cardiac resynchronization therapy ( crt ) is an important device - based , non - pharmacological approach that has shown to improve the outcome in selected patients with chronic heart failure ( hf ) .
large randomized trials have demonstrated that crt improves left ventricular ( lv ) function and reduces both morbidity and mortality rates . until recently , crt was indicated in patients with advanced hf [ new york heart association ( nyha ) functional class iii 
iv ] , reduced lv systolic function [ ejection fraction ( ef ) 35% ] , evidence of electrical dyssynchrony ( qrs duration 120 ms ) , receiving optimal medical therapy , and who were in sinus rhythm ( sr ) . in the last esc recommendations , for the first time , atrial fibrillation ( af ) patients , who constitute an important subgroup of hf patients treated with crt , have been considered as eligible to receive crt on the condition that the effects of underlying rhythm be neutralized by atrio - ventricular junction ( avj ) ablation .
the aha / acc / hrs guidelines also favourably considered crt in hf patients with af , without however emphasizing the possible need for aggressive rate control .
also , these guidelines remain imprecise in defining differentiated approaches according to the forms of af other than permanent .
the present review explains , in the first instance , in which way af interferes with adequate crt .
secondly , a brief overview on the effects of crt in af patients is presented , followed by some recommendations , based on current evidence , on the most adequate approach according to patient characteristics , emphasizing the extent of atrial arrhythmic [ atrial tachycardia ( at)/af ] burden .
it is important to point out that these recommendations remain unsupported by evidence derived from randomized controlled trials ( rcts ) , which are much needed .
atrial fibrillation ( whether permanent , persistent , or paroxysmal ) poses a number of challenges for adequate crt delivery .
an intrinsic , intermediate - to - high , irregular spontaneous af rhythm reduces the percentage of effectively biventricular paced captured beats ( bvp% ) . even in a patient who has normal rate af , phases of effective biventricular capture alternate with phases of competing af rhythm which causes spontaneous , fusion , or pseudo - fusion beats ( figure  1 )
this suggests that the global effective  crt - dose may be markedly reduced compared with atrial - synchronous rhythm with a short av interval ( as is achieved during sr ) since the number of effective biventricular captured beats are reduced .
moreover , in af patients , during exertion , spontaneous ventricular rate tends to override bvp rates , determining a further reduction of paced beats precisely when patients are most in need of having biventricular capture , thus greatly limiting functional capacity .
another problem is the possible negative impact on prognosis of using combinations of negative chronotropic therapy to achieve adequate rate control .
in fact , some studies have  indirectly suggested that the use of either digoxin or amiodarone in hf may increase morbidity and mortality . a patient with af and hf treated with crt , spontaneous irregular intrinsic beats alternate with fusion and pseudo - fusion beats , thus markedly reducing effective crt .
adequate management of af and other atrial arrhythmias is primarily based on defining the at / af burden and how it impacts negatively on crt delivery .
defining atrial arrhythmic burden is derived from integrating clinical , device - derived data , as well as instrumental findings ( such as echocardiographic measures ) . any hf patient with a history of atrial arrhythmias
requires particular attention , especially in the first months of crt , in order to ensure that resynchronization be adequately delivered . from a clinical standpoint
, it is important to identify symptoms such as palpitations , and more importantly , worsening effort dyspnoea which may suggest that the resynchronization effect is reduced because of the interference of the underlying atrial rhythm .
these clinical aspects should be substantiated by instrumental echocardiographic data , which may show unchanged or further progression of lv dysfunction expressed through increased ventricular volumes and further ef reduction . retrieving relevant information ( bvp% , duration , and numbers of 
mode switch episodes , etc . ) through device monitoring ( figure  2 ) may complement clinical and echocardiographic data and , thus , provide a more complete picture on the extent of af / at burden in each patient .
these different aspects , all obtainable during a routine outpatient visit , allow provision of an approximation of the effective af / at burden influencing crt delivery .
recently , kamath pointed out the importance of an accurate evaluation of crt - dose using sophisticated 12-lead holter monitoring , which seemed to be more accurate than conventional device - based information .
different aspects of crt patients with af before and after avj ablation , which may be appreciated through device features . in a 59-year - old female with permanent af treated with a crt - d device ,
avj ablation yielded the following improvements : better functional status as shown by the number of hours of activity per day ; maximization of bvp% ; and improvement of heart rate variability profile .
rate control strategy encompasses treatment options which effectively reduce and regularize heart rate in patients who usually have permanent af or a persistent af which can not be readily cardioverted to sr .
