Acute Comparative Effect of Right and Left Ventricular Pacing in Patients With Permanent Atrial Fibrillation

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1 Journal of the American College of Cardiology Vol. 43, No. 2, by the American College of Cardiology Foundation ISSN /04/$30.00 Published by Elsevier Inc. doi: /j.jacc Acute Comarative Effect of Right and Left Ventricular Pacing in Patients With Permanent Atrial Fibrillation Electrohysiology Enrico Puggioni, MD,* Michele Brignole, MD,* Michael Gammage, MD, Ezio Soldati, MD, Maria Grazia Bongiorni, MD, Emmanuael N. Simantirakis, MD, Panos Vardas, MD, Fredrik Gadler, MD, Lennart Bergfeldt, MD, Corrado Tomasi, MD, Giacomo Musso, MD,# Gianni Gasarini, MD,** Attilio Del Rosso, MD Lavagna, Pisa, Reggio Emilia, Imeria, Mestre, and Fucecchio, Italy; Birmingham, United Kingdom; Heraklion, Greece; and Stockholm, Sweden OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We tested the hyothesis that left ventricular (LV) acing is suerior to right ventricular (RV) aical acing in atients undergoing atrioventricular (AV) junction ablation and acing for ermanent atrial fibrillation. The otential benefit of LV over RV acing needs to be evaluated without the confounding effect of other variables that can influence cardiac erformance. An acute intraatient comarison of the QRS width and echocardiograhic arameters between RV versus LV acing was erformed within 24 h after ablation in 44 atients. Both modes of acing were also comared with re-imlantation values. Comared with RV acing, LV acing caused a 5.7% increase in the ejection fraction (EF) and a 16.7% decrease in the mitral regurgitation (MR) score; the QRS width was 4.8% shorter with LV acing. Similar results were observed in atients with or without systolic dysfunction and/or native left bundle branch block, excet for a greater imrovement in MR in the latter grou. Comared with re-ablation measures, the EF increased by 11.2% and 17.6% with RV and LV acing, resectively; the MR score decreased by 0% and 16.7%; and the diastolic filling time increased by 12.7% and 15.6%. Rhythm regularization achieved with AV junction ablation imroved EF with both RV and LV acing; LV acing rovided an additional modest but favorable hemodynamic effect, as reflected by a further increase of EF and reduction of MR. The effect seems to be equal in atients with both deressed and reserved systolic functions and in those with and without native left bundle branch block. (J Am Coll Cardiol 2004;43:234 8) 2004 by the American College of Cardiology Foundation Pacing from the aex of the right ventricle (RV) is considered not otimal, as it rovides a nonhysiologic asynchronous contraction, which results in a decrease in cardiac erformance (1,2). In atients with ermanent atrial fibrillation (AF) who received atrioventricular (AV) junction ablation and acing from the RV aex, the beneficial See age 239 hemodynamic effect of regularization of heart rhythm is thus assumed to be artly counteracted by the adverse hemodynamic effect of a nonhysiologic acing mode (3). From the Cardiology Deartments, *Osedali del Tigullio, Lavagna, Italy; Queen Elizabeth Hosital, Birmingham, United Kingdom; Osedale S. Chiara, Pisa, Italy; University Hosital, Heraklion, Greece; Karolinska Hosital, Stockholm, Sweden; Osedale S. Maria Nuova, Reggio Emilia, Italy; #Osedale Civile, Imeria, Italy; **Osedale Umberto I, Mestre, Italy; and Osedale S. Pietro Igneo, Fucecchio, Italy. This study is officially endorsed by the Working Grou on Pacing of the Euroean Society of Cardiology. The Steering Committee was suorted by a limited grant from Vitatron, The Netherlands, and St. Jude Medical, Italy, which have agreed not to interfere with the scientific issues of the study. Manuscrit received June 14, 2003; revised manuscrit received August 2, 2003, acceted Setember 8, The Otimal Pacing Site (OPSITE) study (4) is a rosective, randomized, single-blinded, cross-over comarison between RV and left ventricular (LV) acing for atients with ermanent AF undergoing ablation and acing theray. The study consists of acute and chronicevaluations. The rotocol has been ublished reviously (4). In this reort, we focus on the acute comarison of RV and LV acing in a model of AF and AV junction ablation, which allows the net effect of LV over RV acing to be studied without the confounding effect of two other variables that can influence cardiac erformance namely, the effect of atrial contribution (including the effect of the PR interval) and the irregularity of the ventricular rhythm. Single-site LV acing was comared with single-site RV acing to eliminate the otential confounding effect of simultaneous biventricular stimulation. Moreover, the acute evaluation was erformed shortly after ablation, allowing a minimum time for cardiac adatation, which is another confounding factor. We assumed that the acute hemodynamic effect of LV acing would be better than that of RV acing. Secondary objectives were the comarison between two redefined

