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J Am Coll Cardiol, 2006; 48:1642-1648, doi:10.1016/j.jacc.2006.05.072
(Published online 26 September 2006). © 2006 by the American College of Cardiology Foundation |
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Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Manuscript received January 11, 2006; revised manuscript received April 26, 2006, accepted May 1, 2006.
* Reprint requests and correspondence: Dr. Jeroen J. Bax, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. (Email: jbax{at}knoware.nl).
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Abstract |
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BACKGROUND: Atrioventricular (AV) node ablation and subsequent long-term RV pacing is a well-established treatment option in patients with atrial fibrillation (AF).
METHODS: In 55 patients with drug-refractory AF, AV node ablation and implantation of a pacemaker was performed. At baseline and after a mean of 3.8 ± 1.7 years, LV dyssynchrony (by M-mode echocardiography and tissue Doppler imaging), LV function, and volumes and functional status were assessed.
RESULTS: After long-term RV pacing, 27 patients (49%) had developed LV dyssynchrony. Concomitantly, these patients worsened in heart failure symptoms (New York Heart Association functional class increased from 1.8 ± 0.6 to 2.2 ± 0.7, p < 0.05), with a decrease in LV ejection fraction (from 48 ± 7% to 43 ± 7%, p < 0.05) and an increase in LV end-diastolic volume (from 116 ± 39 ml to 130 ± 52 ml, p < 0.05). Conversely, patients without LV dyssynchrony did not deteriorate in heart failure symptoms, LV function, or LV volumes.
CONCLUSIONS: Long-term RV pacing can induce LV dyssynchrony in almost 50% of patients treated with AV node ablation for chronic AF. The development of LV dyssynchrony was associated with deterioration in heart failure symptoms, systolic LV function, and LV dilatation.
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Atrioventricular (AV) node ablation and subsequent permanent pacing is a well-established treatment option in patients with chronic, drug-refractory AF (4). Atrioventricular node ablation and permanent pacing may improve quality of life and exercise capacity (5) and may be superior to pharmacologic therapy in controlling symptoms of AF (4,6).
However, recent studies have shown detrimental effects of long-term right ventricular (RV) pacing (7,8). Left ventricular (LV) dilatation (remodeling) (7) with a decrease in LV ejection fraction (8) after long-term RV pacing has been reported. The underlying cause of these adverse effects is unknown but may be related to induction of LV dyssynchrony after long-term RV pacing, with subsequent deterioration of LV function. To evaluate this hypothesis, the effects of long-term RV pacing on LV function and dyssynchrony were evaluated in patients with chronic AF with normal LV function and without valvular disease undergoing AV node ablation and RV pacing.
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Methods |
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Ablation and pacemaker implantation. Atrioventricular node ablation was performed with a 4-mm quadripolar mapping/ablation catheter (EPT, Boston Scientific, Natick, Massachusetts) accessed through the femoral vein. A temporary pacing electrode was placed in the RV apex for backup pacing. Radiofrequency energy was applied at the AV node until complete AV block was achieved. Thereafter the pacemaker was implanted. Pacemaker leads were inserted through the subclavian vein using standard implantation techniques. The RV leads were positioned in the RV apex in all patients. After implantation, pacemakers were routinely programmed to VVIR mode.
Echocardiography. All patients underwent echocardiography before the ablation procedure and after long-term RV pacing. Images were recorded with patients in the left lateral decubitus position using a commercially available system (Vingmed Vivid Seven, General Electric-Vingmed, Milwaukee, Wisconsin). Images were obtained using a 3.5-MHz transducer at a depth of 16 cm in the parasternal (long- and short-axis) and apical (2-chamber and 4-chamber) views. Standard 2-dimensional images and color Doppler data triggered to the QRS complex were saved in cine-loop format.
Left ventricular end-diastolic and end-systolic volumes and LV ejection fraction were calculated from apical 2- and 4-chamber images using the biplane Simpson’s rule (9). Furthermore, LV end-diastolic diameter was measured from the parasternal long-axis images.
The severity of mitral regurgitation was graded semiquantitatively using color-flow Doppler in the conventional parasternal long-axis and apical 4-chamber images (10). Mitral regurgitation was characterized as: minimal = 1+ (jet area/left atrial area <10%), moderate = 2+ (jet area/left atrial area 10% to 20%), moderate-severe = 3+ (jet area/left atrial area 20% to 45%), or severe = 4+ (jet area/left atrial area >45%) (10).
Ventricular dyssynchrony.
