during the past two decades there have been major advances in the pharmacological treatment of chronic heart failure . despite this
, severe heart failure remains a syndrome associated with very high mortality , profound reduction in quality of life , and frequent hospitalisation .
cardiac transplantation can be an extremely effective therapy in such cases , but its provision is severely rationed by the lack of available donor organs .
other cardiac surgical interventions including revascularisation , dynamic cardiomyoplasty and myocardial reduction surgery have been employed , but are currently of unproven value .
it is in this context that pacemaker therapy is currently being intensively evaluated as a therapy for such patients .
initial interest in the role of pacing as a potential treatment for congestive heart failure ( chf ) focused on prolonging diastolic filling time by reducing or abolishing presystolic av valve regurgitation .
rutishauser et al first reported the phenomenon of presystolic av valve regurgitation in patients with chf and complete heart block .
it became apparent with the advent of doppler echocardiography that such presystolic regurgitation of the mitral and/or tricuspid valves is common in patients with first - degree av or complete heart block .
presystolic regurgitation has also been reported in chf patients with normal av conduction times if left ventricular end diastolic pressure ( lvedp ) is markedly increased .
the av pressure gradient , when lvedp is high and the conduction time is prolonged , is thought to reverse before the onset of ventricular systole .
although this promotes valve closure , there is incomplete closure , resulting in valvular regurgitation and reduced ventricular filling time . in the context of a ventricle that is abnormally stiff ( and therefore highly dependent on filling time , especially on exercise ) , this can have considerable adverse haemodynamic consequences .
the presence of interventricular conduction prolongation ( wide qrs complex ) further shortens the left ventricular filling period .
hochleitner et al first reported beneficial effects from dual - chamber short av delay ( 100 ms ) pacing in patients on a transplantation waiting list , but did not establish the mechanism of benefit .
brecker et al subsequently reported improved exercise capacity and haemodynamics in 12 chf patients with short av delay pacing . pacing with
a short av interval eliminated the presystolic component of av valve regurgitation and increased ventricular diastolic filling times .
these observations were supported by smaller uncontrolled studies . since then , further reports of unselected patients have shown no overall short- or medium - term benefits ; while individual patients have improved , others have deteriorated .
these mixed results may be explained by the fact that benefits from the reduction in presystolic av valve regurgitation may be offset by the electromechanical dyssynchrony of right ventricular ( rv ) pacing .
right - sided pacing results in paradoxical motion of the interventricular septum ( as seen in left bundle branch block [ lbbb ] ) .
this may adversely affect lv performance as it may reduce lv diastolic filling time , result in dyssynchronous ( and inefficient ) lv contraction and reverse the normal base - apex activation sequence . in a study of patients with coronary heart disease but without chf ,
betocchi et al demonstrated that right - sided av sequential pacing caused an upward shift in the lv diastolic pressure - volume relation .
there was also a reduction in lv peak filling rate , an increase in the time constant of isovolumic relaxation ( tau ) , and a reduction in cardiac index .
rosenqvist et al used radionuclide ventriculography to assess exercise responses in 12 patients without chf .
cardiac output measured on exercise ( with similar heart rates ) was higher during atria pacing than during either dual chamber pacing or ventricular pacing .
paradoxical septal motion was apparent during ventricular pacing and dual chamber pacing , with a 25% impairment of regional septal ejection fraction .
there is , therefore , clear evidence that rv pacing impairs both systolic and diastolic function of the lv in patients without chf .
several studies in normal dogs and in patients without chf have suggested that pacing from the rv outflow tract or inter - ventricular septum may be superior to rv apical pacing .
both acute haemodynamic and long - term studies in patients with chf , however , have not shown any benefit .
further evidence against rv pacing for chf comes from the observation that it results in an increase in plasma nor - epinephrine levels   ( a powerful adverse prognostic marker in chf ) .
the response to right - sided av sequential pacing in chf may depend on a balance between beneficial alleviation of presystolic mitral regurgitation ( mr ) and tricuspid regurgitation ( tr ) ( in those patients with av conduction delay and elevated lvedp ) , and adverse consequences of dyssynchrony of left ventricular contraction and filling .
consistent with this , nishimura et al reported that benefit was confined to those patients with presystolic mr and prolonged av conduction , whereas other patients showed a worsening of haemodynamics .
it has been suggested , on this basis , that the decision to implant such a pacemaker should be based on the haemodynamic response to an acute pacing study . however , enthusiasm for right - sided short av delay pacing as a treatment for chf has waned .
in much the same way that rv pacing induces lv dysfunction , a similar dysfunction may arise from lbbb in patients with chf .
this conduction abnormality is present in 10 - 53% of patients with chf and , when present , is associated with a worse prognosis . '
resynchronisation ' of rv and lv contraction , by simultaneous ( biventricular ) pacing , would therefore appear logical .
