresusceptible to stretch-related remodeling than patients withparoxysmal AF. DF of AF is directly correlated with LApressure in patients with persistent AF, suggesting that atrialstretch may contribute to maintenance of AF in humans.
References1. Ravelli F, Allessie M. Effects of atrial dilatation on refractory period and
vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbitheart. Circulation 1997;96:1686–1695.
2. Kalifa J, Jalife J, Zaitsev AV, et al. Intra-atrial pressure increases rate andorganization of waves emanating from the superior pulmonary veins duringatrial fibrillation. Circulation 2003;108:668–671.
3. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, Wolf PA.Independent risk factors for atrial fibrillation in a population-based cohort. TheFramingham Heart Study. JAMA 1994;271:840–844.
4. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert consensusstatement on catheter and surgical ablation of atrial fibrillation: recommenda-tions for personnel, policy, procedures and follow-up. A report of the HeartRhythm Society (HRS) Task Force on catheter and surgical ablation of atrialfibrillation. Heart Rhythm 2007;4:816–861.
6. Yoshida K, Chugh A, Ulfarsson M, et al. Relationship between the spectral
characteristics of atrial fibrillation and atrial tachycardias that occur after cath-eter ablation of atrial fibrillation. Heart Rhythm 2009;6:11–17.
2
2
2
2
2
2
2
2
3
3
3
3
187Yoshida et al Atrial Pressure and Dominant Frequency of AF
7. Ng J, Kadish AH, Goldberger JJ. Effect of electrogram characteristics on therelationship of dominant frequency to atrial activation rate in atrial fibrillation.Heart Rhythm 2006;3:1295–1305.
8. Everett THt, Akar JG, Kok LC, Moorman JR, Haines DE. Use of global atrialfibrillation organization to optimize the success of burst pace termination. J AmColl Cardiol 2002;40:1831–1840.
9. Lin WS, Prakash VS, Tai CT, et al. Pulmonary vein morphology in patients withparoxysmal atrial fibrillation initiated by ectopic beats originating from thepulmonary veins: implications for catheter ablation. Circulation 2000;101:1274–1281.
10. Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002;415:219–226.11. Qi J, Xiao J, Zhang Y, et al. Effects of potassium channel blockers on changes
in refractoriness of atrial cardiomyocytes induced by stretch. Exp Biol Med(Maywood) 2009;234:779–784.
12. Misier AR, Opthof T, van Hemel NM, et al. Increased dispersion of “refracto-riness” in patients with idiopathic paroxysmal atrial fibrillation. J Am CollCardiol 1992;19:1531–1535.
13. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begetsatrial fibrillation. A study in awake chronically instrumented goats. Circulation1995;92:1954–1968.
14. Saygili E, Rana OR, Reuter H, et al. Losartan prevents stretch-induced electricalremodeling in cultured atrial neonatal myocytes. Am J Physiol Heart CircPhysiol 2007;292:H2898–H2905.
15. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and therecurrence of atrial fibrillation. Circulation 2003;107:2589–2594.
16. Grubitzsch H, Grabow C, Orawa H, Konertz W. Factors predicting the time untilatrial fibrillation recurrence after concomitant left atrial ablation. Eur J Cardio-thorac Surg 2008;34:67–72.
17. Matsuo S, Lellouche N, Wright M, et al. Clinical predictors of termination andclinical outcome of catheter ablation for persistent atrial fibrillation. J Am CollCardiol 2009;54:788–795.
18. Sanders P, Berenfeld O, Hocini M, et al. Spectral analysis identifies sites ofhigh-frequency activity maintaining atrial fibrillation in humans. Circulation2005;112:789–797.
19. Haissaguerre M, Sanders P, Hocini M, et al. Catheter ablation of long-lastingpersistent atrial fibrillation: critical structures for termination. J CardiovascElectrophysiol 2005;16:1125–1137.
21. Tabata T, Oki T, Yamada H, et al. Role of left atrial appendage in left atrial
reservoir function as evaluated by left atrial appendage clamping during cardiacsurgery. Am J Cardiol 1998;81:327–332.
2. Corradi D, Callegari S, Benussi S, et al. Myocyte changes and their left atrialdistribution in patients with chronic atrial fibrillation related to mitral valvedisease. Hum Pathol 2005;36:1080–1089.
3. Douglas YL, Jongbloed MR, Gittenberger-de Groot AC, et al. Histology ofvascular myocardial wall of left atrial body after pulmonary venous incorpora-tion. Am J Cardiol 2006;97:662–670.
4. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneityin the enhanced vulnerability to atrial fibrillation induction caused bytachycardia-induced atrial electrical remodeling. Circulation 1998;98:2202–2209.
5. Swartz MF, Fink GW, Lutz CJ, et al. Left versus right atrial difference indominant frequency, K(�) channel transcripts, and fibrosis in patients de-veloping atrial fibrillation after cardiac surgery. Heart Rhythm 2009;6:1415–1422.
6. Mansour M, Mandapati R, Berenfeld O, Chen J, Samie FH, Jalife J. Left-to-rightgradient of atrial frequencies during acute atrial fibrillation in the isolated sheepheart. Circulation 2001;103:2631–2636.
7. Atienza F, Almendral J, Moreno J, et al. Activation of inward rectifier potassiumchannels accelerates atrial fibrillation in humans: evidence for a reentrant mech-anism. Circulation 2006;114:2434–2442.
8. Chen YJ, Chen SA, Tai CT, et al. Role of atrial electrophysiology and autonomicnervous system in patients with supraventricular tachycardia and paroxysmalatrial fibrillation. J Am Coll Cardiol 1998;32:732–738.
9. Klein LS, Miles WM, Zipes DP. Effect of atrioventricular interval duringpacing or reciprocating tachycardia on atrial size, pressure, and refractoryperiod. Contraction-excitation feedback in human atrium. Circulation 1990;82:60 – 68.
0. Calkins H, el-Atassi R, Kalbfleisch S, Langberg J, Morady F. Effects of an acuteincrease in atrial pressure on atrial refractoriness in humans. Pacing Clin Elec-trophysiol 1992;15:1674–1680.
1. Tse HF, Pelosi F, Oral H, Knight BP, Strickberger SA, Morady F. Effects ofsimultaneous atrioventricular pacing on atrial refractoriness and atrial fibrillationinducibility: role of atrial mechanoelectrical feedback. J Cardiovasc Electro-physiol 2001;12:43–50.
2. Fan K, Lee KL, Chow WH, Chau E, Lau CP. Internal cardioversion of chronicatrial fibrillation during percutaneous mitral commissurotomy: insight into re-versal of chronic stretch-induced atrial remodeling. Circulation 2002;105:2746–2752.
3. John B, Stiles MK, Kuklik P, et al. Reverse remodeling of the atria aftertreatment of chronic stretch in humans: implications for the atrial fibrillation
