Anodal Capture in Cardiac Resynchronization Therapy Implications for Device Programming

Anodal Capture in Cardiac Resynchronization Therapy Implications for Device Programming DAVID TAMBORERO,* LLUIS MONT,* ROBERTO ALANIS, ANTONIO BERRUEZO,* JOSE MARIA TOLOSANA,* MARTA SITGES,* BARBARA VIDAL,* and JOSEP BRUGADA* From the *Thorax Institute, Hospital Clínic, University of Barcelona, and Institut de Investigació, Biomèdica August Pi i Sunyer (IDIBAPS), Catalonia, Spain, and Guidant Corporation Spain, Madrid, Spain. Introduction: Right ventricular (RV) anodal capture (AC) has been reported in cardiac resynchronization therapy (CRT), when left ventricular (LV) pacing uses pseudobipolar (LV tip to RV proximal electrode) configuration. The aim of the study was to analyze the prevalence of AC and its implications for device programming. Methods and Results: When AC occurred, the resulting QRS morphology was evaluated with the following pacing modes: (1) LV tip pacing plus RV AC, (2) Biventricular (BiV) pacing (i.e., both LV and RV tip pacing), and (3) BiV pacing plus RV AC. Several interventricular pacing (VV) intervals from 50 ms of LV preactivation to 30 ms of RV preactivation were tested in modes 2 and 3. From 38 consecutive patients, AC was achieved in 14 (in 74% of the pacemakers and in none of the defibrillators). LV tip pacing plus RV AC obtained narrower QRS than BiV pacing at all VV intervals in seven of the patients with AC (50%). When BiV pacing is combined with RV AC, it produced a ventricular depolarization through two wave fronts (one from the LV tip and the second from either the ring or the tip of the RV lead depending on the VV interval programmed). Conclusions: AC obtained the narrowest QRS of all tested pacing modes in a significant proportion of patients undergoing CRT. Though the stimulus was delivered from three sites (BiV pacing plus RV AC mode), only two wave fronts of ventricular activation were seen by ECG. (PACE 2006; 29:940 945) VV timing, anodal stimulation, cardiac resynchronization therapy Introduction Cardiac resynchronization therapy (CRT) has proven beneficial in patients with heart failure and electrical conduction disturbances. 1 7 Ventricular dissynchrony is corrected by pacing both ventricles through leads placed in the right (R) and left (L) ventricles (V). Optimization of CRT requires the adjustment of atrioventricular and interventricular (VV) pacing delays. 8 10 In LV pseudobipolar (i.e., LV tip to RV proximal electrode) configuration, unexpected RV anodal capture (AC) has recently been reported during LV pacing. 11 Furthermore, when RV AC occurs during biventricular (BiV) pacing, it has been hypothesized that three wave fronts of ventricular depolarization occur from LV tip and RV tip plus RV proximal electrode (the triple-site pacing phenomenon). 11,12 Apparently, pacing from three different sites produces a hemodynamic benefit detected by echocardiography. 13 The aim of this study was to establish the prevalence and charac- There were no conflicts of interest in the realization of this work. Address for reprints: David Tamborero, Bioengineer, Cardiovascular Institute, Hospital Clínic Universitari de Barcelona, Villarroel 170, Barcelona 08036, Catalonia, Spain. Fax: 00-34- 934513045; e-mail: dtambore@clinic.ub.es Received March 15, 2006; revised May 12, 2006; accepted May 30, 2006. teristics of RV AC in CRT devices and to evaluate how this phenomenon may affect the device programming. Finally, we analyzed whether triplesite pacing mode produces QRS variations. Methods Patients with severe congestive heart failure, low LV ejection fraction, wide QRS (>120 ms), and class III or IV in the New York Heart Association (NYHA) classification despite optimal medical treatment underwent CRT. A bipolar LV lead was implanted transvenously through the coronary sinus. A bipolar passive fixation RV lead was positioned at the RV apex. Distance between RV lead electrodes was 16 mm in pacemakers and 12 mm in defibrillators. The RV lead of the CRT defibrillators used part of the distal shocking coil as RV anode (integrated design), and no true bipolar design (employing a dedicated ring as anode) was used in any defibrillator lead of this series. All CRT devices allowed VV interval programming and LV pacing in pseudobipolar or bipolar configuration (plus unipolar configuration in CRT pacemakers). RV AC was confirmed by QRS change during LV pacing when configuration was changed from bipolar to pseudobipolar. Absence of RV AC was noted when it did not occur at maximal LV output voltage (7.5 V) at 0.5 ms of pulse width. The RV AC threshold was defined as the minimal LV pseudobipolar output that was able to capture RV. C 2006, The Authors. Journal compilation C 2006, Blackwell Publishing, Inc. 940 September 2006 PACE, Vol. 29

