Europace Advance Access originally published online on June 8, 2007
Europace 2007 9(10):869-874; doi:10.1093/europace/eum119
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CARDIAC RESYNCHRONISATION THERAPY
Acute and chronic effects of cardiac resynchronization in patients developing heart failure with long-term pacemaker therapy for acquired complete atrioventricular block
1 Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 2 Division of Cardiology, Nagoya Dai-ni Red Cross hospital, Nagoya, Japan; 3 Department of Cardiovascular Research, Research Institute of Environmental Medicine (RIEM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; 4 Division of Cardiovascular Diseases, University of Alabama at Birmingham, Birmingham, AL, USA; 5 Department of Medicine and Research Center, Montreal Heart Institute, University of Montreal, Quebec, Canada; 6 Department of Pharmacology, McGill University, Montreal, Quebec, Canada
Manuscript submitted 17 February 2007. Accepted after revision 3 May 2007.
* Corresponding author. Tel: +81 52 789 5006; fax: +81 52 789 5003. E-mail address: y-tsuji{at}hh.iij4u.or.jp
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Abstract |
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Aims We assessed the effects of cardiac re-synchronization therapy (CRT) in patients who developed otherwise unexplained heart failure (HF) during right ventricular apical (RVA)-pacing for acquired complete atrioventricular block (CAVB).
Methods and results Eighteen consecutive CAVB patients with HF during RVA-pacing were assessed with haemodynamic studies immediately and 12 months after CRT-upgrade. Ten patients had idiopathic CAVB and 13 showed normal left ventricular (LV) function at RVA-pacemaker implantation. HF developed after 81 ± 10 months. RVA-pacing duration correlated (r = 0.49, P < 0.05) with LV ejection fraction (LVEF) deterioration. Biventricular- (BiV) and LV-pacing acutely improved the systolic function comparably, but only BiV improved diastolic function. One-year post-CRT-initiation, New York Heart Association classification improved 35 ± 3% (P < 0.05) and the number of hospitalizations decreased 85 ± 3% (P < 0.0001). CRT decreased LV end-diastolic diameter (LVEDd) 7 ± 2% (P < 0.01) and increased LVEF by 23 ± 7% (P < 0.01). The CRT-induced reduction in LVEDd tended to be greater in patients with RVA-pacing for < 5 years vs. > 5 years (7.7 ± 2.5 vs. 3.6 ± 1.0 mm, P = 0.08).
Conclusion CRT-upgrade improves the cardiac function and symptoms in CAVB patients with HF progression related to RVA-pacing. Because adverse LV-remodelling may be partly irreversible, consideration should be given to BiV- and LV-pacing upgrade as soon as possible after the indications appear, and prospective studies of the optimal timing of CRT-upgrade may be useful.
Key Words: Pacing, Heart failure, Resynchronization, Complete AV block
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Introduction |
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Large clinical trials in patients with conventional pacemakers for sinus node dysfunction1
,2 and implantable cardioverter-defibrillators (ICDs)3 suggest that ventricular desynchronization imposed by right ventricular apical (RVA) pacing can be an important contributor to heart failure (HF) development. Patients with normal systolic function subjected to permanent RVA pacing have an increased risk of developing HF over 3–5 years, although the risk is considered to be low, and patients with reduced systolic function often develop HF with RVA pacing in < 1 year.4 A study by Thambo et al.5 provided direct evidence that in young patients with congenital complete atrioventricular block (CAVB) prolonged ventricular dyssynchrony induced by the long-term RVA pacing is associated with deleterious left ventricular (LV) remodelling, including cardiac output reduction, LV dilatation, and LV asymmetrical hypertrophy. The potentially harmful effects of long-term RVA pacing have also been recognized in older patients with acquired CAVB.6,7 However, the impact of RVA pacing on HF occurrence may be underestimated in CAVB patients because of the presence of other factors, such as age, LV dysfunction prior to RVA pacing, the natural progression of the pre-existing disease, and the clinical experience that most patients with normal cardiac function seem tolerant to RVA pacing.
Cardiac resynchronization therapy (CRT) with biventricular (BiV) pacing is an established adjunctive treatment for patients with HF and intrinsic left bundle branch block (LBBB) or ventricular conduction disorders.8–12 CRT is now extended to HF patients with conventional pacemakers based on the rationale that iatrogenic LBBB produced by RVA pacing is equally deleterious. Although many studies have already addressed the clinical efficacy of upgrading to CRT devices in HF patients with ischaemic or non-ischaemic cardiomyopathy, atrial arrhythmias, and RVA pacemaker after AV nodal ablation,13–17 clinical data from the series of acquired CAVB patients are scarce.