2 JACC Vol. 43, No. 2, 2004 January 21, 2004:234 8 Puggioni et al. LV Versus RV Pacing 235 Abbreviations and Acronyms AF atrial fibrillation AV atrioventricular EF ejection fraction LBBB left bundle branch block LV left ventricle/ventricular MR mitral regurgitation OPSITE Otimal Pacing Site study RV right ventricle/ventricular subgrous of atients with reserved or deressed systolic function and the comarison of the two modes of acing with baseline measures to evaluate the effect of AV junction ablation. METHODS Table 1. Patient Characteristics at Enrollment (n 49) Age (yrs) 72 8 Gender (males) 24 (54%) Duration of atrial fibrillation (yrs) No. of hositalizations er atient New York Heart Association functional class Minnesota Living With Heart Failure Questionnaire (score) min walking test (m) Standard electrocardiogram Mean heart rate (beats/min) Left bundle branch block 22 (50%) Other intraventricular conduction disturbances 10 (23%) Holter monitoring Minimum heart rate (beats/min) Mean heart rate (beats/min) Maximum heart rate (beats/min) Associated structural heart disease Coronary artery disease 15 (34%) Others 29 (66%) Concomitant medications Digoxin 32 (72%) Diuretics 35 (80%) Nitrates 7 (16%) Angiotensin-converting enzyme inhibitors 33 (75%) Beta-blockers 22 (50%) Calcium antagonists 10 (23%) Airin 4 (9%) Warfarin 37 (84%) Class I antiarrhythmic drugs 3 (7%) Amiodarone 7 (16%) Sotalol 1 (2%) Data are resented as the mean value SD or number of atients. The following atients were eligible for enrollment in the OPSITE study: 1) atients with ermanent AF in whom a clinical decision was made to undertake comlete AV junction ablation and ventricular acing because of a drugrefractory, severely symtomatic, uncontrolled high ventricular rate; and 2) atients with ermanent AF, drugrefractory heart failure, deressed LV function, and/or left bundle branch block (LBBB) in whom a clinical decision was made to undertake LV synchronization acing. Patient exclusion criteria were as follows: 1) New York Heart Association functional class IV heart failure; 2) severe concomitant noncardiac diseases; 3) need for surgical intervention; 4) myocardial infarction within three months; 5) sustained ventricular tachycardia or ventricular fibrillation; and 6) reviously imlanted acemaker. Two different subgrous were redefined for analysis: atients with an ejection fraction (EF) 40% and absence of an LBBB attern (grou A) and atients with heart failure (i.e., those with EF 40% and/or LBBB attern) (grou B). All atients underwent acemaker imlantation and AV junction ablation; acemaker imlantation and ablation could take lace at different times ( 6 weeks aart), but simultaneous rocedures were recommended. The RV leads were ositioned in the RV aex. The LV leads were ositioned via the coronary sinus in a osition considered most aroriate by the imlanting hysician; in case of failure of acing through the coronary sinus, an eicardial lead was inserted. A conventional dual-chamber acemaker was used; the atrial ort of the acemaker was connected to the LV lead, and the ventricular ort was connected to the RV lead. The acute noninvasive study, which was erformed within 24 h after AV junction ablation, consisted of echocardiograhic evaluation and measurements of the QRS duration. The acemaker was alternately rogrammed to ace in the LV or RV only in randomized order, at a rate of 70 beats/min. The RV and LV acing studies were erformed during the same session; the oerator who erformed the test and analyzed the records was not informed of the mode of acing. The echocardiograhic examination was erformed using standard views, according to the guidelines of the American Society of Echocardiograhy (5). Echocardiograhic long-axis and aical two- and fourchamber views were obtained to assess the LV end-diastolic diameter, LV end-systolic diameter, EF (area length method), aortic flow integral (ulsed Doler), isovolumic relaxation time, mitral flow integral (ulsed Doler), mitral flow eak, mitral deceleration time, diastolic filling time, and severity of mitral regurgitation (MR) (by means of a semiquantitative three-score scale). The measures obtained were the average of six consecutive beats. Statistical analysis. The assumtion for the samle size calculation was that, based on a revious study (6), LV acing would be able to increase EF by 9%, comared with RV acing. The samle size able to rovide 80% ower to show an intraatient difference, with a robability of 95%, was 40 atients. Paired and unaired two-tailed t tests were used for comarison of continuous variables. A value 0.05 was considered as significant. RESULTS The study grou consisted of 44 atients who had undergone successful AV junction ablation and acemaker imlantation between July 2001 and July The RV leads were ositioned in the RV aex in all atients. The LV leads

