Comparison of Effectiveness of Right Ventricular Septal Pacing Versus Right Ventricular Apical Pacing

Comparison of Effectiveness of Right Ventricular Septal Pacing Versus Right Ventricular Apical Pacing Oscar Cano, MD*, Joaquín Osca, MD, PhD, María-José Sancho-Tello, MD, Juan M. Sánchez, MD, Víctor Ortiz, MD, José E. Castro, MD, Antonio Salvador, MD, PhD, and José Olagüe, MD Chronic right ventricular apical pacing (RVAP) has been associated with negative hemodynamic and clinical effects. The aim of the present study was to compare RVAP with right ventricular septal pacing (RVSP) in terms of echocardiographic features and clinical outcomes. A total of 93 patients without structural heart disease and with an indication for a permanent pacemaker were randomly assigned to receive a screw-in lead either in the RV apex (n ⴝ 46) or in the RV mid-septum (n ⴝ 47). The patients were divided into 3 subgroups according to the percentage of ventricular pacing: control group (n ⴝ 21, percentage of ventricular pacing <10%), RVAP group (n ⴝ 28), or RVSP group (n ⴝ 32; both latter groups had a percentage of ventricular pacing >10%). The RVAP group had more intraventricular dyssynchrony and a trend toward a worse left ventricular ejection fraction compared to the RVSP and control groups at 12 months of follow-up (maximal delay to peak systolic velocity between any of the 6 left ventricular basal segments was 57.8 ⴞ 38.2, 35.5 ⴞ 20.6, and 36.5 ⴞ 17.8 ms for RVAP, RVSP, and control group, respectively; p ⴝ 0.006; mean left ventricular ejection fraction 62.9 ⴞ 7.9%, 66.5 ⴞ 7.2%, and 66.6 ⴞ 7.2%, respectively, p ⴝ 0.14). Up to 48.1% of the RVAP patients showed significant intraventricular dyssynchrony compared to 19.4% of the RVSP patients and 23.8% of the controls (p ⴝ 0.04). However, no overt clinical benefits from RVSP were found. In conclusion, RVAP was associated with increased dyssynchrony compared to the RVSP and control patients. RVSP could represent an alternative pacing site in selected patients to reduce the harmful effects of traditional RVAP. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1426 –1432) Although RVAP is known to be associated with asynchronous ventricular activation, at present, limited echocardiographic data are available regarding the effects of alternative pacing sites on the ventricular activation pattern.1–3 The aim of the present study was to prospectively compare the echocardiographic features and clinical outcomes of patients undergoing right ventricular apical pacing (RVAP) or right ventricular septal pacing (RVSP). Methods We conducted a randomized, single-center, single-blind, prospective study in which patients with an indication for permanent cardiac pacing because of atrioventricular block or sick sinus syndrome were randomly assigned to receive an active fixation lead either in the right ventricular apex or in the right ventricular mid-septum. To further characterize the effect of different pacing sites on the echocardiographic and clinical/biologic features, the patients were divided into subgroups according to the per-

Electrophysiology Section, Cardiology Department, Hospital Universitario La Fe, Valencia, Spain. Manuscript received November 24, 2009; revised manuscript received and accepted January 5, 2010. This work was supported by a research grant of the Sociedad Valenciana de Cardiología. *Corresponding author: Tel: (⫹34) 96-652-565-982; fax: (⫹34) 96197-3314. E-mail address: [email protected] (O. Cano). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.01.004

centage of ventricular pacing (%VP) obtained at the baseline evaluation (during the first week after device implantation). Thus, the patients who had had minimal pacing (%VP ⱕ10%) constituted the control group, and those with %VP ⬎10% constituted the study group and were divided into 2 subgroups, depending on the location of the ventricular pacing lead according to randomization (RVAP and RVSP groups). The 10% cutoff value was selected with the thought that this percentage could best divide the subset of patients with minimal pacing (mainly those with sick sinus syndrome or paroxysmal atrioventricular block) from the rest of the population sample, who were expected to require ventricular pacing most of the time (permanent atrioventricular block). We also took into account that in the Mode Selection Trial (MOST), the lowest risk of heart failure hospitalization was observed in patients with a mean %VP of ⱕ10%.4 All patients with sick sinus syndrome or paroxysmal atrioventricular block received a pacemaker with true mode change algorithms, which were thus programmed in the AAI ↔ DDD mode to prevent unnecessary right ventricular pacing. Patients were excluded before randomization if they met any of the following criteria: age ⬍18 years; the presence of heart failure or any significant structural heart disease (left ventricular [LV] hypertrophy ⬎15 mm, LV ejection fraction [EF] ⬍50%, moderate or greater degrees of valvulopathy, previous myocardial infarction, or significant coronary artery disease); chronic pulmonary heart disease, and any musculoskeletal disease hampering the realization of a 6-minute walkwww.AJConline.org