first , lowering heart rate to intermediate - to - low rate allows better diastolic filling and increases stroke volume in hearts with conserved frank 
the recourse to rate control drugs and/or activation of device - based algorithms is reasonable as first - line approach when af / at burden is low / intermediate .
rate control drugs considered effective in hf patients with depressed lv function include digoxin , amiodarone , and beta - blockers . however , more recent findings derived from randomized trials have suggested caution in the use of digoxin and amiodarone in patients with hf . some device - derived features may be helpful to improve rate control and thus improve crt delivery
these features include ventricular rate regularization ( vrr ) which consists in performing bvp , which 
overrides intrinsic rhythm , through faster ventricular - paced depolarization allowing to reduce short cycles through retrograde concealed penetration of the av node .
the benefits of rate control achieved by activating vrr function is well established in patients with chronic af and no or only mild hf treated with a single chamber right ventricular ( rv ) pacing . in these patients , vrr has been demonstrated to confer acute haemodynamic benefits , to restore autonomic balance , and to provide a more regular rhythm during exercise , thus potentially improving functional status .
ventricular sense response ( also called  trigger function ) which triggers lv pacing after a premature rv sense event is detected : this option may be activated in all crt devices of the latest generation . in the context of crt
, the effectiveness of such rate control and rate regularization algorithms combined with the use of rate control drugs has not been investigated in an rct .
findings derived from different large observational cohort studies on the effects of crt in patients with permanent af have yielded contrasting results .
one of these studies observed that treatment combining negative chronotropic drugs and activation of device features ( vrr and trigger mode ) , even if permitting 85% of biventricular stimulation , did not yield significant long - term improvements in functional status , lvef , or lv end - systolic volume ( lvesv ) reduction .
the ineffectiveness of this approach further found confirmation through another more extensive multicentre european study , which reported relatively high death rate , particularly occurring for worsening progressive hf in af patients treated with negative chronotropic drugs .
quite differently , other smaller studies have advocated that to achieve good results after crt in terms of survival , aggressive rate control strategy is not necessary .
it is worth emphasizing , however , that when the survival curves of the hf patients with af treated with a combined device - based / drug regimen are compared , yearly death rate for any cause is considered to be remarkably high , amounting to over 14%/year in both separate cohorts of non - ablated patients ( figure  3 ) .
comparison of kaplan  meier analysis for freedom from death for any cause between the gasparini et al . and the khadjooi et al .
sr , sinus rhythm ; af , atrial fibrillation ; af - drugs : atrial fibrillation with preserved av node conduction ; af - abl , atrial fibrillation group with ablated av node . it therefore follows that in hf patients treated with crt who present a high or intermediate at / af burden , the pursuit of an aggressive treatment strategy , such as avj ablation , is warranted .
atrio - ventricular junction ablation is commonly performed in patients with symptomatic , drug - refractory , fast , permanent af as part of the conventional  ablate and pace strategy , and has been shown to confer symptomatic relief .
atrio - ventricular junction ablation in individuals with af treated with crt has mainly been confined to selected patients in whom high - rate af or at jeopardizes satisfactory biventricular stimulation , and in crt - implantable cardioverter defibrillator ( icd ) recipients determines inappropriate icd interventions .
the problem of inappropriate icd therapies during af , constituting 30% of all icd interventions , has an important negative impact on the quality of life of patients and may be completely resolved after avj ablation .
however , in the context of crt in hf patients with concomitant af , a growing amount of evidence has demonstrated that avj ablation may be useful to optimize crt delivery by eliminating the deleterious haemodynamic effects of a competing , irregular , spontaneous intrinsic rhythm .
the mustic af randomized trial , besides being the first randomized trial demonstrating possible benefits of crt in hf patients with permanent af and conventional indication for crt , also showed that in these patients , the preferred mode of ventricular stimulation was biventricular as opposed to rv .
the study enrolled af patients with either slow - rate af or those who underwent ablation of the av node ; the effects between pacing modes were compared using a crossover design with two 3-month periods . although no result was found in the intention - to - treat analysis between the two modes ( because of high numbers of dropouts ) , hf patients who completed the study improved in terms of functional status with bvp .
two other prospective studies investigated the effects of pacing mode in the management of af with rapid ventricular rates following avj ablation .
rate control achieved following avj ablation significantly improved symptoms and functional status with no difference between the pacing modalities , whether lv or rv , but in a population with much better lv function .