3 236 Puggioni et al. JACC Vol. 43, No. 2, 2004 LV Versus RV Pacing January 21, 2004:234 8 Table 2. Results Baseline RV Pacing LV Pacing RV vs. Baseline LV vs. Baseline LV vs. RV EF LVEDD (mm) NS 0.9 NS 0.4 NS LVESD (mm) NS 12.5 NS 1.6 NS IRT (ms) NS 7.0 NS 1.3 NS MR (score) NS FVI Ao (cm) NS 6.2 NS E max (cm/s) NS 1.6 NS 0.4 NS FVI (cm) NS 2.2 NS 1.7 NS DT (ms) NS 3.5 NS 0 NS DFT (ms) NS QRS (ms) *Paired t test. Data are resented as the mean value SD. DFT diastolic filling time; DT deceleration time; EF ejection fraction; E max maximum rotodiastolic mitral flow; FVI flow velocity integral; FVI Ao aortic flow velocity integral; IRT isovolumetric relaxation time; LV left ventricular; LVEDD left ventricular end-diastolic diameter; LVESD left ventricular end-systolic diameter; MR mitral regurgitation; NS not significant; RV right ventricular. were ositioned via the coronary sinus in the midosterolateral site in 39 atients and in the anterior site in 3 atients. In two atients in whom the coronary sinus aroach had failed, the lead was imlanted in an eicardial mid-osterolateral osition through a limited thoracotomy. The clinical characteristics are shown in Table 1. Of these, 14 belonged to grou A and 30 to grou B (22 of grou B also had LBBB). The results of the comarison between RV and LV acing are shown in Table 2. Comared with RV, LV acing resulted in a significant increase of EF, a decrease of MR, and a small reduction of the QRS duration. Similar results were observed in atients with normal cardiac function (grou A) and in those with deressed systolic function (grou B) for all variables excet for MR, which was more reduced in grou A atients (Table 3). Similar findings were also observed in atients with and without native LBBB (Table 4). Among atients with native LBBB, all but three also had an EF 40%. A comarison with re-imlantation data is shown in Table 2. Both RV and LV acing imroved EF and rolonged the diastolic filling time; LV acing also reduced the MR score, whereas RV acing did not. Both RV and LV acing decreased aortic and mitral stroke velocity, thus suggesting a deleterious effect on contraction, but this effect was less ronounced with LV acing. DISCUSSION The main findings of this study are that rhythm regularization achieved with AV junction ablation imroves EF with both RV and LV acing; however, LV acing gives an additive modest but favorable hemodynamic effect, as judged by a further increase of EF and reduction of MR magnitude. This effect seems to be equal in atients with and without deressed systolic function and in atients with and without LBBB. As a consequence of the rotocol used, the effect of LV acing could be evaluated without several otentially confounding factors (i.e., the effect of atrial contribution [including the effect of the PR interval], irregularity of the ventricular rhythm, simultaneous biven- Table 3. Comarison Between Grou A and Grou B Patients RV Grou A (n 14) Grou B (n 30) LV RV LV Grou A vs. Grou B EF NS NS LVEDD (mm) NS NS NS LVESD (mm) NS NS IRT (ms) NS NS NS MR (score) FVI Ao (cm) NS NS NS E max (cm/s) NS NS NS FVI Mi (cm) NS NS NS DT (ms) NS NS NS DFT (ms) NS NS NS QRS (ms) NS NS NS *Paired t test. Unaired t test for grou A versus B. Data are resented as the mean value SD. FVI Mi mitral flow velocity integral; other abbreviations as in Table 2. Value

4 JACC Vol. 43, No. 2, 2004 January 21, 2004:234 8 Puggioni et al. LV Versus RV Pacing 237 Table 4. Comarison Between Patients With LBBB and Those Without RV tricular stimulation, and cardiac adatation to chronic stimulation). An increase in EF over baseline was already resent as a result of RV acing. Because a direct imrovement of cardiac function by RV acing is unlikely, this imrovement seems likely to be due to the effects of rhythm regularization and the reduction in the ventricular rate following AV junction ablation, resulting in imrovements in ventricular filling, the Frank-Starling mechanism, and the intervalforce relation (7 10). In addition, RV acing showed a neutral effect on MR and indeed a worsening of aortic and mitral flow, robably reflecting the asynchronous contraction caused by nonhysiologic acing from the aex of the RV (1,2). Thus, the cardiac erformance after AV junction ablation and RV acing is the net result of two oosite effects. Left ventricular acing, comared with RV acing, substantially reduced the magnitude of MR and did not worsen aortic and mitral flow. The lessened MR tended to lower the EF because of higher afterloading conditions on the LV resent during MR, unless inotroic/contractile erformance was imroved. In one study (11), functional MR was reduced in atients in sinus rhythm, and this effect was directly related to the increased closing force. In the resent study, the EF imroved by a further 6%, as comared with RV acing ( 17% vs. baseline). Thus, the