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Figure 1. Right anterior oblique (RAO) and left anterior oblique (LAO) fluoroscopic views of ventricular pacing lead located in mid-septal position.

ing test. The clinical interview, physical examination findings, and transthoracic echocardiographic results served to rule out any of these previous conditions. Finally, once the patient was eligible to enter the study, block randomization was used, keeping in mind the permanent pacing indication (atrioventricular block or sick sinus syndrome). All patients provided informed consent, and the study was performed according to the Institutional Guidelines of the La Fe University Hospital. The primary objective of the study was to compare the echocardiographic features (LV systolic function, LV volumes, and dyssynchrony parameters) in the 3 subgroups. The secondary objectives included the comparison of the clinical and biologic parameters (New York Heart Association Functional class, quality-of-life scores, as assessed by the European Quality of Life Scale [EuroQol] EQ-5D instrument, distance in the 6-minute walking test, and N-terminal pro-hormone brain natriuretic peptide [NT-proBNP] levels). Finally, a combined clinical end point, including new-onset atrial fibrillation or heart failure and heart failure hospitalizations, was also assessed at 12 months of follow-up. The diagnosis of new-onset heart failure was established using the modified Framingham criteria.5 All procedures were performed by the same 2 implanters (JO and JEC) using direct subclavian puncture. Under fluoroscopic guidance, an active fixation (screw-in), bipolar and steroid-eluting pacing lead was introduced with a stylet and directed to the RVA or RVS, depending on randomization. In the RVSP group, an S-shaped preformed stylet similar to that described by Vlay6 was used to advance the lead toward the pulmonary valve. At that point, the lead was gently withdrawn to reach the right ventricular mid-septal zone. Two orthogonal fluoroscopic views (right anterior oblique and left anterior oblique) and electrocardiographic features were used to confirm the final mid-septal position, as

Table 1 Baseline characteristics Variable

Controls (n ⫽ 21)

RVAP (n ⫽ 28)

RVSP (n ⫽ 32)

Age (years) Men New York Heart Association class Atrial fibrillation Pacing indication Atrioventricular block Sick sinus syndrome Pacing mode VVI DDD Hypertension* Diabetes mellitus† Hypercholesterolemia‡ Drug therapy at inclusion Angiotensin-converting enzyme inhibitors ␤ Blockers Diuretics Calcium channel antagonists Lipid-lowering agents

70 ⫾ 11 14 (67%) 1.2 ⫾ 0.4 4 (19%)

72 ⫾ 10 14 (50%) 1.3 ⫾ 0.4 6 (21%)

72 ⫾ 9 20 (63%) 1.4 ⫾ 0.6 7 (22%)

2 (10%) 19 (90%)

26 (93%) 2 (7%)

31 (97%) 1 (3%)

3 (14%) 18 (86%) 13 (62%) 0 (0%) 8 (38%)

3 (11%) 25 (89%) 16 (57%) 12 (43%) 14 (50%)

4 (12%) 28 (88%) 22 (71%) 7 (23%) 15 (48%)

7 (33%)

12 (43%)

15 (48%)

5 (24%) 4 (19%) 6 (29%) 7 (33%)

5 (18%) 9 (32%) 6 (21%) 12 (43%)

2 (6.5%) 12 (39%) 10 (32%) 14 (45%)

* Defined as systolic blood pressure of ⱖ140 mm Hg, diastolic blood pressure of ⱖ90 mm Hg, or if patient prescribed antihypertensive medication. † Defined as serum fasting glucose of ⱖ7.0 mmol/L or taking medication. ‡ Defined as cholesterol of ⱖ6.4 mmol/L or treatment with lipid-lowering drugs.