ANODAL CAPTURE IN CARDIAC RESYNCHRONIZATION THERAPY In all CRT patients, a 12-lead electrocardiogram (ECG) was recorded in several modes: (1) intrinsic rhythm, (2) RV pacing, (3) LV pacing, and (4) BiV pacing varying VV interval from 50 ms of LV preactivation (VV = 50) to 30 ms of RV preactivation (VV =+30) by 10-ms steps. In modes 3 and 4, the LV lead was initially programmed to bipolar configuration. The presence of RV AC was then tested, programming LV pacing to pseudobipolar configuration. In patients in whom RV AC was confirmed, modes 3 and 4 were also registered, programming LV lead to pseudobipolar configuration in order to evaluate LV pacing plus simultaneous RV AC and the possible phenomenon of triple-site pacing, respectively. QRS duration was measured from the earliest ventricular activity to the last ventricular deflection in any ECG lead, considering the first stimulation artifact as the beginning of depolarization during ventricular pacing. ECG was recorded digitally and time measurements were performed at a screen speed of 100 mm/s with signal amplified at 10 mm/mv. Three consecutive QRS complexes were measured with electronic calipers that have a 1-ms resolution. Two blinded observers performed all measurements and a maximal discordance of 5 ms was accepted. When this discordance was observed, measurements were repeated until concordance was obtained. Statistical Analysis Continuous data were expressed as mean ± standard deviation. QRS width measurements were compared by Student s t-test for paired analysis. A P < 0.05 was considered statistically significant. Results Thirty-eight consecutive CRT patients were evaluated. Of them, 19 received a CRT pacemaker and the remaining 19 received a CRT defibrillator. Their demographic characteristics are shown in Table I. All LV leads were located in a posterior or a posterolateral vein. RV AC was found in 14 patients of the CRT pacemaker group (74%) but in none of the CRT defibrillator group (Fig. 1). Mean RV AC threshold was 3.3 ± 1.6 V at 0.5 ms pulse width. The use of part of the distal shocking coil as the RV lead proximal electrode in the defibrillator devices meant that the surface of the electrode was too large to create enough current density for RV AC to occur. 14 QRS Width Measurements BiV pacing in bipolar configuration (without AC) obtained the narrowest QRS by LV preactivation at VV = 30 in 47% of the 38 patients of the series and by VV = 0 in the remaining 53%. Overall, Table I. Demographic Characteristics Patients 38 Pacemaker devices (n) 19 (50%) Age (years) 67 ± 8 Male sex (n) 23 (60%) Basal QRS width (ms) 175 ± 28 Etiology of cardiomyopathy 16 (42%) Ischemic (n) 5 (13%) Valvular heart disease (n) 17 (45%) Idiopathic (n) 74 ± 9 LV end-diastolic diameter (mm) 59 ± 11 LV end-systolic diameter (mm) 24 ± 7 LV ejection fraction (%) LV = left ventricle. the narrowest QRS obtained by bipolar BiV pacing was shorter than the intrinsic QRS (151 ± 20 vs 189 ± 28 ms; P = 0.001). In 7 of the 14 patients (50%) in whom RV AC occurred, LV pacing in pseudobipolar configuration (LV tip pacing plus simultaneous RV ring capture) obtained a shorter QRS than bipolar BiV pacing at any VV tested. In these cases, the mean QRS shortening obtained through AC compared with the shortest QRS obtained by bipolar BiV pacing was 15 ± 4 ms (range 6 26 ms). Ventricular Depolarization Pattern During BiV Pacing Plus RV AC In patients with RV AC, LV pacing in pseudobipolar configuration produced simultaneous capture of the LV tip and the RV ring. The QRS obtained in this pacing mode differed from that obtained by bipolar BiV pacing (without RV AC) at VV = 0 according to the RV lead site at which depolarization is initiated, that is, the RV ring or the RV tip. Furthermore, one of these two pacing modes obtained a narrower QRS than the other (from 4 to 34 ms depending on each patient), possibly due to the RV lead positioning: one of the RV lead electrodes may be closer to the native conduction system of the heart and produces a shorter QRS. Theoretically, when LV lead is programmed in pseudobipolar configuration and RV AC occurs, BiV pacing at VV = 0 would act as simultaneous ventricular pacing from three different sites: LV tip, RV tip, and RV ring, a phenomenon known as triple-site pacing. 