Does Reducing Unnecessary Right Ventricular Pacing Improve Sympathetic Activity and Innervation of Heart in Sinus Node Disease Patients?

Transcription

1 Does Reducing Unnecessary Right Ventricular Pacing Improve Sympathetic Activity and Innervation of Heart in Sinus Node Disease Patients? MVP and SafeR Study Mihoko Miyamoto, 1 MD, Yuichiro Kimura, 1 MD, Junya Hosoda, 1 MD, Katsumi Matsumoto, 1 MD, Kohei Matsushita, 1 MD, Toshiyuki Ishikawa, 1 MD, and Satoshi Umemura, 1 MD Summary Ventricular desynchronization imposed by ventricular pacing causes regional disturbances of adrenergic innervation in the left ventricular myocardium and increases the risk of heart failure and atrial fibrillation (AF) in patients with sinus node disease (SND). As a result, decreased iodine-123 metaiodobenzylguanidine (I- 123 MIBG) uptake occurs in patients with an implanted permanent pacemaker. Fourteen SND patients with an implanted pacemaker equipped with an algorithm for reducing unnecessary right ventricular pacing (RURVP) were enrolled. Pacemakers were programmed to RU- RVP mode for the first 12 weeks, and then reprogrammed to DDD for the last 12 weeks. At the end of each mode, data on cumulative percent ventricular pacing (%Vp), atrial high rate episodes (%AHR), I- 123 MIBG myocardial scintigraphy, brain natriuretic peptide (BNP), human atrial natriuretic peptide (hanp), and myocardial damage indices typified by troponin T and C-reactive protein (CRP) were collected. %Vp was lower in RURVP than in DDD (0.2% versus 95.7%, P = ). BNP, hanp, troponin T, and CRP did not differ significantly between the pacing modes. However, I- 123 MIBG findings of patients with full ventricular pacing in DDD improved in RURVP. In contrast, among patients without full ventricular pacing in DDD, their I- 123 MIBG findings did not differ significantly between the pacing modes. In SND patients with normal cardiac function and intact atrioventricular conduction, the reduction of %Vp in RURVP was due to the reduction of ineffective pacing and fusion pacing in DDD. Therefore, these 2 types of pacing do not affect cardiac pump function. (Int Heart J 2012; 53: ) Key words: I- 123 MIBG myocardial scintigraphy, Pacemaker Several clinical studies have suggested that frequent and unnecessary right ventricular apical (RVA) pacing may have the adverse long-term effects of increasing the risk of developing atrial fibrillation (AF) or congestive heart failure. 1,2) The detrimental effects of frequent RVA pacing are supposed to be attributable mainly to ventricular dyssynchrony. For these reasons, new pacing algorithms such as managed ventricular pacing (MVP) or SafeR have been developed, with the aim of reducing unnecessary right ventricular pacing (RU- RVP). These are designed to automatically switch to DDD from AAI mode in the event of major AV conduction disorders, and return automatically to AAI mode as soon as spontaneous AV conduction has resumed. MVP has been demonstrated to significantly reduce the amount of unnecessary right ventricular pacing in patients with symptomatic bradycardia. 3,4) The CAN-SAVE R study showed that the SafeR mode was effective, and that the mean percent V pacing was < 1% in patients without atrioventricular block (AVB). 5) Iodine-123 metaiodobenzylguanidine (I- 123 MIBG) is correlated with the degree of myocardial damage and is useful in evaluating the sympathetic activity and innervation of the left ventricle. 6) I- 123 MIBG is a guanethidine analogue that shares the same uptake, storage, and release pathway as norepinephrine. A decrease in myocardial I- 123 MIBG uptake has been described in congestive heart failure, cardiomyopathies, myocardial infarction, and systemic diseases associated with autonomic dysfunction. 7,8) Nakata, et al reported that uptake of I- 123 MIBG in the posterior wall decreased in patients with an implanted permanent pacemaker, and such abnormalities were more prominent with VVI than with DDD pacemakers. 9) They suggested that increased sympathetic activity by ventricular pacing may result in down-regulation of cardiac sympathetic nervous system activity. The aim of this study was to ascertain whether RURVP (MVP or SafeR mode) reduces the percentage of ventricular pacing and the incidence of atrial tachycardia (AT), and whether it improves brain natriuretic peptide (BNP), human atrial natriuretic peptide (hanp), other indices of myocardial dam- From the 1 Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan. Address for correspondence: Mihoko Miyamoto, MD, Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa , Japan. Received for publication June 13, Revised and accepted October 4,