previously described (Figure 1).7–9 Ventricular leads from 4 different manufacturers (Selox SR, Biotronik, Berlin, Germany; Flextend 2, Guidant, Boston Scientific, Natick, Massachusetts; CapSureFix 5076, Medtronic, Minneapolis, Minnesota; and Tendril SDX, St. Jude Medical, Secaucus, New Jersey) were used, depending on the implanter’s pref-

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Table 2 Evolution of clinical and biologic parameters during follow-up Variable

Control Group (n ⫽ 21) Baseline

NT-proBNP (pg/ml) 6-Minute walking test (m) New York Heart Association functional class EuroQol EQ-5D index EuroQol EQ-5D visual analogue scale

6-mo Follow-Up

RVAP (n ⫽ 28) 12-mo Follow-Up

Baseline

6-mo Follow-Up

RVSP (n ⫽ 32) 12-mo Follow-Up

Baseline

6-mo Follow-Up

12-mo Follow-Up

438 ⫾ 504 500 ⫾ 717 269 ⫾ 346 653 ⫾ 718 483 ⫾ 626 406 ⫾ 438 700 ⫾ 851 446 ⫾ 430 442 ⫾ 568 413 ⫾ 82 442 ⫾ 64 459 ⫾ 63 402 ⫾ 91 428 ⫾ 103 433 ⫾ 95 389 ⫾ 102 424 ⫾ 96 427 ⫾ 90 1.16 ⫾ 0.42 1.15 ⫾ 0.28 1.18 ⫾ 0.44 1.30 ⫾ 0.43 1.31 ⫾ 0.48 1.29 ⫾ 0.44 1.45 ⫾ 0.60 1.18 ⫾ 0.42 1.25 ⫾ 0.42 0.94 ⫾ 0.08 0.91 ⫾ 0.11 0.90 ⫾ 0.12 0.89 ⫾ 0.28 0.86 ⫾ 0.17 0.86 ⫾ 0.22 0.91 ⫾ 0.08 0.90 ⫾ 0.10 0.90 ⫾ 0.12 0.79 ⫾ 0.18 0.82 ⫾ 0.11 0.86 ⫾ 0.13 0.79 ⫾ 0.14 0.80 ⫾ 0.17 0.81 ⫾ 0.17 0.77 ⫾ 0.15 0.84 ⫾ 0.13 0.83 ⫾ 0.16

Figure 2. Echocardiographic evaluation of intraventricular dyssynchrony with tissue Doppler imaging. (A,B) Images showing 61 ms of anterior-to-inferior wall delay in patient in RVAP, indicating presence of significant intraventricular dyssynchrony. (C,D) Images showing only 7 ms of septal-to-posterior wall delay in patient in RVSP.

erence, and were equally distributed between the 2 randomization arms. The patients were initially evaluated within the first week after implantation (baseline evaluation) and after 6 and 12 months of follow-up. All scheduled visits in-

cluded a complete clinical interview, physical examination, 12-lead electrocardiogram, quality-of-life evaluation with the EuroQuol EQ-5D instrument, transthoracic echocardiography, 6-minute walking test, pacemaker interrogation, and measurement of NT-proBNP.

78.2 ⫾ 26.6† 862 ⫾ 91 83.9 ⫾ 23.7 31.7 ⫾ 9.8 63.2 ⫾ 6.5 17.3 ⫾ 13‡ 20 ⫾ 19.9‡ 22.5 ⫾ 19.9‡ 29.4 ⫾ 24.9 45.3 ⫾ 23.7‡ 82.5 ⫾ 24.5† 865 ⫾ 107 82.2 ⫾ 22.1 29.1 ⫾ 11.8 64.2 ⫾ 8 16.1 ⫾ 14.3 39 ⫾ 39.7† 37.2 ⫾ 36.9† 25.6 ⫾ 22.6 59 ⫾ 38.9† 88.4 ⫾ 17.1* 868 ⫾ 115 79.5 ⫾ 29.8 30.1 ⫾ 14.5 62.9 ⫾ 7.9 31.5 ⫾ 24.6* 31.2 ⫾ 33.6 30.7 ⫾ 27.1*‡ 26.9 ⫾ 23.3*‡ 57.8 ⫾ 38.2*‡ 80.3 ⫾ 28.8* 869 ⫾ 91 81.3 ⫾ 23.8 31.9 ⫾ 10.2 61.3 ⫾ 8.6 28.9 ⫾ 20.7*‡ 33.4 ⫾ 32.7‡ 42.1 ⫾ 38.8*‡ 37.2 ⫾ 30.5* 62.4 ⫾ 37.6*‡ 85.5 ⫾ 19.2* 849 ⫾ 109 88.6 ⫾ 24.3 33.2 ⫾ 12.9 62.9 ⫾ 6.3 24.3 ⫾ 18.1 33.2 ⫾ 39.4* 36.6 ⫾ 37.5* 29.9 ⫾ 26.1 68.3 ⫾ 43.8* * p ⬍0.05 for comparison between control group and RVAP groups. † p ⬍0.05 for comparison between control and RVSP groups. ‡ p ⬍0.05 for comparison between RVAP and RVSP groups. § RR interval at echocardiographic evaluation.