11 13 However, in our series this pacing mode always showed an identical QRS morphology to the narrower one obtained either by pseudobipolar LV pacing or by bipolar BiV pacing at VV = 0. It seems that when electrical stimulus PACE, Vol. 29 September 2006 941

TAMBORERO, ET AL. Figure 1. Precordial leads of an ECG recorded during the capture threshold test of LV lead in pseudobipolar (LV tip to RV ring) configuration. Above 4V, LV pacing plus RV anodal capture is always present. Between 3V and 4V, RV anodal capture is intermittent. Below 3V, only LV capture occurs (until LV pacing fails). LV = left ventricle; RV = right ventricle. is deployed from both RV ring and tip, ventricular activation occurs only from the wave front of the RV lead electrode that reaches the conduction system first. We hypothesize that the other activation front encounters refractory the conduction system and does not cause significant ventricular depolarization. Since the two pacing sites at the RV lead are close together, only one of them significantly captures the ventricle (Fig. 2). Effect of VV Interval Programming During BiV Pacing Plus RV AC The timing between LV and RV tip pacing is determined by the VV interval programming from the device whereas the RV AC phenomenon occurs simultaneously to the LV pacing. Therefore, the programmed VV interval also determines the delay between the RV ring capture and the RV tip pacing during BiV pacing plus RV AC. The earlier the LV preactivation, the earlier the RV ring capture occurs, preventing the ventricular depolarization from the RV tip. In our series, BiV pacing plus RV AC at long LV preactivation (interval VV = 50) always showed the same QRS as pseudobipolar LV pacing (i.e., LV tip plus RV ring simultaneous capture). This QRS remained unaltered in spite of the fact that LV preactivation was reduced by VV programming until a specific VV value was reached (jump VV). At this point, QRS morphology changed suddenly and coincided with that obtained by conventional BiV pacing (without RV AC), i.e., progressive fusion complex between LV and RV according to VV value (Fig. 3). Therefore, jump VV is the VV delay that causes the origin of ventricular depolarization to jump from the RV ring to the RV tip. The value of jump VV varies from patient to patient, and it may be due to differences in RV lead positioning. In our series, jump VV was between 10 and +20 in all cases. A jump VV 0 means that a capture from the RV tip reaches the conduction system faster than a capture from the RV ring, and this occurred in 57% of our cases. Table II depicts the QRS width according to VV value during BiV pacing plus RV AC in all the patients in whom this phenomenon was possible. Discussion Cathodal capture, which initiates a single activation front from the tip of the pacing lead, is the established mechanism for pacing cardiac tissue. However, AC may also occur due to hyperpolarization of the underlying tissue. 15 This phenomenon has been described in CRT systems that use a narrow electrode as RV anode, that is, all CRT pacemakers and CRT defibrillators with true 942 September 2006 PACE, Vol. 29