imrovement of EF in the resence of less MR imlies even more benefit from LV acing. On the other hand, the aortic flow did not imrove with LV acing, as much as exected from the reduction of MR. Small changes in aortic flow may indicate that only a small reduction in MR took lace. In brief, the observed modifications were generally modest and, in some way, contrasting. Anyway, in general, it seems that LV acing is able to counteract some of the adverse effects of RV acing. The acute hemodynamic effects of LV acing were similar in the atients with reserved and deressed systolic function, as well as in atients with and without native LBBB. This finding is original. Indeed, until now, LV and No LBBB (n 22) LBBB (n 22) LV RV LV LBBB vs. No LBBB EF NS NS LVEDD (mm) NS NS NS LVESD (mm) NS NS NS IRT (ms) NS NS NS MR (score) NS 0.03 FVI Ao (cm) NS NS NS E max (cm/s) NS NS NS FVI Mi (cm) NS NS NS DT (ms) NS NS NS DFT (ms) NS NS NS QRS (ms) NS NS NS *Paired t test. Unaired t test for LBBB versus no LBBB. Data are resented as the mean value SD. LBBB left bundle branch block; other abbreviations as in Tables 2 and 3. Value biventricular acing modes have been studied mainly in atients with severely comromised LV systolic function and LBBB. Pacing from the aex of the RV causes an electrocardiograhic attern of LBBB. In one study (12) erformed in atients with otherwise normal hearts, the resence of LBBB was associated with a significant deterioration of cardiac function of about 10% to 20%. In the ublished data, the widely used criterion for LV (or biventricular) acing is the resence of LBBB with a wide QRS comlex (13 15). The criterion of a aced QRS width 200 ms was also used in one study (14). Our observation otentially extends the indication for LV acing to all atients who are candidates for ablation and acing theray. This latter assertion needs to be verified in a larger oulation, as the resent study is robably underowered to show differences between subgrous. We cannot exclude some interobserver variability of echocardiograhic evaluations that could confound the results. However, the intraatient comarison allowed us to reduce the interobserver variability. There is increasing evidence for a favorable effect of cardiac resynchronization acing in atients with heart failure and an intraventricular conduction delay, who are in sinus rhythm either during acute hemodynamic (16 22) or clinical follow-u studies (6,23 28). Much less is known about atients with ermanent AF. An acute hemodynamic study (13) showed similar hemodynamic benefits of LV-based acing either in sinus rhythm or in AF. Caillary wedge ressure decreased from 24 4 mm Hg at baseline to 19 5mmHgand21 6mmHg during LV and biventricular acing, resectively; aortic systolic blood ressure increased from mm Hg baseline to mm Hg and mm Hg during LV and biventricular acing, resectively. In another small, acute, controlled study (6), LV acing, comared with RV acing, caused an imrovement of EF from 34 14% to 37 12% and in the aortic flow integral from cm to cm. The magnitude of the acute imrovement is modest,

5 238 Puggioni et al. JACC Vol. 43, No. 2, 2004 LV Versus RV Pacing January 21, 2004:234 8 however. It is uncertain how much these hemodynamic effects correlate with the clinical outcome. The results of the first randomized clinical study have recently been reorted (14). The intention-to-treat analysis did not show any statistically significant difference in either the rimary or secondary end oints between biventricular and RV acing; however, in the on-treatment analysis, the mean walked distance increased significantly by 9.3% and eak oxygen utake increased by 13% during biventricular acing. The average magnitude of the effect was modest, although very helful, in terms of clinical imrovement. This is not surrising if we consider that, in AF atients, an imrovement is achieved by AV junction ablation, er se, which reduces the amount of the otential additional benefits obtainable through LV acing. On the other hand, it is aarent from the ublished data that ugrading to biventricular acing is greatly effective in atients with congestive heart failure with a low EF, who have had the revious intervention of AV junction ablation and RV acing (29). The results of the chronic hase the OPSITE study (4) will hoefully hel to increase our knowledge of the benefits of different acing sites in these atients. Rerint requests and corresondence: Dr. Michele Brignole, Head of the Deartment of Cardiology, Osedali del Tigullio, Via don Bobbio, Lavagna, Italy. mbrignole@asl4. liguria.it. REFERENCES 1. Zile M, Blaustein A, Shimizu G, et al. Right ventricular acing reduces the rate of left ventricular relaxation and filling. J Am Coll Cardiol 1987;10: Ausubel K, Furman S. The acemaker syndrome. Ann Intern Med 1985;103: Brignole M, Menozzi C, Gianfranchi L, et al. 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