5.1 ⫾ 3.5*† 824 ⫾ 72 86.2 ⫾ 28.4 31.5 ⫾ 11.3 62.6 ⫾ 7.1 18.6 ⫾ 11.5 21.6 ⫾ 22.2 20.4 ⫾ 22.7 12.6 ⫾ 10.7 37.6 ⫾ 20.8 Mean percentage of ventricular pacing RR interval (ms)§ Left ventricular end-diastolic volume (ml) Left ventricular end-systolic volume (ml) Left ventricular ejection fraction (%) Interventricular delay (ms) Septal-to-posterior wall delay (peak) (ms) Septal-to-lateral wall delay (peak) (ms) Anterior-to-inferior wall delay (peak) (ms) Maximal delay to peak systolic velocity (ms)

4.9 ⫾ 2.7*† 837 ⫾ 92 80.5 ⫾ 24.1 29.2 ⫾ 11.6 63.6 ⫾ 7.2 20.5 ⫾ 15.9 13.6 ⫾ 13.7 16.0 ⫾ 12.4 27.4 ⫾ 19.7 40.3 ⫾ 17.0

5.2 ⫾ 4.1*† 820 ⫾ 72 79.5 ⫾ 22.4 26.8 ⫾ 11.1 66.6 ⫾ 7.2 17.4 ⫾ 14.5 21.0 ⫾ 22.9 17.2 ⫾ 13.3 12.5 ⫾ 9.5 36.5 ⫾ 17.8

6-mo Follow-Up 6-mo Follow-Up 6-mo Follow-Up Baseline

A total of 93 patients were enrolled from January 2006 to August 2007, with 46 patients randomized to RVAP and 47 to RVSP. Seven patients were lost to follow-up, because they refused to continue in the study after inclusion (3 in the RVAP group and 4 in the RVSP group). One patient in the RVSP group was excluded after developing an incapacitating hemorrhagic stroke in the third month of follow-up and another patient from the RVAP group was excluded because a malignant tumor diagnosis hampered the scheduled visits. Three patients died during the 12 months of follow-up, 2 in the RVSP and 1 in the RVAP group, none from cardiovascular causes. Thus, a total of 81 patients were analyzed, 40 randomized to RVAP and 41 to RVSP (53 men, mean age 72 ⫾ 10 years, mean LVEF 63 ⫾ 8%). Once the mean %VP was assessed at the baseline evaluation, a control group (n ⫽ 21) consisting of patients with a mean %VP of ⱕ10% was established. The patients with a %VP ⬎10% were divided in 2 subgroups, depending on the location of the ventricular pacing lead: RVAP (n ⫽ 28) and RVSP (n ⫽

Table 3 Evolution of echocardiographic parameters during follow-up

Results

Variable

Control Group (n ⫽ 21)

12-mo Follow-Up

Baseline

RVAP (n ⫽ 28)

12-mo Follow-Up

Baseline

RVSP (n ⫽ 32)