2 354 MIYAMOTO, ET AL Int Heart J November 2012 age typified by troponin T and C-reactive protein (CRP), and the washout rate (WR) and heart to mediastinum (H/M) ratio of I- 123 MIBG. Methods Study population: Patients with symptomatic bradycardia were selected for enrollment. They underwent implantation or replacement of a dual-chamber pacemaker equipped with MVP mode (Adapta DR, Advisa DR, EnRhythm DR, Medtronic Inc.) or SafeR mode (Reply DR, Sorin Group) at Yokohama City University Hospital. Pacing leads were positioned in the right atrial appendage and right ventricular apex. Patients were excluded if they (1) were 19 years or younger, (2) had a history of heart failure, (3) had a history of myocardial ischemia, (4) presented with chronic AF, (5) presented with second-degree AVB or permanent complete AVB in ambulatory ECG before implantation, (6) were recipients of an implanted cardiac defibrillator (ICD), (7) were likely to undergo cardiac surgery in the next 6 months, or (8) were not able to understand the study objectives and protocol. AV conduction was determined by basal ECG prior to pacemaker implantation. QRS intervals in all patients before implantation were within 120 milliseconds. All patients gave written informed consent according to a protocol approved by the Medical Ethics Committee of Yokohama City University Hospital (B ). Device characteristics: Adapta DR, Advisa DR, and En- Rhythm DR are dual-chamber pacemakers equipped with MVP mode, which are intended to reduce unnecessary right ventricular pacing. MVP provides AAI with ventricular backup. If AV conduction fails for 2 out of 4 atrial to atrial depolarization intervals, the device switches to DDD with preprogrammed sensed AV (SAV) and paced AV (PAV) intervals. Checks for AV conduction are then performed. The first check occurs 1 minute after switching to DDD, and if AV conduction resumes, the pacemaker switches back to AAI. If loss of AV conduction persists, subsequent checks periodically occur until AV conduction resumes. The time interval for the checks progressively doubles (ie, 2, 4, 8 minutes and so on) up to 16 hours, and then the checks occur every 16 hours thereafter. Reply DR is also a dual-chamber pacemaker equipped with SafeR mode, which is intended to reduce unnecessary right ventricular pacing. This algorithm is based on atrial activity, using 4 criteria to test AV conduction by monitoring the number of blocked P waves and measuring the PR interval: (1) First-degree AVB, 7 consecutive atrial cycles in which the PR interval exceeds the programmed value. (2) Second-degree AVB, 3 blocked P waves within 12 atrial cycles. (3) Third-degree AVB, 2 consecutive blocked P waves. (4) Ventricular pause. In order to prevent cycling to DDD mode during atrial arrhythmias, the pacemaker switches to DDD mode only if there is a ventricular pause longer than the programmed value (up to 4,000 milliseconds). The system reverts to AAI mode after 12 consecutive cycles with a spontaneous PR interval and tests AV conduction every 100 cycles to confirm its integrity, as well as every day at 8 AM. If these conditions are not met, DDD mode is maintained. Study design: This study was initiated in March 2010 and terminated in January The primary objective was to assess whether RURVP (MVP or SafeR mode) reduces cumulative percent ventricular pacing (%Vp), atrial high rate episodes (%AHR), BNP, hanp, other indices of myocardial damage typified by troponin T and CRP, and WR and H/M