ANODAL CAPTURE IN CARDIAC RESYNCHRONIZATION THERAPY Figure 2. QRS obtained with three different pacing modes in two CRT pacemaker patients: (1) QRS 1 :LV pacing in pseudobipolar configuration, simultaneously capturing the LV tip and the RV ring due to the RV anodal capture phenomenon. (2) QRS 2 : Unipolar biventricular pacing (without RV anodal capture) at VV = 0, simultaneously capturing the RV tip and the LV tip. (3) QRS 3 : Biventricular pacing at VV = 0 using LV pseudobipolar configuration (with RV anodal capture), deploying electrical stimulus simultaneously from LV tip, RV ring, and RV tip. QRS 3 generated by triple-site capture pacing mode always shows the same QRS pattern to capture from either RV ring (QRS 1 ) or RV tip (QRS 2 ) depending on which QRS complex is narrower, but no new QRS morphology appears. Therefore, in patient A: QRS 3 = QRS 1, whereas in patient B: QRS 3 = QRS 2. LV left ventricle; RV right ventricle; VV interventricular pacing delay. In the figures on the left, pacing sites are represented by the red circles. bipolar design of the RV lead (in which the RV anode is a ring electrode). The phenomenon has not been seen in defibrillators that use integrated design (distal shocking coil as RV anode). The main finding of our study is that pacing through the LV electrode with RV AC achieves a narrower QRS than BiV pacing (without RV AC) at all VV intervals in 50% of cases. Since previous observations suggest that the narrowing of QRS is the best predictor of clinical response to CRT, 16 it may be useful to test this pacing configuration when AC is possible and stable at a reasonable threshold. BiV pacing when RV AC occurs has recently been defined as triple-site capture, which would involve ventricular depolarization due to three different activation fronts. 11 13 Bulava et al. 13 showed by tissue Doppler imaging that this configuration achieved better resynchronization in a significant number of patients due to the additional benefit of pacing from a third site (the RV ring). Although our data suggest that only one of the activation fronts from the RV lead actually produces significant ventricular depolarization, resynchronization improvement reported by the authors could be due to the jump in the origin of ventricular depolarization PACE, Vol. 29 September 2006 943

TAMBORERO, ET AL. Figure 3. Precordial leads showing the QRS morphologies obtained by LV pseudobipolar pacing with RV anodal capture (panel 1), BiV pacing with RV anodal capture (the triple-site capture pacing mode) at different VV intervals (panels from 2 to 6), and BiV pacing without RV anodal capture at different VV intervals (panels from 7 to 9). From panel 2 to 4, the QRS obtained is unchangeable and identical to the QRS of panel 1. Jump VV is reached in panel 5. Then, the QRS obtained shows different degrees of fusion between LV and RV according to VV interval as conventional BiV pacing. Therefore, panel 5 is identical to panel 8 and panel 6 identical to panel 9. Observe the contamination in the QRS complex produced by the stimulation artifact that should not be confused with QRS variations. LV = left ventricle; RV = right ventricle; BiV = biventricular; VV = interventricular stimulation delay. VV < 0 indicates LV preactivation and VV > 0 indicates RV preactivation. from the RV tip to the RV ring and would be in accordance with the narrowing of QRS obtained by this pacing mode in our series. AC from the LV ring has not been observed in any patient of this series during LV bipolar pacing, and it may be due to the epicardial location of the LV lead. Therefore, variations in QRS when LV pacing configuration is changed from bipolar to pseudobipolar should be only attributed to the RV ring capture phenomenon. In BiV pacing when RV AC is present, VV interval programming determines whether depolarization is obtained from the RV tip or from the RV ring, which produces a different QRS pattern. We suggest that the change in QRS morphology occurs when the origin of the activation front that invades the conduction system jumps from RV ring to RV tip. Therefore, the jump VV value is different for each patient because it depends on the RV lead position regarding the conduction system of the heart. When the ventricular depolarization is from the RV lead ring, it acts as pseudobipolar LV pacing canceling any ventricular preactivation. When it is from the RV lead tip, it acts as conventional BiV pacing taking into account the VV delay programming. Study Limitations This study is based on QRS evaluation. The best QRS does not automatically reflect the best resynchronization, so these data should be contrasted with more detailed studies. Echocardiographic findings may be required to compare BiV pacing through RV AC with conventional BiV pacing or with LV pacing alone. 17 Additionally, although AC is achieved in a significant proportion 944 September 2006 PACE, Vol. 29