12-mo Follow-Up

Images were obtained by the same single investigator using an iE33 model (Philips Medical Systems, Eindhoven, The Netherlands) with a 3.5-MHz transducer in the parasternal (long- and short-axis views) and apical (2-, 3-, and 4-chamber) views. The LV end-diastolic and end-systolic volumes and LV ejection fraction were calculated from the apical 2- and 4-chamber images using the biplane Simpson rule.10 Interventricular dyssynchrony was calculated as the difference between the left and right pre-ejection intervals measured with pulse Doppler echocardiography. The maximum difference of the time to the peak systolic velocity for the 6 segments at the basal level measured from the beginning of the QRS using pulse tissue Doppler imaging was considered the intraventricular dyssynchrony. Thus, the anterior-to-inferior wall delay, septal-to-posterior wall delay, and septal-to-lateral wall delay were measured in the apical 2-, 3-, and 4-chamber planes, respectively. All tissue Doppler imaging echocardiographic measurements were taken as averages of ⱖ3 representative cycles. Additionally, we considered the maximal delay to peak systolic velocity with tissue Doppler imaging between any of the 6 LV basal segments as a measurement of global asynchrony. All the echocardiographic evaluations in the control group were performed during intrinsic basal rhythm (not paced), and in the study subgroups (RVAP and RVSP) were performed during spontaneous paced rhythm. When native atrioventricular conduction was present at the echocardiographic evaluation, shortening of the atrioventricular interval was used to acutely ensure ventricular pacing. A stable heart rate was required to obtain reproducible measurements of LV dyssynchrony. The continuous data are expressed as the mean ⫾ SD or range, as appropriate. The categorical variables were compared using the chi-square test. One-way analysis of variance was used to compare the repeated measures of continuous variables between groups, followed by a post hoc Bonferroni’s test, as appropriate. p Values of ⱕ0.05 were considered statistically significant. All results were analyzed on an intention-to-treat basis.

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80.6 ⫾ 25.9† 870 ⫾ 76 78.1 ⫾ 21.4 25.8 ⫾ 9.9 66.5 ⫾ 7.2 24.1 ⫾ 16.9 19.3 ⫾ 18.8 14.9 ⫾ 13.6‡ 13.9 ⫾ 14.1‡ 35.5 ⫾ 20.6‡

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Figure 3. Box plots showing comparison of echocardiographic parameters at 12 months of follow-up in 3 subgroups. (A) Interventricular delay (p ⬍0.05, compared between control and RVAP group). (B) Anterior-to-inferior wall delay (p ⬍0.05, compared between control and RVAP group and RVAP and RVSP groups. (C) Maximal delay to peak systolic velocity (p ⬍0.05 for comparison between control and RVAP groups and between RVAP and RVSP groups. (D) LVEF (p ⫽ NS, but with trend toward worse LVEF in patients in RVAP seen).

32). Only 4 patients (14.3%) in the RVAP group and 3 patients (9.4%) in the RVSP group had preserved and stable native conduction. Programming changes during the echocardiographic evaluation to ensure ventricular pacing were necessary in 3 RVAP patients (10.7%) and 2 RVSP patients (6.2%). The baseline characteristics of the population are listed in Table 1. The pacing and sensing parameters remained stable and comparable between the 2 locations during implantation and at the 6- and 12-month follow-up visits. Only 1 case of lead dislodgment requiring surgical reposition was registered in each randomization arm (p ⫽ NS). The paced QRS duration was significantly longer in patients in the RVAP group (mean paced QRS duration at 12 months 162.2 ⫾ 15.1 ms for RVAP vs 151.3 ⫾ 18.3 ms for the RVSP group, p ⬍0.001). The baseline clinical parameters and NT-proBNP values were comparable among the 3 groups (Table 2). The RVAP group tended to have more interventricular dyssynchrony than the RVSP group, but the difference was not statistically significant (24.3 ⫾ 18.1 ms for RVAP, 16.1 ⫾ 14.3 ms for RVSP, and 20.5 ⫾ 15.9 ms for controls, p ⫽ 0.055, between RVAP vs RVSP, using the Bonferroni test). The RVAP and RVSP groups had more intraventricular dyssyn-

chrony at baseline than the control group, without differences in LV volume or LVEF (Figure 2 and Table 3). No differences in the clinical parameters were found at 6 months of follow-up (Table 2). The NT-proBNP levels were comparable (p ⫽ 0.94), with patients in the RVSP group experiencing an important reduction from baseline levels that did not reach statistical relevance (⌬NT-proBNP ⫺66.4 ⫾ 525.8 pg/ml in the RVAP group vs ⫺291.8 ⫾ 659.1 pg/ml in the RVSP group; p ⫽ 0.17). The echocardiographic evaluation revealed that patients in the RVAP group had more interand intraventricular dyssynchrony than the RVSP and control groups, without differences in LV systolic function (interventricular dyssynchrony 28.9 ⫾ 20.7 ms vs 17.3 ⫾ 13 ms and 18.6 ⫾ 11.5 ms, respectively, p ⫽ 0.02; maximal delay to peak systolic velocity 62.4 ⫾ 37.6 ms vs 45.3 ⫾ 23.7 ms and 37.6 ⫾ 20.8 ms, p ⫽ 0.01). All dyssynchrony parameters were comparable between the control group and RVSP group (Table 3). At 1 year of follow-up, no single clinical parameter showed any difference among the 3 groups (Table 2). Patients in the RVAP group had significantly more interventricular dyssynchrony than did the controls, and patients in the RVSP group had comparable values to those obtained