the technical feasibility of such an approach was reported by two groups in 1994 ; in these reports , lead implantation was performed at thoracotomy .
cazeau et al subsequently reported acute haemodynamic benefit from temporary av sequential biventricular pacing in eight patients with severe chf .
the first of these was from blanc et al , in which chf patients with first - degree av block and/or lbbb , and a pulmonary capillary wedge pressure > 15 mmhg were paced with a short av delay and either biventricular , lv or rv pacing .
leclercq et al , in a similar patient group , also observed an equal magnitude of benefit from lv and biventricular pacing , comparing biventricular pacing with baseline or rv pacing ( dual chamber pacing ) in this study .
the long - term results of the ' resynchronisation for heart failure ' ( in sync ) trial were recently reported .
this was an open study of biventricular pacing in patients with medically refractory nyha iii / iv heart failure with qrs duration > 150 ms and left ventricular ejection fraction < 35% .
the predetermined end points were 6 min walk distance , nyha functional class and quality of life at 1 , 3 , 6 and 12 months versus baseline .
there were significant improvements in all three parameters at each time point when compared with baseline .
several randomised and non - randomised studies of biventricular pacing are currently in progress or planned .
table 1 summarises the design ( and where available results ) of studies that are either completed or due to finish soon , whereas table 2 lists the studies that have yet to commence or are in the early phases .
most of these studies are now assessing clinically important end points such as exercise capacity and quality of life in patients with severe chf and lbbb .
the multisite stimulation in cardiomyopathy ( mustic ) study   is the first single - blind , randomised , cross - over study of ventricular resynchronisation therapy in chf .
the cross - over design enabled patients to act as their own control , being paced for 3 months in each mode ( ie biventricular / no ventricular stimulation ) .
the mustic study contained two patient groups : one in sinus rhythm and one in atrial fibrillation post - atrioventricular nodal ablation .
this is based on the previous demonstration that , among patients with chf and poorly controlled atrial fibrillation , av nodal ablation and right ventricular pacing can result in symptomatic improvement .
the inclusion criteria for all patients were nyha class iii or iv , an ejection fraction < 35% and significant ventricular conduction delay .
biventricular pacing significantly improved both primary end points ( vo2 max and 6 min walk distance ) .
there were significant improvements in quality of life ( minnesota questionnaire ) and also in rehospitalisation ( both prespecified secondary end points ) . at the end of the cross - over phase , 86% of patients chose ( blind )
although further studies will need to address the question of mortality benefit , the availability of a non - pharmacological treatment that improves exercise capacity and quality of life would be a major advance .
the quality - of - life issue is particularly pertinent as the baseline data in mustic confirms the profound impairment of quality of life in nyha class iii and iv heart failure .
the only concern is that some deaths occurred very soon after changes in pacemaker programming ( ie soon after the cross - over from atria pacing to biventricular pacing or at the onset of biventricular pacing ) , raising the possibility that patients ' biventricular pacing may be arrhythmogenic , perhaps because of the presence of two ventricular activation wave fronts .
the timing of these few early deaths in a small subset may be a chance finding but requires clarification .
studies completed or well advanced af , atrial fibrillation ; av , atrioventricular ; chf , congestive heart failure ; dcm , dilated cardiomyopathy ; ef , ejection fraction ; ihd , ischaemic heart disease ; lvad , left ventricular assist device ; lvedd , left ventricular end - diastolic diameter ; qol , quality of life ; rv , right ventricular .
studies planned or in an early phase aicd , automatic implantable cardioverter defibrillator ; chf , congestive heart failure ; ef , ejection fraction ; lvedd , left ventricular end - diastolic diameter ; ot , optimal therapy ; qol , quality of life .
preliminary results from the acute and chronic phases of the pacing therapies for congestive heart failure ( path - chf ) study have also been reported recently .
the acute results emphasised the importance of optimising av delay , and showed that lv pacing was superior to both rv pacing and biventricular pacing .
in the chronic study , significant improvements in vo2 max , quality of life , 6 minute walk distance , nyha class and ejection fraction were observed , with a progressive increment of benefit over the first 6 months .
patients with severe chf due to dilated cardiomyopathy in sinus rhythm with intraventricular conduction delay underwent biventricular pacemaker insertion at thoracotomy .
a single - blind , cross - over phase of biventricular pacing or no ventricular stimulation ( 6 weeks in each phase ) followed by a 12 week longitudinal paced phase is present .
many patients with chf meet the criteria for an implantable cardioverter defibrillator ( icd ) .
patients in ventak chf with severe drug refractory chf , a qrs duration > 120 ms and indications for icd implantation will undergo implantation of a biventricular pacemaker / icd .
the end points of the two studies are the same except that antitachycardia and defibrillator efficacy and safety are included as additional secondary end points .