ratio of I- 123 MIBG. For the first 12 weeks, the pacemakers were programmed to MVP or SafeR mode, then reprogrammed to conventional DDD mode for the last 12 weeks. At the 12-week and 24-week follow-up visits, %Vp and %AHR, which is highly likely to represent AT or AF burden, were obtained from stored pacemaker data. We also performed or measured I- 123 MIBG, ECG, chest X-rays, cardiac ultrasonography, BNP, hanp, troponin T, and CRP. Device programming: Device programming was performed according to the standard pacemaker clinic practices of Yokohama City University Hospital. Device programming (MVP or SafeR mode, lower rate, upper tracking rate, SAV and PAV intervals in DDD mode, and AT detection rate) are summarized in Table I. SAV and PAV intervals were programmed to more than nominal (120 milliseconds and 150 milliseconds, respectively). I- 123 MIBG: I- 123 MIBG was performed in all patients. Lugol s solution (1 ml) was given orally 2 hours before a slow intravenous injection of I- 123 MIBG 111 MBq (FUJIFILM RI Pharma Co., Ltd., Tokyo). Myocardial images were taken with a rotation-type gamma camera equipped with low and medium energy general purpose collimators (Toshiba E. CAM Signature). The first acquisition was performed at 15 minutes (early image) and a delayed image was acquired at 4 hours after a bolus injection. MIBG uptake by the heart and the upper mediastinum was recorded using a manually drawn region of interest (ROI) with a computer system (Toshiba GMS-7700A). Background subtraction to standardize the cardiac uptake was used in the upper mediastinal area. H/M ratio, introduced by Merlet and colleagues, 8) was computed to quantify cardiac I- 123 MIBG accumulation. The clearance rate from the myocardium (washout rate: WR) was calculated as follows: ( Initial myocardial I- 123 MIBG uptake Delayed myocardial I- 123 MIBG uptake / Initial I- 123 MIBG uptake ) 100. Percentage change of WR was calculated as follows: ( WR in RURVP mode WR in DDD mode / WR in RURVP mode ) 100. We defined the No. Age Sex Mode Table I. Programming Parameters Rate (bpm) PAV (ms) SAV (ms) AT detection rate (bpm) 1 72 M MVP F MVP F MVP M SafeR M SafeR M MVP F MVP M SafeR F MVP M MVP F MVP M MVP F MVP M SafeR PAV indicates paced atrioventricular interval; SAV, sensed atrioventricular interval; and AT, atrial tachycardia.

3 Vol 53 No 6 RIGHT VENTRICULAR PACING AND SYMPATHETIC ACTIVITY 355 percentage change of WR < -10 as an improvement of WR in RURVP mode. Statistical analysis: The nonparametric Mann-Whitney U test was used to test for significant differences between RURVP and DDD modes. Data are presented as the median [interquartile range (IQR)]. The chi-square test was used for comparisons of the improvement of WR between patients with and without full ventricular pacing capture in DDD mode. Data analysis was carried out using SPSS commercial software (12.0J software program for Windows, SPSS Inc., Tokyo). A value of P < 0.05 was considered statistically significant. Results Study population: Fourteen patients were enrolled in this study between March 2010 and March The characteristics of the study population are summarized in Table II. Patients were 72 ± 3 years old and 57.1% were men. Six patients had type I, 2 had type II, and 6 had type III sick sinus syndrome classified according to the Rubenstein system. The mean follow-up duration was days with a range of days. Among the 14 patients, 9 had undergone implantation of a pacemaker for the first time and 5 had replacement of a pacemaker. Ten patients had implantation of a pacemaker equipped with MVP mode and 4 had implantation of a pacemaker equipped with SafeR mode. %Vp: %Vp in RURVP and DDD modes is shown in Table III and Figure 1. %Vp was significantly reduced in RURVP mode compared to DDD mode (0.2 [0.7] % versus 95.7 [32.2] %, P = ). Although %Vp obtained from stored data in DDD mode was 95.7%, a wide QRS complex (QRS > 120 milliseconds) with ventricular pacing on 24-week follow-up visits ECG was seen only in 5 patients (Nos. 1, 3, 7, 9, 14 in Table I), and in the other 9 