Cardiac resynchronization therapy (CRT) is a fundamental device-based, nonpharmacological approach that has been shown to improve morbidity and mortality in selected patients with chronic heart failure. At the present time CRT is indicated, as class I, in patients with New York Heart Association (NYHA) class III–IV, ejection fraction 35% or less, QRS duration more than 120 ms, on optimal medical therapy, and in sinus rhythm . Recently, after Multicenter Automatic Defibrillator Implantation Trial CRT, patients in NYHA class II are eligible too . Patients with atrial fibrillation, who constitute an important sub-group of heart failure patients, are nowadays considered eligible for receiving CRT, as described in the latest American Heart Association/American College of Cardiology/Heart Rhythm Society of Cardiology and European Society of Cardiology Guidelines as class IIA level of evidence B [1,3].
Although CRT indications are well described and widely accepted by the cardiology community, some CRT aspects still need to be defined and emphasized.
In particular, device programming is an important issue in CRT that may require individual tailoring. As of now, different articles concerning optimal device programming have been published but the importance of maximized biventricular pacing delivery is an emerging concept [4,5,6▪▪].
The problem of optimal ‘cardiac resynchronization therapy dose’
Although it is axiomatic that an antibiotic is administered in a standard dose for the majority of patients (obviously weight adjusted), the dose of some drugs in special categories of patients has to be defined and philosophy may change over the years. For instance, beta-blocker administration in heart failure patients was considered a contraindication in the 1970s, but then turned into the basic treatment of chronic heart failure, and nowadays the guidance is that it should be administered at the maximum tolerated dosage.
A similar analogy can be drawn between β-blockers and CRT with respect to the maximum tolerated dosage. Obviously, there can be no possibility of benefit after CRT if biventricular pacing does not reliably occur.
It has been clear from the beginning of CRT that in sinus rhythm patients atrioventricular programming is of paramount importance to enable a correct and constant biventricular stimulation: no one would have programmed a long atrioventricular delay (e.g. 300 ms) in this setting.
Until recently, the importance of and need to maximize biventricular-pacing percentage have never been emphasized. The first study stressing this point was published by our group in 2006  using an arbitrary cutoff rate of biventricular pacing of 85% of the pacing time needed to define CRT as effective in atrial fibrillation patients.
In the following years, the appropriate target for biventricular (BIV) pacing percentage remained ill-defined, until Koplan et al.[7▪] found in a large retrospective analysis of more than 1800 patients that the greatest magnitude of reduction in heart failure hospitalization and all-cause mortality were observed with a BIV pacing cutoff of 92%. Furthermore, patients paced 92% or less presented worse outcomes and were less likely to improve by one NYHA functional class from implant to 6 months than patients paced more than 92%.
This striking evidence was confirmed and even amplified by the elegant work of Hayes et al.[6▪▪]. They analyzed a cohort of more than 30 000 patients of the ALTITUDE study, followed up by the remote-monitoring LATITUDE (Latitude by Boston Scientific, Natick, Massachusetts, USA) network in order to determine the correlation between the biventricular pacing percentage and total mortality.
Mortality was inversely correlated with the percentage of biventricular pacing in the presence of both normal sinus and paced atrial rhythm, and even in atrial fibrillation. The novel finding was that the greatest magnitude of reduction in mortality was observed with a biventricular pacing cutoff more than 98%. BIV capture was the single most important variable predicting improvement after CRT, reducing heart failure hospitalizations, and, most importantly, increasing survival.
Last but not least, the ALTITUDE study evaluated a large number of atrial fibrillation patients: in this case, atrial fibrillation patients with a BIV pacing percentage more than 98.5% presented a survival rate equivalent to that of their counterparts in normal sinus rhythm. Conversely, atrial fibrillation patients with a BIV pacing percentage less than 98.5% showed a significantly higher mortality with respect to sinus rhythm patients.
What are the barriers that inhibit gaining 100% biventricular pacing in clinical practice?
Theoretically (and even more practically), CRT requires BIV pacing percentage to be as close to 100% as possible. Effective delivery of continuous CRT may be hindered by the presence of native ventricular conduction, due to long atrioventricular delay programming, atrial tachycardia or atrial fibrillation.
There are several mechanisms that lead to a reduction of biventricular pacing in clinical practice. The most intuitively obvious is the loss of left ventricle (LV) pacing due to dislodgment or lack of capture of the LV lead.
This is usually accompanied by a sharp clinical worsening due to loss of LV capture and potential detrimental effect of right ventricle pacing in an already failing heart. A standard electrocardiographic evaluation usually enables a correct diagnosis.
A second mechanism is intrinsic conduction ‘beating’ the programmed atrioventricular delay.
In sinus rhythm patients, a lower BIV percentage is observed if native atrioventricular conduction overrides the programmed atrioventricular delay.