the feasibility of combined trans - venous biventricular pacing / automatic implantable cardioverter defibrillator implantation has recently been reported , leading to the addition of an icd / pacing limb to the mustic study .
there are several studies in the ' design and recruitment ' stage , some of which now address the issue of mortality and healthcare cost issues ; for example , cardiac resynchronisation in heart failure ( care - hf ) .
this study aims to assess mortality in a controlled patient group by randomising patients to biventricular pacing and optimal therapy , or optimal therapy alone .
all - cause mortality and hospital admissions for decompensated chf will be evaluated together with an assessment of a 6 minute walk distance and vo2 max .
the second end points of this study will be nyha status , mortality , quality of life , neurohormone levels and echocardiographic indices .
table 2 summarises the design of other important studies planned or in the early phases , including pacman , miracle , companion and relevant .
we are at a crucial point with this series of large clinical trials in the adoption or otherwise of pacing for the treatment of severe chf .
current philosophy on the use of pacing in chf assumes that the mechanism of benefit arises from resynchronisation of ventricular contraction in patients with lbbb .
if the mechanism of benefit was due to a resynchronisation of both ventricles , then biventricular pacing ( in which synchronous depolarisation occurs together with a narrowing of the qrs complex ) would be expected to be superior to lv pacing ( which is associated with a much broader qrs complex ) . in acute haemodynamic studies , however , lv pacing has been shown to be either equal to   or superior to   biventricular pacing .
kass et al reported that patients with the greatest qrs prolongation showed the greatest acute haemodynamic benefit , but there was no relationship between qrs narrowing associated with pacing and acute haemodynamic improvement .
lv pacing was specifically superior to biventricular pacing despite a much broader paced qrs complex .
it is certainly true that analysis of pressure - volume loops suggested that the mechanism of benefit was an improvement in lv contractile function , with no significant change in lv diastolic compliance .
varma et al , in a recent study , assessed the impact of different pacing sites on lv coordination using lv pressure - dimension loops in patients with chf and lbbb .
dyssynchrony of intraventricular conduction results in a low ' cycle efficiency ' , yet there was no consistency regarding the optimal pacing chamber or site to improve cycle efficiency .
this group conversely observed that lv pacing provided greater overall acute haemodynamic benefit than biventricular pacing .
kerwin et al recently showed that biventricular pacing did not improve intraventricular dyssynchrony , but did improve interventricular dyssynchrony .
although kass et al did not find evidence to support it , the possibility of an improvement in diastolic filling can not be excluded .
right ventricular pacing clearly worsens diastolic filling , so the converse with lv pacing is certainly possible .
chf patients with high lvedps have marked diastolic ventricular interaction ; that is , the filling of the lv is constrained by the rv and by the pericardium .
our preliminary data suggests that , by permitting the lv to fill before the rv , lv pacing may improve filling in these patients with diastolic ventricular interaction , whether or not they have underlying lbbb .
all of these factors serve to emphasise the need to understand the effects of pacing on pathophysiology , in order to design optimally larger clinical trials .
it is unlikely , given the non - uniform nature of the pathophysiology and the multiple potential effects of pacing ( reduction in presystolic mr , recoordination of intraventricular versus interventricular contraction sequence with improvement in both contractile and diastolic function ) , that a ' one size fits all ' strategy is optimal .
it is possible that benefit may not be confined to patients with lbbb , nor necessarily that all such patients will benefit .
previous experience of a dichotomy between symptomatic and prognostic effects with positive inotropic agents in chf should sound a note of caution . encouraging preliminary data in this regard
suggest that the improvement in myocardial contractile performance with biventricular pacing is associated with a fall in myocardial o2 consumption . furthermore , whereas rv pacing increases plasma norepinephrine , biventricular pacing is associated with a reduction .
we must , however , remember that simply by virtue of their size , large ' clinical trials ' will not always provide the answers for individual patients . unless such studies are directed by a sound understanding of pathophysiology , of its non - uniformity , and of the effects of therapy on this pathophysiology ,
this may lead to inappropriate therapy for some patients and missed therapeutic opportunities for others .
 despite the major advances in medical drug therapy , heart failure remains a syndrome associated with high mortality and morbidity . 
 biventricular or left ventricular ( lv ) short atrioventricular ( av ) delay pacing is being tested in congestive heart failure patients with left bundle branch block . the aim is to resynchronise the dyscoordinate lv contraction . 
 a number of studies are underway , but it is clear that while some patients respond remarkably , this is highly variable . 
 accurate identification of patients likely to benefit will be crucial . 
 the mechanism of benefit is unclear 
 . a greater understanding of the physiological consequences of pacing will be necessary to accurately identify these patients . 
Introduction
Short atrioventricular delay right-sided pacing
Biventricular and left ventricular pacing
The future
Acknowledgement