At baseline and after long-term RV pacing, LV dyssynchrony was assessed. Septal-to-posterior wall motion delay (SPWMD) was assessed using an M-mode recording from the parasternal short-axis view at the papillary muscle level. The interval between the maximal posterior displacement of the septum and the maximal displacement of the LV posterior wall was calculated (11). As reported by Pitzalis et al. (11,12), SPWMD 
130 ms was used as the cutoff value for LV dyssynchrony.
Furthermore, interventricular dyssynchrony was calculated as the difference between LV electromechanical delay (time from QRS onset to aortic systolic flow onset) and RV electromechanical delay (time from QRS onset to pulmonary systolic flow onset) (13). An interventricular delay 40 ms was used as a cutoff value for interventricular dyssynchrony as previously described (13,14).
In addition, LV dyssynchrony was assessed using color-coded tissue Doppler imaging (TDI) after long-term RV pacing in 52 patients. The frame rates ranged from 80 to 115 frames/s, depending on the sector width of the range of interest; pulse repetition frequencies ranged from 0.5 to 1 kHz, resulting in aliasing velocities ranging from 16 to 32 cm/s. Tissue Doppler imaging parameters were measured from color-coded images of 3 consecutive heart beats by offline analysis. Data were analyzed using commercially available software (Echopac 6.1, General Electric-Vingmed). To assess LV dyssynchrony, the sample volume was placed in the basal portions of the septum and lateral wall; the time to peak systolic velocity was obtained in the septum and lateral wall, and the septal-to-lateral delay in peak velocity was calculated as an indicator of LV dyssynchrony. A septal-to-lateral delay 65 ms was used as a cutoff value for LV dyssynchrony assessed with TDI, as previously reported (15). The interventricular dyssynchrony and TDI images were evaluated by 2 independent observers blinded to the results of the SPWMD.
Statistical analysis. Results are presented as mean values ± SD or number (%). Continuous data were compared using paired or unpaired Student t test when appropriate. Correlation between SPWMD and TDI was assessed using Pearson’s linear correlation. Agreement between SPWMD and TDI was expressed in a 2 x 2 table using kappa statistics. A kappa value of <0.4 represents poor agreement, a kappa between 0.4 and 0.75 represents fair to good agreement, and a kappa value of >0.75 is considered an excellent agreement based on the Fleiss classification (16). A p value <0.05 was considered statistically significant.
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40 ms, representing interventricular dyssynchrony. Mean SPWMD before AV node ablation and pacemaker implantation was 63 ± 31 ms (range 4 to 122 ms). None of the patients had a SPWMD 130 ms at baseline, indicating absence of LV dyssynchrony in all patients.
After long-term RV pacing, mean SPWMD was 121 ± 64 ms (range 11 to 240 ms). In 27 patients (49%) a SPWMD 130 ms was present, indicating LV dyssynchrony. Accordingly, the study population was divided into 2 groups: with or without LV dyssynchrony at follow-up, based on a SPWMD delay 130 ms after long-term RV pacing. Baseline characteristics of the 2 groups are listed in Table 1. There were no differences in baseline characteristics between the 2 groups (Table 1).
Intraventricular dyssynchrony.
Intraventricular dyssynchrony as assessed with TDI was available in 52 patients after long-term RV pacing. The patients who did not develop LV dyssynchrony on M-mode echocardiography after long-term RV pacing also did not exhibit LV dyssynchrony on TDI (mean septal-to-lateral delay 37 ± 45 ms). In contrast, the patients who developed LV dyssynchrony as assessed by M-mode echocardiography also displayed LV dyssynchrony on TDI (mean septal-to-lateral delay 109 ± 26 ms, p < 0.05 vs. patients without LV dyssynchrony). Of note, all patients with SPWMD 130 ms on M-mode had a septal-to-lateral delay 65 ms assessed with TDI (Table 2). In contrast, 4 patients without dyssynchrony on M-mode had a septal-to-lateral delay 65 ms assessed with TDI. A linear relation was found between SPWMD and septal-to-lateral delay (R = 0.66, p < 0.01) (Fig. 1). When applying the cutoff values (SPWMD 130 ms, septal-to-lateral delay 65 ms) for LV dyssynchrony, an excellent agreement (kappa = 0.85) between SPWMD and TDI to detect LV dyssynchrony was observed (Fig. 2). Disagreement between SPWMD and TDI was based on 4 patients (8%) in whom LV dyssynchrony could be detected only with TDI (Table 2).