A careful atrioventricular programming immediately after CRT implantation and at each follow-up visit is mandatory. The recent Adaptive CRT trial [8▪] evaluated the safety and efficacy of a new algorithm designed to provide automatic ambulatory adjustment of CRT pacing configuration. The algorithm periodically analyzes interventricular and intraventricular delays, choosing the adequate atrioventricular interval and permitting a complete fusion beat between native conduction and LV only pacing. The study demonstrated that the Adaptive CRT algorithm is as well tolerated and effective as BIV pacing customized by continuous echocardiographic optimizations, which might be costly, time consuming or not available at each follow-up.
It is even more important to consider that, in a great number of patients, CRT promotes cardiac reverse remodeling. LV volume reduction may be reflected in a faster atrioventricular conduction. It is not unusual to observe sinus rhythm patients who, after 6–12 months of CRT, report some kind of ‘weakness during effort’. In that situation, it is helpful to perform a periodic ergometric test to document correct BIV pacing during effort. Sometimes at higher rates the programmed atrioventricular interval is not short enough to guarantee complete BIV pacing. Incidentally, this implies the loss of biventricular pacing just when it is most needed.
Probably, the most important and frequent cause of unsatisfactory BIV pacing percentage is atrial arrhythmia, determining long periods of high-rate native conducted beat overriding effective biventricular pacing.
In particular, permanent atrial fibrillation poses a number of challenges for adequate CRT delivery. Even during low rate atrial fibrillation, phases of completely effective biventricular capture alternate with phases of competing atrial fibrillation conducted rhythm, thereby determining pure native beats, fusion (hybrid between paced and intrinsic morphologies) and pseudofusion (pacing spikes delivered, but intrinsic morphology not modified) beats. As a consequence, in atrial fibrillation patients the global effective ‘CRT-dose’ may be markedly reduced compared with sinus rhythm patients. Even more, it is worthwhile to consider, particularly in atrial fibrillation patients, that low heart rates allow longer diastolic filling time, increasing stroke volume according to the Frank–Starling mechanism. The regularization of heart rate further reinforces favorable effects on diastolic function.
What tools can be used to maximize biventricular-pacing percentage in atrial fibrillation patients?
The spectrum of negative chronotropic drugs considered effective in heart failure patients with atrial fibrillation is limited, and includes β-blockers, digoxin and amiodarone, although the latter two may increase morbidity and mortality. Some device-derived features (like conducted atrial fibrillation response, biventricular trigger, ventricular rate regulation) are specifically designed to improve rate control in atrial arrhythmias. However, even if partially effective at rest (despite higher average rates, which are clearly deleterious to the diastolic function), their efficacy during exercise seems to be marginal. The percentage of BIV pacing recorded by device counters is often artificially inflated during atrial fibrillation due to erroneous counting of the abovementioned fusion or pseudofusion complexes. This dichotomy between device counters’ estimation of percentage BIV pacing and true BIV capture was elegantly illustrated by Kamath et al. utilizing 12 lead ECG Holter monitoring. This article showed that patients with a BIV pacing more than 90% demonstrated an astonishing 40% rate of pseudofusion and fusion beats.
Atrioventricular junction (AVJ) ablation for the management of atrial fibrillation in heart failure patients treated with CRT is the only tool that permits complete rhythm regularization and heart rhythm control, thus favoring a ‘pure’, constant delivery of CRT.
Until recently, AVJ ablation in atrial fibrillation patients treated with CRT has mainly been confined to selected patients in whom high-rate atrial fibrillation or atrial tachycardia jeopardizes satisfactory biventricular stimulation or to CRT-ICD recipients receiving inappropriate ICD interventions during fast atrial fibrillation, with an important negative impact on the quality of life of patients.
However, in the context of CRT in heart failure patients with concomitant atrial fibrillation, there has been a growing amount of evidence to support the usefulness of AVJ ablation to reach benefits equivalent to sinus rhythm.
Soft end point improvements have been extensively documented in both the short term and the long term in atrial fibrillation patients receiving CRT, but benefits appear more relevant in atrial fibrillation patients treated with AVJ ablation or spontaneous low-rate atrial fibrillation. Concerning mortality data, it is surprising to note that in many different studies the mortality rate of nonablated atrial fibrillation patients has always been reported as around 14% per year, whereas in AVJ-ablated patients a three-fold reduction of mortality was observed .
The recent meta-analysis by Ganesan and Brooks [11▪▪] confirmed the dramatic reduction of total and cardiovascular mortality conferred by AVJ ablation in atrial fibrillation patients, showing a significant reduction of both total (RR 0.42) and cardiovascular (RR 0.44) mortality. The accompanying editorial to this meta-analysis claimed a ‘clear picture’ regarding the survival benefits conferred by atrioventricular node ablation in atrial fibrillation patients [12▪].
Last but not least, AVJ ablation is the most powerful predictor of sinus rhythm resumption in permanent atrial fibrillation patients treated with CRT . The conversion from atrial fibrillation to sinus rhythm even after many years of CRT seems to be related to the higher biventricular pacing (BVP) observed in ablated patients, and consequent volume and ‘electric’ reverse remodeling.