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among patients in the RVAP group (25% for RVAP, 12.5% for RVSP, and 14.3% for controls, p ⫽ NS for comparison between RVAP and RVSP groups). Discussion

Figure 4. Percentage of patients with ⬎60 ms of maximal intraventricular delay between any of 6 LV basal segments measured with tissue Doppler imaging.

from the control group (31.5 ⫾ 24.6 ms for RVAP, 24.1 ⫾ 16.9 ms for RVSP, and 17.4 ⫾ 14.5 ms for controls, p ⫽ 0.047 for the comparison between the RVAP and controls and p ⫽ 0.33 for the comparison between RVAP and RVSP). Once again, the RVAP group had more intraventricular dyssynchrony compared to RVSP and controls (maximal delay to peak systolic velocity between any of the 6 LV basal segments, 57.8 ⫾ 38.2 ms for RVAP, 35.5 ⫾ 20.6 ms for RVSP, and 36.5 ⫾ 17.8 ms for controls, p ⫽ 0.006; Figure 3). No differences between RVSP and controls were found. Of the RVAP patients, 48% had significant global intraventricular dyssynchrony (⬎60 ms between any of the 6 LV basal segments) at 1 year of follow-up versus 20% in RVSP group and 24% in control group (p ⫽ 0.04; Figure 4). Patients in the RVAP tended to have a lower LVEF than those in the RVSP group and controls (62.9 ⫾ 7.9% for RVAP, 66.5 ⫾ 7.2% for RVSP, and 66.6 ⫾ 7.2% for controls, p ⫽ 0.14). The presence of global intraventricular dyssynchrony was associated with a significantly lower LVEF among patients in the RVAP group (LVEF 59.1 ⫾ 7.9% for RVAP with significant global intraventricular dyssynchrony vs 66.1 ⫾ 6.5% for those without dyssynchrony, p ⫽ 0.02). A total of 8 RVAP patients (28.5%) and 14 RVSP patients (43.7%) experienced a LVEF increase of ⱖ5 points from baseline to the 12-month follow-up evaluation, and 8 RVAP patients (28.5%) and 5 RVSP patients (15.6%) experienced a LVEF decrease of ⱖ5 points (p ⫽ NS for both comparisons). A positive correlation between the QRS duration and global intraventricular dyssynchrony was found in the paced subgroups (r ⫽ 0.33, p ⫽ 0.05). New-onset heart failure tended to be more frequent in the RVAP group at the end of follow-up without reaching statistical significance (23.1% for RVAP vs 10% for both RVSP and controls, p ⫽ NS). Two patients in each pacing subgroup (RVAP and RVSP) developed paroxysmal or persistent atrial fibrillation during follow-up. A total of 4 hospitalizations were registered for patients in the RVAP because of heart failure (14.3%) compared to 1 heart failure hospitalization in the control group (4.8%) and none in the RVSP subgroup (p ⫽ 0.069). Two additional hospitalizations because of noncardiovascular causes were registered in the RVAP subgroup. Finally, the combined clinical end point (new-onset atrial fibrillation or heart failure and heart failure hospitalizations) also tended to be more frequent