The aim of the present study was to characterize the clinical features of patients with acquired CAVB who developed HF during long-term RVA pacing, and to evaluate the haemodynamic effects of BiV- and LV-pacing acutely before upgrade and after 12 months.
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Methods |
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Study population
Eighteen consecutive pacemaker-dependent CAVB patients with HF admitted for upgrade to CRT at Nagoya Dai-ni Red Cross Hospital between June 2002 and May 2005 were reviewed. Table 1 shows clinical profiles from each patient. All patients had at least one hospitalization for HF and had continuous RVA pacing from dual-chamber pacemakers previously implanted for CAVB. At the time of upgrade to CRT, all patients had received HF medications optimized by cardiologists, including ß-blockers, angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, and/or spironolactone (Table 1), unless contraindicated. All were in sinus rhythm. Echocardiography showed LV dilatation and LV dysfunction with a mean LV end-diastolic diameter (LVEDd) of 67 ± 2 mm and LV ejection-fraction (LVEF) of 28 ± 2%. Written informed consent was obtained from each patient and cardiac catheterization was performed before the scheduled upgrade procedure.
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Haemodynamic assessment before upgrade procedure
Haemodynamic study was performed in order to identify responders with a standard protocol described previously.18
In brief, multipolar pacing electrodes were placed into the high-right atrium, the RVA, and a cardiac vein running along the LV free wall, midway between base and apex. A 6F micro-manometer-tipped catheter (CA-6100-PLB; CD Leycom instrumemt, Zoetermeer, The Netherlands) was placed into the LV cavity. Baseline data were obtained during AV sequential RVA pacing in DDD mode at a rate of 90 bpm. Pacing in the DDD mode was applied from the LV alone and LV and RVA simultaneously, with six preset AV delays. Data recording began 3 min after a pacing site was changed. The baseline data were obtained repeatedly before pacing at different sites was commenced. The following haemodynamic measurements were made with custom software (ADInstruments JAPAN Inc., Nagoya, Japan): LV dP/dtmax, LV dP/dtmin, LV end-diastole pressure (LVEDP), and isovolumic pressure half-time (T1/2). Haemodynamic and electrical signals were digitized at a sampling rate of 12 kHz and stored in a PC.
Upgrade to cardiac resynchronization
Fifteen of the 18 patients were upgraded to a BiV CRT system. Three patients with a history of syncope because of ventricular tachyarrhythmias were upgraded to a conventional ICD with bipolar single-site LV pacing (LV-ICD), substituted for the CRT-D device, which was unavailable in Japan during the study period.
A LV lead was implanted into a lateral or a posterolateral branch of cardiac vein, using a transvenous approach to access the CS in 15 patients. In the remaining three patients who showed tortuous CS branches, the LV lead was implanted surgically (Table 1). Eight patients received the InSync system (model 8040, Medtronic Inc., Minneapolis, USA). Before that, a conventional pacemaker with two ventricular leads through a Y-adaptor kit (5866-38M, Medtronic Inc.) was used for CRT in seven patients. Medtronic (model 4968 and 5071) leads were used for surgical implantation of the LV lead.
12-month follow-up
Clinical follow-up were performed at 12 months. New York Heart Association (NYHA) functional class, echocardiographic parameters including LVEDd, LVEF (Simpson formula), left atrial diameter (LAD) and mitral regurgitation (MR) quantified using a semi-quantitative scale, and plasma B-type natriuretic peptide (BNP) concentration were compared with pre-upgrade values.
Statistical analysis
All data are expressed as mean ± SE. Statistical significance was assessed by ANOVA followed by Bonferroni–Dunn-corrected t-tests. P < 0.05 were considered statistically significant.
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Results |
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Patient characteristics
All patients exhibited RVA-paced rhythm over a follow-up period of 81 ± 10 months. The duration of RVA pacing correlated with LVEF reduction (Figure 1). Fifteen patients were upgraded to CRT with BiV pacing and three patients to LV-ICD.
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Acute haemodynamic study
Haemodynamic data were obtained during the protocol from all the patients. At baseline, LV dP/dtmax was 831 ± 51 mmHg/s, LV dP/dtmin –808 ± 48 mmHg/s, LVEDP 18.4 ± 2.9 mmHg, and T1/2 47.0 ± 0.2 ms. The effects of BiV vs. LV pacing on haemodynamics are shown in Figure 2. All patients showed >5% improvement in LV dP/dtmax with BiV and LV pacing. BiV and LV pacing increased LV dP/dtmax by 29.1 ± 4.6 and 25.8 ± 4.6%, respectively (P = n.s. for BiV vs. LV, Figure 2A). The decreases in LV dP/dtmin and T1/2 were greater with BiV than with LV pacing (dP/dtmin: –18.9 ± 5.1, –9.9 ± 4.4%, P < 0.05, T1/2: –10.4 ± 2.3, –3.3 ± 1.4%, P < 0.05, respectively). There was no significant difference in LVEDP between BiV and LV pacing (Figure 2B). BiV pacing shortened QRS duration by 18.4 ± 3.4% (P < 0.01), whereas LV pacing produced a non-significant 3.5 ± 3.0% reduction.
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P < 0.05, for BiV vs. LV. T1/2, Isovolemic pressure half time; LVEDP, Left ventricular end-diastolic pressure.12-month outcome
Data from 18 patients upgraded to CRT with BiV and LV pacing are depicted and summarized in Figure 3A. At 12 months, NYHA functional class improvement was clearly observed in all patients (from 3.0 ± 0.1 to 1.9 ± 0.1). Echocardiography showed a mean LVEF of 34.2 ± 2.7%, a significant increase from their baseline value of 28.3 ± 2.0% (22.6 ± 7.2% improvement, P < 0.01). The mean LVEDd decreased from 67.1 ± 2.0 to 62.3 ± 2.0 mm (7.0 ± 1.5%, P < 0.01) and LAD from 42.4 ± 1.8 to 40.6 ± 1.6 mm (4.1 ± 1.7%, P < 0.05). MR severity was reduced from 1.9 ± 0.1 to 1.4 ± 0.1 (22.3 ± 6.3%, P < 0.01). Plasma BNP level decreased from 579.0 ± 98.0 to 320.3 ± 54.7 pg/mL (32.4 ± 11.5%, P < 0.05). The number of HF hospitalizations per year substantially decreased from 2.1 ± 0.2 before to 0.3 ± 0.1 after upgrade (P < 0.0001, Table 1). The reduction in LVEDd with CRT tended to be greater in patients with RVA-pacing duration of < 5 years than in those with >5 years (7.7 ± 2.5, 3.6 ± 1.0 mm, P = 0.08, Figure 3B). VT events and/or appropriate ICD discharges for VT/VF were documented during the follow-up period in all three patients upgraded to LV-ICD, although all of them showed an improvement of the NYHA class, an increase in LVEF and reduction in plasma BNP levels.
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Discussion |
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In this study, we characterized 18 patients who developed HF with long-term conventional pacemaker therapy for CAVB. The majority (72%) had normal LV function at the time of conventional pacemaker implantation. After 81 ± 10 months of RVA pacing, they were upgraded to CRT for HF. The duration of RVA pacing correlated with reductions in LVEF, consistent with a role of pacemaker-induced dyssynchrony in promoting LV dysfunction. We also investigated the acute and chronic effects of cardiac resynchronization in these patients. All patients responded to BiV and LV pacing on acute haemodynamic study and all derived chronic benefits from upgrade to CRT. Three patients had a modified upgrade system, conventional ICD with single-site LV pacing, utilized as an alternative to CRT-D. Of note, although CRT improved LV function, significant LV dysfunction remained 12 months after upgrade.
Ventricular dyssynchrony imposed by RVA pacing has adverse effects on cardiac function. Many experimental studies have shown that the RVA pacing causes ventricular asynchronous activation, reduces pump function, and causes asymmetrical hypertrophy and cellular abnormalities.4,19 Recently, Thambo et al.5 and Tantengco et al.20 demonstrated the deleterious LV remodelling including cardiac output reduction, LV dilatation, and LV asymmetrical hypertrophy in young patients with congenital CAVB exposed to RVA pacing for 10 years. Our data from older patients with acquired CAVB suggest that long-term RVA pacing was a contributor to HF development, supporting the importance of ventricular asynchrony in LV remodelling and functional impairment.
Several studies are available regarding the efficacy of upgrade to CRT in patients with pre-existing RVA pacing. An early study by Baker et al.14 showed the safety and feasibility of the addition of a LV lead to a conventional pacemaker system to provide BiV stimulation in 60 patients with HF and pre-existing pacemaker therapy for sinus node dysfunction, CAVB, or catheter ablation of the AV junction for atrial arrhythmias, and observed 30% improvement in the NYHA class and 26% increase in LVEF 3 months after upgrade. Leon et al.15 studied 20 patients with chronic atrial fibrillation, AV junction ablation, and RVA pacing (mean duration of 26 months) and found 29% improvement in the NYHA class, 44% increase in LVEF, 8.5% decrease in LVEDd, and 81% decrease in HF hospitalizations 3–6 months after upgrade. The magnitudes of improvements in NYHA class and echocardiographic parameters and the reduction in HF hospitalizations in the present study are comparable to these two previous reports. However, in contrast with our data showing that all patients remained alive over 12 months after upgrade, seven patients died or were transplanted during a period of 3–12 months and two patients died of worsening HF over 1 year after implantation in the two studies, respectively. Recently, Horwich et al.21 evaluated mechanical dyssynchrony and indices of LV function by tissue Doppler imaging (TDI) echocardiography during RVA pacing and CRT within 1 day after upgrade in 15 HF patients with pacemaker dependency because of CAVB. CRT was associated with significantly reduced LV intraventricular delay, increased LVEF (by 29%) and decreased LV end-diastolic volume (by 6%). Longer-term follow-up data were not provided in their study. Another recent report compared mechanical dyssynchrony and indices of LV function before and 3 months after CRT between 32 chronically RVA-paced patients and 39 patients with intrinsic LBBB without pacemakers.16 The authors showed that there was no difference between RVA-paced and non-paced patients for any parameters of interventricular or intraventricular dyssynchrony, and that CRT reduced each parameter for dyssynchrony and improved LV function and symptoms similarly in both. Non-responders by the NYHA class were distributed equally.16
In our study, although we did not evaluate mechanical dyssynchrony with TDI echocardiography, all patients showed at least >5% increase in dP/dtmax on acute haemodynamic study, an improvement in the NYHA class and a reduction in HF hospitalizations, suggesting significant mechanical dyssynchrony and response to CRT in all. The lower non-responder rate in our study compared to the above investigations may be explained by differences in the underlying heart diseases. The majority of patients in earlier studies had coronary artery disease (CAD) or idiopathic dilated cardiomyopathy (DCM) as a cause of HF, which may have contributed importantly over and above any role of dyssynchrony per se, as opposed to our patients in whom dyssynchrony seems to play a primary role.
Potential significance
Despite wide recognition of the potential adverse effects of chronic RVA pacing on ventricular function, the conventional procedure has substantially been applied to acquire CAVB patients in need of permanent ventricular pacing. The present report is the first of which we are aware to describe a series of acquired CAVB patients, most of whom had normal ventricular function at the time of RVA pacing initiation, with subsequent progression to HF that appeared to be related to RVA pacing and responded clinically to CRT. Moreover, the reduction in LVEDd with CRT tended to be greater in patients with shorter duration of RVA pacing, suggesting that upgrade to BiV or LV pacing should perhaps be considered early upon signs of LV-function deterioration in pacemaker-dependent individuals subjected to RVA pacing, in order to preserve cardiac function. Some significant components of advanced LV remodelling, particularly structural changes like tissue fibrosis, may be irreversible.22 The correlation that we noted between the duration of RVA pacing and the LV function deterioration, along with the incomplete reversibility of LV dysfunction with CRT that we observed, suggests that the early consideration for CRT upgrade might be helpful, by limiting symptomatic worsening and possibly by preventing irreversible adverse LV remodelling. These results raise the possibility that CRT upgrade in patients with LV functional impairment because of RVA pacing should be considered before the clinical signs of progressive congestive HF develop. However, our study does not prove that earlier intervention improves outcomes. Further studies designed to test this notion prospectively are needed.
Study limitations
The study was conducted retrospectively in a small patient population. We performed acute haemodynamic examination before the upgrade in all 18 patients—invasive studies were not performed with the chronically implanted CRT devices. As upgrading to single LV pacing was performed in three patients only, we cannot compare the long-term outcome between LV and BiV pacing. No control group was incorporated, because patients at pre-upgrade served as their own controls and it would have been unethical not to upgrade patients to CRT, given their clinical condition.
The rate of HF development after RVA-pacemaker implantation was not established in the present study. Approximately 210 patients underwent conventional pacemaker implantation for CAVB in our institution from August 1991 to January 2003, corresponding to the time of pacemaker implantation in patients enrolled in this study. Thus, the prevalence of HF in this population was at least of the order of 
8.5%. However, since a significant number of patients had their principal follow-up at other hospitals, there may have been additional cases of HF of which we are unaware.
We cannot exclude the possibility that HF development in chronically paced patients resulted from natural progression of the underlying heart disease, especially in the six patients with cardiac sarcoidosis. This study was composed of patients with a specific pattern of aetiologies of CAVB. Cardiac sarcoidosis is more common23 and the incidence of CAD is less in Japanese than in Caucasians. Our results thus may have to be interpreted with caution.
Despite severe LV dysfunction in our patients, CRT provided substantial improvement. However, LV function was not restored to the normal mean pre-RVA pacemaker implantation LVEF for the group as a whole. The lack of complete recovery may, at least in part, reflect irreversible LV remodelling after the long periods (up to > 13 years) of RVA pacing. This finding underscores the potential need to detect patients with LV functional deterioration caused by RVA pacing early enough to allow for optimal reversal with CRT upgrade.
Conflict of interest: none declared.
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