The long ‘gold rush’ to reach 100% biventricular pacing
The need to optimize medical treatment is well established: maximized dosage of β-blockers and ACE-inhibitors is requested in patients with heart failure. The same holds true for CRT: the maximum biventricular pacing percentage should always be pursued and achieved for all patients.
Nowadays, there is a growing body of evidence on the necessity to approach 100% BVP. Since our arbitrary cutoff of ‘theoretically effective’ BVP pacing more than 85% presented in 2006 , a lot of consistent and homogeneous data has continuously raised this ‘gold rush’ standard to 90 [7▪], 92  and recently to 98% [6▪▪]. This cutoff seems to highlight dramatically improved survival rates in patients undergoing CRT and would appear mandatory in the subgroup of atrial fibrillation patients.
What to do in clinical practice?
The clinician should not be satisfied until assured that the absolute highest BIV percentage has been achieved, keeping 100% as the goal. Together with the importance of continuous monitoring during follow-up (even with a home monitoring system), even small gains in the BIV pacing percentage might also be clinically important.
For this reason, at every follow-up, the BIV percentage should be recalculated (and if possible monitored with a home system) and, if unsatisfactory, atrioventricular nodal-blocking therapies, atrioventricular delay reprogramming in sinus rhythm patients or atrioventricular nodal ablation in atrial fibrillation patients should be evaluated.
In addition, it should always be kept in mind that the settings considered ‘optimal’ at prehospital discharge might easily change during follow-up and/or with physical activity.
This article draws attention to the fact that, to obtain the maximized results from CRT, a maximized biventricular pacing is strongly needed. Lower BIV pacing percentage results in worse outcomes and even brief periods of its reduction may correlate with acute heart failure episodes.
One hundred percent BIV pacing should always be pursued, as it is quite evident that the dose–response for CRT is even more important than for the majority of pharmacological therapies.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 82).
1. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices). Circulation 2008; 117:e350–e408.
2. Moss AJ, Hall WJ, Cannom DS, et al.
MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009; 361:1329–1338.
3. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Authors/Task Force Members. Eur J Heart Fail 2012; 14:803–869.
4. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy
on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. JACC 2006; 48:734–743.
5. Gasparini M, Auricchio A, Metra M, et al. Multicentre Longitudinal Observational Study (MILOS) Group. Long-term survival in patients undergoing cardiac resynchronization therapy
: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008; 29:1644–1652.
6▪▪. Hayes DL, Boehmer J, Day J. Cardiac resynchronization therapy
and relationship of percentage biventricular pacing. Heart Rhythm 2011; 8:1469–1475.
This is the striking evidence showing the importance of biventricular pacing percentage in relation to cardiac survival.
7▪. Koplan BA, Kaplan AJ, Weiner S, et al. Heart failure decompensation and all-cause mortality in relation to percentage biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol 2009; 53:355–360.
This is the first work on CRT to focus on the importance of BIV pacing percentage for CRT outcome.
8▪. Martin DO, Lemke B, Birnie D, et al.
Investigation of a novel algorithm for synchronized left-ventricular pacing and ambulatory optimization of cardiac resynchronization therapy
: results of the adaptive CRT trial. Heart Rhythm 2012; 9:1807–1814.
This study provides evidence of the safety and effectiveness of a new algorithm for optimized atrioventricular delay.
9. Kamath GS, Cotiga D, Koneru JN, et al. The utility of 12-lead Holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy
. J Am Coll Cardiol 2009; 53:1050–1055.
10. Gasparini M, Regoli F, Galimberti P, et al. Cardiac resynchronization therapy
in heart failure patients with atrial fibrillation. Europace 2009; 11 (Suppl 5):v82–v86.
11▪▪. Ganesan A, Brooks A, Roberts-Thompson, et al
. Role of AV nodal ablation in cardiac resynchronization therapy
in patients with coexistent atrial fibrillation and heart failure: a systematic review. J Am Coll Cardiol 2012; 59: 719–726.
This is the most recent review to focus on the importance of atrioventricular nodal ablation in atrial fibrillation patients treated with CRT.
12▪. Gasparini M, Galimberti P. AV junction ablation in heart failure patients with atrial fibrillation treated with cardiac resynchronization therapy
: the picture is now clear!. J Am Coll Cardiol 2012; 59:727–729.
This is the editorial to Ganesan's work and provides a summary on atrioventricular nodal ablation in atrial fibrillation patients treated with CRT.
13. Gasparini M, Steinberg JS, Arshad A, et al. Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy
: a longitudinal observational study. Eur Heart J 2010; 31:976–983.
14. Delnoy PP, Ottervanger JP, Luttikhuis HO, et al. Comparison of usefulness of cardiac resynchronization therapy
in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol 2007; 99:1252–1257.