This is the first study in a large series of patients demonstrating that the electrical dyssynchrony induced by permanent RVAP is associated with significant mechanical dyssynchrony compared to RVSP. However, these beneficial features did not seem to correlate with a positive effect on clinical outcomes, at least during the first year after implantation, although the combined clinical end point and heart failure hospitalizations tended to be more frequent in patients in the RVAP group. Our results support that RVSP is more physiologic than RVAP, as determined by the significant reduction in the paced QRS duration and, especially, the improvement achieved in dyssynchrony parameters. A positive and statistically significant correlation was found between the paced QRS duration and global dyssynchrony. Moreover, patients in the RVAP tended to have a lower LVEF than patients in the RVSP and control groups at the end of follow-up. The search for alternative pacing sites has arisen after corroborated evidence of the deleterious effects of traditional RVAP.4,11 The right ventricular outflow tract/septum has been one of the most widely explored alternative pacing sites.6 –9,12–18 Previous experimental studies have demonstrated the negative effects of the asynchronous electrical activation provoked by permanent RVAP resulting in worsening of the LVEF, impairment of LV diastolic function, and alterations in regional myocardial blood flow.1 Similarly, RVAP has been associated with wall motion abnormalities, myocardial perfusion defects, and impaired LV function in humans.2 However, at present, no data demonstrating that the electromechanical dyssynchrony induced by RVAP can be counteracted by alternative pacing sites have been published in large series. Only one randomized study has previously evaluated the effect of RVSP on dyssynchrony parameters in a small sample population. Flevari et al19 studied 36 patients with atrioventricular block who were randomized to receive a ventricular pacing lead placed at the RV apex or RV low septum. At 12 months of followup, lower septal pacing was associated with a more synchronous contraction pattern and with an increase in LVEF compared to RVAP. Our results are in concordance with the findings from that small series. In contrast, a nonrandomized small study recently showed that RVSP was associated with impairment of LV dyssynchrony parameters compared to RVAP and controls.20 Ng et al20 conducted a crosssectional study in which they compared echocardiographic dyssynchrony and the LV function parameters between RVSP (n ⫽ 17) or RVAP (n ⫽ 17) and a control group of nonpaced patients (n ⫽ 22). They found that the RVSP patients had a lower LVEF, lower circumferential strain, and greater circumferential dyssynchrony. They concluded that these detrimental effects associated with RVSP might have resulted from the heterogeneity of the real pacing sites included under the umbrella of RVSP concept. The number of patients included in the present study was very small, and no clinical data were available.

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No significant differences in terms of clinical outcomes were found in our population sample. This could be probably be explained by the clinical profile of our population sample, which included patients with structurally normal hearts and without any significant co-morbidities. Probably, longer follow-up would increase the possibilities of finding clinical benefits. The results of 3 ongoing, large, randomized multicenter clinical trials with a minimum of 24 months of follow-up (Selective Site Pacing Clinical Trial [Optimize RV], Right Ventricular Apical and High Septal Pacing to Preserve Left Ventricular Function [Protect Pace], and Right Ventricular Apical versus Septal Pacing [RASP]) and almost 800 patients included should provide a definitive answer.21 The presence of an appreciable amount of inter- and intraventricular dyssynchrony at baseline evaluation in both paced groups could be hypothetically explained by some degree of acute electrical stunning associated with both atrioventricular block and the temporary right ventricular apical pacing used before implantation. This electrical stunning would disappear over time in RVSP patients but would persist in RVAP patients. The present study represents a single-center experience, the sample size was relatively small, and follow-up was limited to 1 year. However, we believe we have provided useful information regarding the echocardiographic features of RVSP that have not yet been well established in the published data. Although the investigators were not blinded to the randomization, all were strongly encouraged to avoid accessing the randomization information during the scheduled follow-up visits; thus, we consider that investigator bias was unlikely. The use of pulsed tissue Doppler imaging to measure LV dyssynchrony has limitations (influence of breathing, patient movement, and alterations in heart rate), although recent investigations have reported a good correlation with real-time transthoracic 3-dimensional echocardiography, considered a powerful tool for the evaluation of dyssynchrony.22 1. Rosenqvist M, Isaaz K, Botvinick EH, Dae MW, Cockrell J, Abbott JA, Schiller NB, Griffin JC. Relative importance of activation sequence compared to atrioventricular synchrony in left ventricular function. Am J Cardiol 1991;67:148 –156. 2. Tse HF, Yu C, Wong KK, Tsang V, Leung YL, Ho WY, Lau CP. Functional abnormalities in patients with permanent right ventricular pacing: the effects of sites of electrical stimulation. J Am Coll Cardiol 2002;40:1451–1458. 3. Prinzen FW, Hunter WC, Wyman BT, McVeigh ER. Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging. J Am Coll Cardiol 1999;33:1735–1742. 4. Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL, Lamas GA; MOde Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003;107:2932–2937. 5. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971;285:1441–1446. 6. Vlay SC. Right ventricular outflow tract pacing: practical and beneficial: a 9-year experience of 460 consecutive implants. Pacing Clin Electrophysiol 2006;29:1055–1062.

7. McGavigan AD, Roberts-Thompson KC, Hillock RJ, Stevenson IH, Mond HG. Right ventricular outflow tract pacing: radiographic and electrocardiographic correlates of lead position. Pacing Clin Electrophysiol 2006;29:1063–1068. 8. Lieberman R, Grenz D, Mond HG, Gammage MD. Selective site pacing: defining and reaching the selected site. Pacing Clin Electrophysiol 2004;27(Pt. II):883– 886. 9. Mond HG, Hillock RJ, Stevenson IH, McGavigan AD. The right ventricular outflow tract: the road to septal pacing. Pacing Clin Electrophysiol 2007;30:482– 491. 10. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, et al; American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 –367. 11. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, Kutaleck SP, Sharma A; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002;288:3115–3123. 12. Schwaab B, Fröhlig G, Alexander C, Kindermann M, Hellwig N, Schwerdt H, Kirsch CM, Schieffer H. Influence of right ventricular stimulation site on left ventricular function in atrial synchronous ventricular pacing. J Am Coll Cardiol 1999;33:317–323. 13. Stambler BS, Ellenbogen K, Zhang X, Porter TR, Xie F, Malik R, Small R, Burke M, Kaplan A, Nair L, Belz M, Fuenzalida C, Gold M, Love C, Sharma A, Silverman R, Sogade F, Van Natta B, Wilkoff BL; ROVA Investigators. Right ventricular outflow versus apical pacing in pacemaker patients with congestive heart failure and atrial fibrillation. J Cardiovasc Electrophysiol 2003;14:1180 –1186. 14. Giudici MC, Thornburg GA, Buck DL, Coyne EP, Walton MC, Paul DL, Sutton J. Comparison of right ventricular outflow tract and apical lead permanent pacing on cardiac output. Am J Cardiol 1997;79:209 –212. 15. Victor F, Mabo P, Mansour H, Pavin D, Kabalu G, de Place C, Leclercq C, Daubert JC. A randomized comparison of permanent septal versus apical right ventricular pacing: short-term results. J Cardiovasc Electrophysiol 2006;17:238 –242. 16. Lieberman R, Padeletti L, Schreuder J, Jackson K, Michelucci A, Colella A, Eastman W, Valsecchi S, Hettrick DA. Ventricular pacing lead location alters systemic hemodynamics and left ventricular function in patients with and without reduced ejection fraction. J Am Coll Cardiol 2006;48:1634 –1641. 17. Muto C, Ottaviano L, Canciello M, Carreras G, Calvanese R, Ascione L, Iengo R, Accadia M, Celentano E, Tuccillo B. Effect of pacing the right ventricular mid-septum tract in patients with permanent atrial fibrillation and low ejection fraction. Pacing Clin Electrophysiol 2007; 18:1032–1036. 18. Kypta A, Steinwender C, Kammler J, Leisch F, Hofmann R. Longterm outcomes in patients with atrioventricular block undergoing septal ventricular lead implantation compared with standard apical pacing. Europace 2008;10:574 –579. 19. Flevari P, Leftheriotis D, Fountoulaki K, Panou F, Rigopoulos AG, Paraskevaidis I, Kremastinos DT. Long-term nonoutflow septal versus apical right ventricular pacing: relation to left ventricular dyssynchrony. Pacing Clin Electrophysiol 2009;32:354 –362. 20. Ng AC, Allman C, Vidaic J, Tie H, Hopkins AP, Leung DY. Longterm impact of right ventricular septal versus apical pacing on left ventricular synchrony and function in patients with second- or thirddegree heart block. Am J Cardiol 2009;103:1096 –1101. 21. Kaye G, Stambler BS, Yee R. Search for the optimal right ventricular pacing site: design and implementation of three randomized multicenter clinical trials. Pacing Clin Electrophysiol 2009;32:426 – 432. 22. Vieira ML, Cury AF, Naccarato G, Oliveira WA, Mônaco CG, Rodrigues AC, Cordovil A, Tavares GM, Lira Filho EB, Pfeferman A, Fischer CH, Morhy SS. Analysis of left ventricular regional dyssynchrony: comparison between real time 3D echocardiography and tissue Doppler imaging. Echocardiography 2009;26:675– 683.