patients QRS complexes were within 120 milliseconds, indicating fusion pacing or intrinsic ventricular activation. %Vp of these 9 patients was 72.0 [65.0] % in DDD mode. On the other hand, %Vp of 5 patients with a Table II. Clinical Characteristics of Study Population (n = 14) Age, years 72 ± 3 Male, n (%) 8 (57.1%) Underlying diseases, n (%) None 5 (35.7%) Hypertension 5 (35.7%) Diabetes mellitus 0 (0%) Paroxysmal AF history 8 (57.1%) Drugs, n (%) Beta-blockers 0 (0%) Class I/III antiarrhythmic drugs 5 (35.7%) Digoxin 0 (0%) Calcium channel blockers 2 (14.3%) ACE-I/ARBs 4 (28.6%) Primary pacemaker indication, n (%) Rubenstein I 6 (42.9%) Rubenstein II 2 (14.3%) Rubenstein III 6 (42.9%) Data presented are mean ± SD or number (%) of patients. AF indicates atrial fibrillation; ACE-I, angiotensin-converting enzyme inhibitor; and ARB, angiotensin receptor blocker. wide QRS complex in DDD mode were more than 99%. PAV and SAV: PAV of 5 patients (Nos. 1, 3, 7, 9, 14 in Table I) and the other 9 patients was 180 [35.0] milliseconds and 200 [20.0] milliseconds, respectively (P = 0.075). SAV of 5 patients (Nos. 1, 3, 7, 9, 14 in Table I) and the other 9 patients was 150 [35.0] milliseconds and 170 [30.0] milliseconds, respectively (P = 0.094). There were no significant differences in PAV or SAV between patients with and without full ventricular pacing capture in DDD mode. %AHR: AT/AF burden in RURVP and DDD modes was 0.1 [0.2] % and 0.1 [2.3] %, respectively (Table III, Figure 2). There was no significant difference in AT/AF burden between the 2 pacing modes. BNP, hanp, troponin T, and CRP: BNP in RURVP and DDD modes was 43.3 [41.7] and 42.1 [39.3] picogram/ml, hanp was 32.8 [18.6] and 32.0 [31.8] picogram/ml, troponin T was [0.005] and [0.007] nanogram/ml, and CRP was 0.05 [0.06] and 0.06 [0.03] milligram/dl, respectively (Table III). There were no significant differences in BNP, hanp, troponin T, and CRP between the 2 pacing modes. I- 123 MIBG: WR in RURVP and DDD modes was 30.3 [4.6] and 29.6 [8.1] %, H/M ratio in early images was 2.24 [0.67] and 2.14 [0.58], and in delayed images was 2.32 [0.70] and 2.16 [0.83], respectively (Table III, Figures 3, 4, 5). There was no significant difference in WR and H/M ratios between the 2 pacing modes. We defined percentage change of WR < -10 as improvement of WR in RURVP mode. The percentage change in 5 patients with full ventricular pacing capture in DDD mode was 7.83%, -10.8%, -3.7%, -12.2%, and -74.1%. Thus, 3 patients (60%) improved in RURVP mode (Table IV). On the other hand, the percentage change in 9 patients without full ventricular pacing capture in DDD mode was -3.4%, -0.7%, -4.4%, 8.4%, 6.5%, 21.1%, -0.2%, -1.0%, and 4.9%, which Table III. Median [interquartile range (IQR)] Vp, AHR, Ap, BNP, hanp, troponin T, CRP, H/M (E), H/M (D), WR of I- 123 MIBG Myocardial Scintigraphy, LVEF, LVDd, and LVDs on Echocardiography in RURVP Mode and DDD Mode RURVP DDD P Vp (%) 0.2 [0.7] 95.7 [32.2] AHR (%) 0.1 [0.2] 0.1 [2.3] 0.69 Ap (%) 91.0 [13.4] 90.5 [17.0] 0.31 BNP (picograms/ml) 43.3 [41.7] 42.1 [39.3] 0.55 hanp (picograms/ml) 32.8 [18.6] 32.0 [31.8] 0.49 Troponin T (ng/ml) [0.005] [0.007] 0.40 CRP (mg/dl) 0.05 [0.06] 0.06 [0.03] 0.33 H/M (E) 2.24 [0.67] 2.14 [0.58] 0.29 H/M (D) 2.32 [0.70] 2.16 [0.83] 0.22 WR (%) 30.3 [4.6] 29.6 [8.1] 0.95 LVEF (%) 69.6 [5.0] 71.2 [8.1] 0.83 LVDd (mm) 45.0 [3.8] 44.4 [3.9] 0.92 LVDs (mm) 26.0 [4.2] 26.1 [3.3] 0.97 Data presented are median [interquartile range (IQR)]. RURVP indicates reducing unnecessary right ventricular pacing mode; Vp, ventricular pacing; AHR, atrial high rate episodes; Ap, atrial pacing; BNP, brain natriuretic peptide; hanp, human atrial natriuretic peptide; CRP, C-reactive protein; H/M (E), heart to mediastinum ratio of I- 123 MIBG at 15 minutes; H/ M (D), heart to mediastinum ratio of I- 123 MIBG at 4 hours; WR, washout rate of I- 123 MIBG; LVEF, left ventricular ejection fraction on echocardiography; LVDd, left ventricular diastolic diameter on echocardiography; and LVDs, left ventricular systolic diameter on echocardiography.