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40 ms was present after long-term RV pacing, indicating the presence of interventricular dyssynchrony. In contrast, in 5 patients (17%) without LV dyssynchrony, an interventricular delay 40 ms was present (p < 0.01 vs. patients with LV dyssynchrony). Clinical and echocardiographic effects of long-term RV pacing. After long-term RV pacing, functional status and LV parameters were re-assessed in all patients. In patients without LV dyssynchrony, NYHA functional class improved from 1.7 ± 0.7 to 1.4 ± 0.5 (p < 0.01), whereas NYHA functional class deteriorated in patients who had developed LV dyssynchrony (from 1.8 ± 0.6 to 2.2 ± 0.7, p < 0.05) (Fig. 3). Furthermore, LV ejection fraction decreased significantly in patients with LV dyssynchrony (48 ± 7% vs. 43 ± 7%, p < 0.05), whereas LV ejection fraction remained unchanged in patients without LV dyssynchrony (Fig. 3).
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Discussion |
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Effects of long-term RV pacing. In patients with drug-refractory AF, ablation of the AV node and permanent pacing have proven to be effective (4). However, the beneficial effect of the therapy may (partially) be reversed by the non-physiologic activation pattern of the interventricular septum. Several studies (7,17–20) have reported negative effects of permanent RV pacing. Regional perfusion defects (17,18), asymmetrical hypertrophy of the ventricular wall (19), and an impairment of LV ejection fraction (20) have been reported after permanent RV pacing.
Furthermore, Thambo et al. (7) recently demonstrated the induction of LV dyssynchrony after long-term RV pacing in 23 patients with congenital complete AV block. Following long-term RV pacing, the mean SPWMD, as a measure of LV dyssynchrony, had significantly increased as compared to baseline (41 ± 16 ms vs. 84 ± 26 ms, p < 0.05). In addition, the septal-to-lateral delay as measured by TDI was significantly larger in patients with permanent pacing as compared with control patients (59 ± 18 ms vs. 19 ± 9 ms, p < 0.01). Similar results were demonstrated in the current study, showing an increase in SPWMD from 63 ± 31 ms to 121 ± 64 ms (p < 0.05) after long-term RV pacing, and in 27 (49%) patients the SPWMD exceeded 130 ms, indicating substantial LV dyssynchrony.
The presence of LV dyssynchrony may result in systolic LV dysfunction (21,22). Thambo et al. (7) reported a significantly lower cardiac output in patients with LV dyssynchrony after long-term RV pacing as compared with healthy volunteers. In addition, LV end-diastolic diameter had significantly increased in these patients as compared with volunteers (5.5 ± 0.7 cm vs. 4.6 ± 0.6 cm, p < 0.05). The observations in the present study are in line with these previous results: patients with LV dyssynchrony after long-term RV pacing showed a decrease in LV ejection fraction, with an increase in LV volumes and LV end-diastolic diameter (Table 3) indicating LV dilatation.
Assessment of LV dyssynchrony. In the current study, LV dyssynchrony was measured by M-mode echocardiography. With M-mode echocardiography the SPWMD can be measured as recently introduced by Pitzalis et al. (11). The SPWMD indicates the delay between the maximal systolic motion of the septum and the LV free wall, reflecting intraventricular dyssynchrony (11). At baseline, none of the patients in the current study had SPWMD exceeding 130 ms, which is used as the upper limit of normal LV synchrony. After long-term RV pacing, however, 27 patients (49%) had developed LV dyssynchrony, as illustrated by a SPWMD >130 ms.
In addition to SPWMD, TDI was used to assess the septal-to-lateral delay. Tissue Doppler imaging is a sophisticated echocardiographic technique that permits measurement and timing of myocardial systolic (and diastolic) velocities. By comparing the differences in time to peak systolic velocities of different LV regions, TDI can identify LV dyssynchrony (23).
Both M-mode using SPWMD and TDI using the septal-to-lateral delay have proven to be effective in the detection of LV dyssynchrony (11,15). In the current study, a good agreement was detected between the SPWMD and septal-to-lateral delay (Fig. 2). In particular, all patients with LV dyssynchrony on M-mode also exhibited LV dyssynchrony on TDI, and only 4 patients (8%) without LV dyssynchrony on M-mode had LV dyssynchrony on TDI, indicating minimal underestimation of LV dyssynchrony by SPWMD. Marcus et al. (24) have recently demonstrated substantial underestimation of LV dyssynchrony by M-mode echocardiography as compared to TDI in patients with severe LV dysfunction. In particular, in patients with ischemic LV dysfunction and akinesia of the (antero-)septum, assessment of SPWMD may not be feasible and TDI may be preferred for accurate detection of LV dyssynchrony (25). In the current study, however, all patients had preserved LV function without significant valvular disease, explaining the better agreement between the 2 techniques.