ANODAL CAPTURE IN CARDIAC RESYNCHRONIZATION THERAPY Table II. QRS Width (ms) Obtained by Varying the Programming of VV Interval During Biventricular Pacing Plus RV Anodal Capture Patient VV = 50 VV = 20 VV = 10 VV = 0 VV =+10 VV =+20 VV =+30 01 156 156 156 130* 132 130 144 02 164 164 162* 162 166 172 190 03 164 164 164 144* 148 152 156 04 142 142 142 142 142 154* 178 05 130 130 130 126* 140 158 174 06 152 152 152 152 158* 166 178 07 144 144 144 144 148* 152 152 08 124 124 124 124 152* 148 160 09 164 164 164 164 164 180* 198 10 164 164 156* 152 162 166 164 11 140 140 140 136* 144 156 162 12 180 180 176* 174 170 180 184 13 146 146 146 146 146 162* 174 14 126 126 126 134* 138 144 152 *Indicates jump VV, when ventricular activation origin jumps from the RV ring to the RV tip. VV = interventricular pacing delay, when < 0 indicates left ventricle preactivation; RV = right ventricle. of patients, the chronic RV AC threshold has not been tested and it is unknown at present. Conclusions RV AC through pseudobipolar LV pacing may be obtained in a significant proportion of patients. In around half of them, this pacing configuration obtains the narrowest QRS. When BiV pacing plus RV AC is used, ventricular depolarization occurs from the RV ring (as pseudobipolar LV pacing) or from the RV tip (as conventional BiV pacing) depending on the VV interval programmed. References 1. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001; 344:873 880. 2. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002; 346:1845 1853. 3. Auricchio A, Stellbrink C, Butter C, et al. Clinical efficacy of cardiac resynchronization therapy using left ventricular pacing in heart failure patients stratified by severity of ventricular conduction delay. J Am Coll Cardiol 2003; 42:2109 2116. 4. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 21:2140 2150. 5. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 15:1539 1549. 6. Diaz-Infante E, Mont L, Leal J, et al. Predictors of lack of response to resynchronization therapy. Am J Cardiol 2005; 12:1436 1440. 7. Vidal B, Sitges M, Marigliano A, et al. Relation of response to cardiac resynchronization therapy to left ventricular reverse remodeling. Am J Cardiol 2006; 6:876 881. 8. Sogaard P, Egeblad H, Pedersen AK, Kim WY, Kristensen BO, Hansen PS, Mortensen PT. Sequential versus simultaneous biventricular resynchronization for severe heart failure: Evaluation by tissue Doppler imaging. Circulation 2002; 16:2078 2084. 9. van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ, Pijls NH. Effect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy. Am J Cardiol 2004; 12:1500 1503. 10. Porciani MC, Dondina C, Macioce R, et al. Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol 2005; 9:1108 1110. 11. van Gelder BM, Bracke FA, Pilmeyer A, Meijer A. Triple site ventricular pacing in a biventricular pacing system. Pacing Clin Electrophysiol 2001; 24:1165 1167. 12. van Gelder BM, Bracke FA, Meijer A. The effect of anodal stimulation on V-V timing at varying V-V intervals. Pacing Clin Electrophysiol 2005; 28:771 776. 13. Bulava A, Ansalone G, Ricci R, et al. Triple-site pacing in patients with biventricular device-incidence of the phenomenon and cardiac resynchronization benefit. J Interv Card Electrophysiol 2004;10:37 45. 14. Thibault B, Roy D, Guerra PG, et al. Anodal right ventricular capture during left ventricular stimulation in CRT-implantable cardioverter defibrillators. Pacing Clin Electrophysiol 2005; 28:613 619. 15. Ranjan R, Chiamvimonvat N, Thakor N, Tomaselli G, Marban E. Mechanism of anode stimulation in the heart. Biophys J 98; 74:1850 1863. 16. Lecoq G, Leclercq C, Leray E, et al. Clinical and electrocardiographic predictors of a positive response to cardiac resynchronization therapy in advanced heart failure. Eur Heart J 2005; 26:1094 1100. 17. Blanc JJ, Bertault-Valls V, Fatemi M, Gilard M, Pennec PY, Etienne Y. Midterm benefits of left univentricular pacing in patients with congestive heart failure. Circulation 2004; 14:1741 1744. PACE, Vol. 29 September 2006 945