4 356 MIYAMOTO, ET AL Int Heart J November 2012 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figures Box and whisker plot of (1) %Vp, (2) %AHR, (3) WR, (4) H/M (E), and (5) H/M (D) in RURVP and DDD. %Vp indicates ventricular pacing; %AHR, atrial high rate episodes; WR, washout rate of I- 123 MIBG; H/M (E), heart to mediastinum ratio of I- 123 MIBG at 15 minutes; and H/ M (D), heart to mediastinum ratio of I- 123 MIBG at 4 hours; and RURVP, reducing unnecessary right ventricular pacing. Ends of box indicate 25 percentile and 75 percentile. Horizontal line in the box indicates statistical median. Extended whiskers mean the farthest points that are within 3/2 times the interquartile range. Superior chriscross means outliers which are more than 3/2 times of upper quartile. Inferior christcross means outliers which are less than 3/2 times of lower quartile.

5 Vol 53 No 6 RIGHT VENTRICULAR PACING AND SYMPATHETIC ACTIVITY 357 Table IV. Comparisons of the Improvement of Washout Rate (WR) Between Patients With and Without Full Ventricular Pacing Capture in DDD Mode (n = 14) Patients with full capture meant no improvement of WR in RURVP mode (Table IV). Other laboratory examinations: All patients underwent chest X-rays and cardiac ultrasonography at the end of each pacing mode. There was no significant difference between the DDD and RURVP modes (Table III). Adverse events: No adverse event related to either pacing mode was reported during the follow-up period. Discussion Patients without full capture Improvement (+) 3 (60%) 0 (0%) Improvement (-) 2 (40%) 9 (100%) Chi-Square Test. Improvement indicates a decrease exceeding 10% of WR in reducing unnecessary right ventricular pacing (RURVP) mode. P = Sweeney, et al reported that ventricular desynchronization imposed by ventricular pacing, even when AV synchrony was preserved, increased the risk of hospitalization for heart failure and AF in SND. 1) On the other hand, AAI pacing, compared with VVI or DDD with long AV delay, significantly lowers mortality and the incidence of heart failure and stroke. 10,11) However, the AAI mode has never been widely used because (1) patients at risk of complete paroxysmal AVB cannot receive an AAI pacemaker, as the risk of developing life-threatening AVB in the long-term is unpredictable at implantation, 11) and (2) during AF, patients may experience symptoms due to a slow ventricular rate. For these reasons, a new pacing algorithm has been developed. The MVP and SafeR modes are designed to preserve intrinsic AV conduction and ventricular activation by automatically switching between AAI and DDD. The SAVE PACe trial 4) showed that MVP mode, as compared with conventional dual-chamber pacing, prevented ventricular desynchronization and moderately reduced the risk of persistent AF in patients with SND. Nakata, et al reported that decreased uptake of I- 123 MIBG in the posterior wall occurred in patients with implanted permanent pacemakers, and such abnormalities were more prominent with the VVI than the DDD pacemaker. 9) They suggested that increased sympathetic activity by ventricular pacing may result in down-regulation of cardiac sympathetic nervous system activity. Moreover, several I- 123 MIBG studies have shown that DDD pacing (%Vp > 95%) through the right ventricular apex, although preserving the atrioventricular sequence, leads to an increase in WR and decreases in H/M(E), H/M(D), which means ventricular pacing causes regional disturbances of adrenergic innervation in the left ventricular myocardium. 12,13) At first we hypothesized that if RURVP reduced %Vp, the decreased ventricular desynchronization would improve the clinical findings as typified by BNP, hanp, troponin T and CRP, and the I- 123 MIBG findings. The major findings of the present study were: (1) RURVP significantly reduced %Vp compared to conventional DDD in patients with SND; (2) AT/ AF burden, other laboratory data (BNP, hanp, troponin T, CRP, WR and H/M ratio of I- 123 MIBG), and cardiac ultrasonography findings showed no significant differences between the pacing modes; and (3) the reduction of %Vp in RU- RVP mode did not improve the I- 123 MIBG findings among patients without full ventricular pacing capture in DDD mode, however, as far as patients with full ventricular pacing capture in DDD mode are concerned, WR of I- 123 MIBG improved in RURVP mode. We analyzed the I- 123 MIBG findings among patients with full ventricular pacing capture in DDD mode. At the 24-week follow-up visits, the ECGs of 5 patients indicated full ventricular