Clinical implications. The observations in the current study demonstrate that RV pacing may induce LV dyssynchrony in a substantial percentage of patients with preserved LV function who undergo AV node ablation. In addition, the induction of LV dyssynchrony was associated with a deterioration of LV function and clinical status. Therefore, it needs to be considered whether these patients should have undergone biventricular pacing rather than RV pacing. Recently, several studies have compared different pacing strategies for patients with AF treated with AV node ablation and permanent pacing. In the PAVE (Post AV nodal ablation Evaluation) trial (8), 184 patients treated with AV node ablation and pacemaker implantation were randomly assigned to RV pacing or biventricular pacing. After 6 months follow-up, the LV ejection fraction was significantly lower in 81 patients who underwent RV pacing as compared with 103 patients with biventricular pacing (41 ± 13% vs. 46 ± 13%, p < 0.05). Unfortunately, LV dyssynchrony was not assessed in the PAVE study.
The OPSITE (Optimal Pacing SITE) study (26) compared RV pacing and biventricular pacing in patients with permanent AF undergoing AV node ablation. After 6 months, patients with RV pacing had a significant lower LV ejection fraction as compared to biventricular pacing (43 ± 11% vs. 45 ± 13%, p < 0.05). In addition, NYHA functional class was significantly lower with RV pacing as compared to biventricular pacing (1.6 ± 0.7 vs. 1.8 ± 0.7, p < 0.05).
In addition, a positive effect of upgrading long-term RV pacing to biventricular pacing has recently been demonstrated. Leon et al. (27) reported an improvement in NYHA functional class and LV function after upgrading to biventricular pacing in 20 heart failure patients with chronic AF, previous AV node ablation, and RV pacing.
The aforementioned studies provide evidence for the benefit of biventricular pacing as compared to RV pacing in patients with chronic AF and AV node ablation (8,26,27). The observations in the present study illustrate that in a substantial part of the patients with preserved LV function who undergo AV node ablation, long-term RV pacing can induce LV dyssynchrony, which appears associated with adverse effects, including an increase in heart failure symptoms, and a decrease in LV function with LV dilatation. Whether LV dyssynchrony results in LV dilatation or vice versa remains unclear. The abnormal electrical activation pattern induced by RV pacing may result in LV dyssynchrony, with subsequent LV dilatation and regional contraction abnormalities (20,22). Conversely, Yu et al. (28) demonstrated that a large LV end-systolic diameter predicted the severity of LV dyssynchrony in patients with heart failure. However, in the present study, no differences in baseline LV dimensions or volumes were found between the patients with and without LV dyssynchrony after long-term RV pacing. Therefore, no predictors for the induction of LV dyssynchrony could be identified.
It may well be that the patients who develop LV dyssynchrony may benefit from biventricular pacing, whereas the patients who do not develop LV dyssynchrony may not need biventricular pacing. Accordingly, patients should be evaluated after RV pacing for development of LV dyssynchrony, and if LV dyssynchrony is induced, biventricular pacing should be considered. Ideally, patients who are at risk for development of LV dyssynchrony should be identified at baseline (before AV node ablation and pacemaker implantation), but the results of the current study could not demonstrate any difference in baseline variables (Table 1). Clearly, additional studies in large populations are needed to confirm the current findings, and to develop selection criteria for patients with normal LV function who may require biventricular pacing rather than RV pacing after AV node ablation for chronic, drug-refractory AF.
Study limitations. Some limitations of the present study need to be addressed. First, this is a retrospective study, and it has a relatively small population. Larger, prospective studies on the development (and prediction) of LV dyssynchrony after AV node ablation are needed. Furthermore, relatively soft end points (NYHA functional class and ventricular remodeling) were used to assess clinical efficacy. However, these parameters are often used as markers for clinical efficacy (8,26,27). Finally, the changes in LV ejection fraction and LV end-diastolic volume in the patients with LV dyssynchrony in the present study are relatively small but statistically significant.
Conclusions. Long-term RV pacing induced LV dyssynchrony in 49% of patients treated with AV node ablation. These patients appear to develop heart failure symptoms with a reduction in LV systolic function and LV dilatation. These patients may benefit from biventricular pacing rather than RV pacing.
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p < 0.05 with dyssynchrony versus without dyssynchrony. White columns = baseline; black columns = follow-up.