the pave trial further confirmed the benefits of the  ablate and pace approach using different pacing modes .
the latter study observed a greater benefit of the bvp mode in patients with depressed lvef ( 45% ) and/or in nyha functional class iii .
further observational studies have investigated the acute and short - term effects of avj ablation in hf patients with af treated with crt and have demonstrated an increase in global lv function , a reduction of mitral regurgitation , and an increase in exercise capacity ; others have confirmed the chronic effects of crt in this patient subgroup , reporting improvements in nyha class , exercise capacity , and global lv function .
it is important to stress that these benefits appear to be confined to af patients with previous avj ablation or spontaneous low - rate af .
one large observational prospective investigation specifically evaluated the effects of avj ablation on crt delivery using a pre - defined protocol .
this study showed that only those af patients who underwent avj ablation ( and thus approaching 100% effective bvp ) showed significant improvements in lvef , lvesv , and exercise capacity .
furthermore , a significantly higher proportion of responders ( response defined as a 10% reduction in lvesv ) were observed in the avj ablation group ( 68% ) compared with the non - ablated group ( 18% ) at 12 months . as later observed by the same groups in a more extensive observational multicentre study , crt combined with avj ablation
conferred a significant reduction of deaths for any cause compared with crt alone , particularly by reducing deaths for progressive hf . taken together , based on current observational data on af populations treated with crt ,
the benefits of avj ablation in allowing appropriate crt delivery seem to outweigh the risks associated with creating pacemaker dependency .
the peculiarity of crt devices ( using an rv and an lv pacing leads ) should , theoretically , at least reduce the risks of pacemaker dependency related to lead fractures or malfunction .
nonetheless , the fear of pacemaker dependency remains a limiting aspect for the wider diffusion of avj ablation .
further studies are of course needed to investigate the extensive benefits of adding avj ablation to crt in hf patients with af following a prospective , randomized , multicentre design .
the avert - af ( atrio - ventricular junction ablation followed by resynchronization therapy in patients with chf and af ) and the an - art study ( av node ablation in crt ) are both concerned with establishing whether avj ablation coupled with bvp may significantly improve functional capacity compared with pharmacological therapy in hf patients with permanent af and depressed ef . it should be stated that such studies aiming to assess the effects of crt according to soft / subjective endpoints may add little to the current recommendations .
there is a great need to design rcts with strong endpoints , even though such designs may be difficult to implement for ethical and financial reasons .
a reasonable and  up - dated approach to investigate the effects of crt in this group involves using device - based surrogates of major clinical events .
device - based remote continuous patient monitoring may provide information on a daily basis of the patients ' functional and clinical status , before the onset of an overt clinical event becomes manifest .
but before these parameters may be validated as surrogates for strong endpoints of major cardiovascular events , better definition of their accuracy is needed .
atrial fibrillation and other atrial rhythm disturbances in patients with hf may have an important negative impact on the clinical benefit conveyed by crt , if these are not appropriately managed .
careful overall evaluation is mandatory to define precisely the at / af burden in order to articulate tailored diagnostic and therapeutic strategies . on the basis of recent observational data , in patients presenting intermediate or elevated at / af burden
, avj ablation may represent a fundamental tool to achieve full crt delivery and , thus , confer marked improvements in global cardiac function , and , further , in survival .
more studies are necessary to further support the recourse to avj ablation in this situation .
efforts should also be dedicated towards establishing tailored treatment approaches to adequately manage different atrial rhythm issues in hf patients treated with crt .
funding to pay the open access publication charges for this article was provided by electrophysiology and pacing unit , irccs istituto clinico humanitas , rozzano , milano .
 cardiac resynchronization therapy ( crt ) is an important device - based , non - pharmacological approach that has shown , in large randomized trials , to improve left ventricular ( lv ) function and reduce both morbidity and mortality rates in selected patients affected by advanced heart failure ( hf ) : new york heart association ( nyha ) functional class iii  
 iv , reduced lv systolic function with an ejection fraction ( ef ) 35% , qrs duration 120 ms , on optimal medical therapy , and who were in sinus rhythm . 
 for the first time , the latest esc and aha / acc / hrs guidelines have considered atrial fibrillation ( af ) patients , who constitute an important subgroup of hf patients , as eligible to receive crt . 
 nevertheless , these guidelines did not include a strategy for defining differentiated approaches according to af duration or burden . in this review , 
 the authors explain in which way af may interfere with adequate crt delivery , how to manage different af burden , and finally present a brief overview on the effects of crt in af patients . 