pacing (QRS > 120 milliseconds) and their %Vp in DDD were more than 99%. When we analyzed the WR of these 5 patients, WR in 3 patients improved in RURVP mode, in contrast among the other 9 patients without full ventricular pacing capture in DDD mode, WR did not differ significantly between the pacing modes. The I- 123 MIBG findings improved among patients with full ventricular pacing capture in DDD mode. However, the I- 123 MIBG findings did not improve among patients without full ventricular pacing capture in DDD mode. In this study, no patients presented with second-degree AVB or complete AVB in ambulatory ECG before implantation. Since SND patients usually have normal AV conduction, the degree of full ventricular pacing capture in DDD mode is only slight. %Vp obtained from stored pacemaker data reflects not only full ventricular pacing but also fusion pacing. Thus, the reduction of %Vp in RURVP mode is mainly due to the reduction of ineffective pacing or fusion pacing, which do not have an influence on clinical findings. This may be one reason why the reduction of %Vp did not improve the clinical findings. Study limitations: The study population was relatively small, therefore, a larger study may be required to assess the clinical efficacy of RURVP mode. Conclusions: RURVP mode reduces the amount of unnecessary right ventricular pacing in SND. With regard to patients without full ventricular pacing capture in DDD mode, the WR of I- 123 MIBG did not improve in RURVP mode. On the other hand, in patients with full ventricular pacing capture in DDD mode, the WR of I- 123 MIBG improved in RURVP mode based on the results of the chi-square test, which means full ventricular pacing causes down-regulation of cardiac sympathetic nervous system activity. That is to say, as far as SND patients with intact AV conduction are concerned, most ventricular pacing in DDD mode is due to ineffective pacing or fusion pacing, which do not affect cardiac pump function. Therefore, the reduction of unnecessary right ventricular pacing does not lead to an improvement of the I- 123 MIBG findings, BNP, or other indices of myocardial damage. References 1. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. 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: Nielsen JC, Kristensen L, Andersen HR, Mortensen PT, Pedersen OL, Pedersen AK. A randomized comparison of atrial and dualchamber pacing in 177 consecutive patients with sick sinus syn-

6 358 MIYAMOTO, ET AL Int Heart J November 2012 drome: echocardiographic and clinical outcome. J Am Coll Cardiol 2003; 42: Gillis AM, Pürerfellner H, Israel CW, et al. Reducing unnecessary right ventricular pacing with the managed ventricular pacing mode in patients with sinus node disease and AV block. Pacing Clin Electrophysiol 2006; 29: Sweeney MO, Bank AJ, Nsah E, et al. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007; 357: Thibault B, Simpson C, Gagné CE, et al. Impact of AV conduction disorders on SafeR mode performance. Pacing Clin Electrophysiol 2009; 32: S Dae MW, O Connell JW, Botvinick EH, et al. Scintigraphic assessment of regional cardiac adrenergic innervation. Circulation 1989; 79: Taki J, Yasuhara S, Takamatsu T, et al. Value of iodine-123 metaiodobenzylguanidine scintigraphy in patients with vasospastic angina. Eur J Nucl Med 1998; 25: Merlet P, Valette H, Dubois-Randé JL, et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med 1992; 33: Nakata A, Hirota S, Tsuji H, Takazakura E. I-123 metaiodobenzylguanidine cardiac scintigraphy in patients with an implanted permanent pacemaker. Jpn Heart J 1995; 36: Albertsen AE, Nielsen JC. Selecting the appropriate pacing mode for patients with sick sinus syndrome: evidence from randomized clinical trials. Card Electrophysiol Rev 2003; 7: (Review) 11. Kristensen L, Nielsen JC, Pedersen AK, Mortensen PT, Andersen HR. AV block and changes in pacing mode during long-term follow-up of 399 consecutive patients with sick sinus syndrome treated with an AAI/AAIR pacemaker. Pacing Clin Electrophysiol 2001; 24: Simantirakis EN, Prassopoulos VK, Chrysostomakis SI, et al. Effects of asynchronous ventricular activation on myocardial adrenergic innervation in patients with permanent dual-chamber pacemakers; an I(123)-metaiodobenzylguanidine cardiac scintigraphic study. Eur Heart J 2001; 22: Marketou ME, Simantirakis EN, Prassopoulos VK, et al. Assessment of myocardial adrenergic innervation in patients with sick sinus syndrome: effect of asynchronous ventricular activation from ventricular apical stimulation. Heart 2002; 88: