Cardiac pacing remains the only effective treatment for patients with symptomatic atrioventricular block (AVB). However, recent concern over the detrimental effects of chronic right ventricular (RV) pacing has motivated clinicians to look into the role of cardiac resynchronization therapy (CRT) in this group of patients. Chronic RV pacing causes ventricular dyssynchrony, which may lead to atrial and ventricular remodeling, mitral regurgitation, and diastolic and systolic dysfunction (see Figure 1).1,2 Tolerance to chronic RV pacing appears to be influenced by baseline left ventricular (LV) function, the cumulative amount of ventricular pacing (VP), the duration of pacing, and other factors that are not currently understood.
Clinical Trials of Chronic Right Ventricular Pacing
Chronic RV pacing has been associated with a higher incidence of heart failure (HF) and atrial fibrillation (AF) than atrial-based pacing modalities in randomized clinical trials.3–10 In the MOST trial, the cumulative percentage of ventricular pacing (cum% VP), rather than the specific pacing mode, was a strong predictor of HF hospitalization and AF. A cum% VP >40% conferred a 2.6-fold increased risk for HF hospitalization in the dual-chamber (DDD) group compared with a lower percentage of pacing in similar patients. Similarly, the risk for AF was increased by 1% for each 1% increase in cum% VP.3,4 In a study by Andersen et al., atrial pacing was associated with a significantly higher survival, less AF, less HF, and fewer thromboembolic complications.5 Fixed-rate single-chamber ventricular pacing (VVI) pacing was associated with a significant increase in LV end systolic diameter and dilatation of the left atrium (LA).6 These findings also appeared to be time-dependent, since there were no significant differences in mortality or HF during the initial three years of follow-up.7
The effects of ventricular dyssynchrony induced by RV pacing appear to be more dramatic in patients with LV dysfunction or a previous history of HF. In the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial, in which all patients had an LV ejection fraction (EF) <40% at enrollment, the primary combined end-point of hospitalization for HF or death was significantly increased in the DDD group compared with the VVI-40 group during a relatively short period of follow-up (mean eight months).8,9 The worse outcome in the DDD group correlated with cum% VP >40%.10
In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, patients with cum% VP >50% had a significantly higher risk for HF and ventricular tachycardia (VT) or ventricular fibrillation (VF) requiring implantable cardioverter–defibrillator (ICD) therapy,11 suggesting that ventricular dyssynchrony induced by RV pacing not only worsens HF, but could also be pro-arrhythmic.
In summary, data from randomized clinical trials have shown that >40% cum% VP is associated with a higher incidence of HF and AF. The adverse outcomes of ventricular dyssynchrony induced by RV pacing appear to be time-dependent and modulated by baseline LV systolic function, with an earlier onset (months rather than several years) in patients with depressed LV systolic function. Moreover, these adverse clinical outcomes have been associated with concomitant atrial and ventricular remodeling.2,6,10–13
Results from observational studies and randomized clinical trials of CRT have consistently demonstrated significant improvements in clinical outcomes, reverse remodeling and survival in patients with New York Heart Association (NYHA) class III and IV HF symptoms, LVEF ≤35%, and a QRS interval duration >120ms.14–18 These data suggest (but do not prove) that in patients with an indication for pacing therapy and in whom excessive RV pacing (>40% cum% VP) cannot be avoided, CRT could avoid or mitigate the detrimental effects of chronic RV pacing.
Clinical Trials of Cardiac Resynchronization Therapy in Patients with Atrioventricular Block
In this group of patients, pacing therapy will necessarily lead to a chronic cum% VP >40%, which has been associated with a higher incidence of AF, HF hospitalization,3–5,10 and ventricular arrhythmias.11 This reality has prompted clinicians to evaluate the role of CRT in patients with AVB who do not have indications for CRT according to current guidelines.
The Post-AV Nodal Ablation Evaluation (PAVE) trial compared chronic biventricular (BiV) pacing with RV ventricular pacing in 184 patients undergoing ablation of the AV node for management of AF. The study end-points were change in the six-minute walk test, quality of life, and LVEF. Patient characteristics were similar in both groups. At six months post-ablation, patients treated with CRT had a significant improvement in six-minute walk distance and LVEF. Patients with an EF ≤45% or with NYHA class II/III symptoms receiving a BiV pacemaker appeared to have a greater improvement in six-minute walk distance than patients with normal systolic function or class I symptoms.19
Leon et al.20 evaluated the effects of a BiV upgrade in 20 patients with severe HF (EF ≤35%, NYHA functional class III or IV) who had previously undergone AV junction ablation and RV pacing for management of AF. Mean follow-up was 17.3 months. There were significant improvements in NYHA functional classification, LVEF, reverse remodeling indices, and hospitalizations after BiV upgrade. In the Homburg Biventricular Pacing Evaluation (HOBIPACE) study, 30 patients with a standard indication for permanent ventricular pacing for AVB and LV dysfunction defined by an LV end-diastolic diameter ≥60mm and an EF ≤40% were randomized to RV or BiV pacing. BiV stimulation was associated with a significant decrease in LV end-diastolic and end-systolic volumes, N-terminal fragment of B-type natriuretic peptide (NT-proBNP) level, and the Minnesota Living with Heart Failure score compared with RV pacing. BiV stimulation was associated with a significant increase in LVEF and exercise capacity.21
Hay et al.22 reported the acute hemodynamic effects of different pacing techniques in nine patients with HF, AF, and severe AVB. Ventricular stimulation was applied to the RV (apex or outflow tract), LV free wall, and both sites (BiV). BiV improved systolic function more than either site alone, and LV pacing was significantly better than RV pacing. However, only BiV improved diastolic function (isovolumic relaxation).
The Optimal Pacing Site (OPSITE) study was a three-month cross-over randomized clinical trial comparing RV with LV pacing (phase 1) and RV with BiV pacing (phase 2) in 56 patients undergoing AV junction ablation for AF. Mean EF was 39% at baseline. Only a modest improvement was observed in quality of life and exercise capacity, and was not clinically significant. Moreover, the improvement in quality of life observed with rhythm regularization was three to 10 times higher than that obtained using RV to LV or BiV pacing. Interestingly, BiV pacing but not LV pacing was slightly superior to RV pacing in the subgroup of patients with preserved systolic function and a narrow QRS interval.23
These findings suggest that patients with AVB, LVEF <45%, and NYHA functional class II–IV appear to benefit from CRT rather than RV pacing alone. These data also suggest that in patients with AVB, BiV pacing may be superior to LV pacing. The benefit of CRT is not yet clear in patients with AVB and a normal LVEF. The results of the OPSITE study seem to differ from the other clinical studies. This discrepancy can probably be explained by the study design (BiV pacing only after completion of phase 1, RV versus LV) and short duration (only three months for each pacing modality) (see Table 1).
The Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block (BLOCK HF) trial is prospectively enrolling patients with an LVEF <50%, NYHA functional class I–III, a class I or IIa indication for a permanent pacemaker, and AVB or AV Wenckebach or PR >300ms when pacing at 100bpm. All patients will receive a CRT pacemaker or CRT ICD, with randomization to RV or BiV pacing. The primary end-point is a combined end-point of overall mortality, HF-related urgent care, and change in LV volume. The Biventricular Pacing for AVB to Prevent Cardiac Desynchronization (Biopace) trial will prospectively compare RV with BiV pacing among 1,200 patients with a standard indication for a pacemaker and a high probability of predominant VP. A balanced randomization among different LVEF subgroups is expected (>50%, 36–50%, and <35%). The primary end-points are survival, quality of life, and six-minute walk test. Similarly, in the PREVENT-HF pilot study, 100 patients with a standard indication for a pacemaker and a high probability of predominant VP will be randomized to RV or BiV pacing. The primary end-point is change in LV end diastolic volume. Secondary outcomes include LVEF, mortality, morbidity, and mitral regurgitation.
Commentary
Patients with symptomatic AVB clearly need cardiac pacing. Such patients usually have a high percentage of ventricular pacing. Given the detrimental effects of chronic RV pacing, the optimal pacing modality needs to be considered in these patients at the time of implantation.
Currently, we implant dual-chamber pacemakers in patients with normal LV function and a standard indication for a pacemaker for AVB. Whether or not CRT will have a role in such patients with a high cum% VP and a normal LVEF is unknown. The Biopace trial will provide further information on this question, since a subgroup of these patients will have a normal LVEF at the time of enrollment. Patients with symptomatic AVB, LVEF <45%, and a high probability of cum% VP >40% may be considered for CRT at the time of implantation. However, current practice guidelines do not yet endorse this approach. The role of CRT in patients with LVEF 35–50% and symptomatic bradycardia due to AVB is currently being evaluated in the BLOCK HF trial, the Biopace trial, and the PREVENT-HF pilot study. Current clinical trials should provide the data to definitively establish the optimal pacing modality in patients with symptomatic AVB, regardless of the status of LV function.