cardiac resynchronisation therapy ( crt ) has now been established as a valuable adjunct therapy in patients with heart failure and intraventricular conduction disturbances . crt is an example where the first evidence of its efficacy was demonstrated in patients , while the underlying pathophysiology was only studied later . in other words :  bedside research preceded bench studies . in subsequent years research moved back and forth between basic research and patient studies . this combination of research has led to a better , although not complete , understanding of the pathophysiology of dyssynchrony and of its treatment by crt . out of this research came the ground - breaking insight that simple disturbances in impulse conduction , which were initially considered innocent , proved to result in a host of molecular and cellular derangements that lead to a vicious circle of remodelling processes that facilitate the development of heart failure . as a consequence , crt primarily corrects conduction abnormalities , but secondarily improves myocardial properties at many levels . interestingly , corrections by crt are not exactly the reversal of paths induced by dyssynchrony , a property that may open new avenues for treatment of heart failure . most commonly , it refers to conditions with increased timing differences of either electrical or mechanical activation in the ventricles . indicators used to this purpose range from the width of the qrs complex in the ecg to the difference in time to peak shortening of strain curves . in most cases electrical dyssynchrony coincides with mechanical dyssynchrony , but mechanical dyssynchrony is found in the absence of a wide qrs complex . the most common causes of  true dyssynchrony are right ventricular ( rv ) pacing and left bundle branch block ( lbbb ) . under these circumstances the normal activation pattern is disturbed because the left ventricle is no longer activated via the left bundle branch and purkinje fibres . instead , the electrical activation spreads from the right ventricle through the septum towards the left ventricle . since activation moving from myocyte to myocyte is much slower than that through the purkinje system , the left ventricular ( lv ) free wall  which is the site most remote from the right ventricle several clinical [ 1 , 2 ] and pre - clinical   electrocardiac mapping studies have shown that the activation in lbbb hearts follows a specific pattern . because conduction often appears slow at the rv - lv junctions , an important contribution of activation comes from the wavefront passing over the apex towards the lv lateral wall ( referred to as u - shaped activation pattern ) . a characteristic feature is also the slow transseptal conduction in lbbb , possibly caused by the vertical orientation of the laminar sheets of myocytes in the septum . the prolonged activation of the left ventricle results in a widened qrs complex on the surface electrocardiogram ( ecg ) . indeed , in vivo the sequence of onset and peak shortening is similar to that of the sequence of electrical activation . recent measurements of electrical activation and peak shortening showed a tight correlation , even in crt candidates . interestingly , the slope of the regression line differed between patients , suggesting as yet poorly understood differences between patients . the dyssynchronous electrical activation of the left ventricle causes the early - activated septum to contract against a reduced load , which leads to pre - stretch of the lv free wall . this pre - stretch increases the contractile force of the lv free wall that , in turn , paradoxically stretches the septum later in systole . both types of systolic stretching can be considered wasted work [ 5 , 6 ] . wasted work expresses the poorly coordinated contraction , which also results in a poorer pump function , for example expressed as lower rate of rise of the lv pressure ( lv dp / dtmax ) . longer lasting lbbb in dogs results in increases of end - diastolic and end - systolic volume and a decrease in ejection fraction ( fig .  1 ; ) . the worsening of pump function with longer lasting lbbb is the consequence of a variety of remodelling processes in the myocardium . these processes can partly be attributed to neurohormonal activation , triggered by poor pump function ( fig .  1 ) . a recent human study showed that the baroreflex alters activity within five seconds after changing the activation sequence . increased sympathetic activation has been demonstrated in dogs during chronic ventricular pacing   and greater systemic vascular resistance in patients during ventricular pacing . a recent clinical investigation showed that , in crt responders , crt creates a more uniform sympathetic stimulation , as assessed by tracer - uptake studies . another part of the remodelling process appears to be triggered by the regional differences in mechanical load . as consistently observed in humans and dogs , mechanical load is low in early - activated regions and high in late - activated regions [ 5 , 12 , 13 ] . the latter changes are also reflected by changes in regional blood flow and oxygen consumption [ 14 , 15 ] . in the long run , this redistribution of mechanical load within the ventricular wall leads to asymmetric hypertrophy [ 16 , 17 ] . other factors that contribute to remodelling are the impaired pump function , which leads to ventricular dilatation and thereby increased wall stress , which in turn stimulates the remodelling processes . moreover , the uncoordinated and dyssynchronous contraction increases the oxygen demand of the myocardium while decreasing the diastolic perfusion time . this combination may lead to lower coronary perfusion reserve and thus higher sensitivity to ischaemia , hibernation and stunning . a series of studies in the canine model of lbbb , whether or not in combination with tachypacing - induced heart failure [ 1719 ] as well as in the mouse heart after chronic rv pacing , have shed light on the changes at the cellular and molecular level in asynchronous hearts . these changes are quite complex , partly mimicking the asymmetry of macroscopic hypertrophy in dyssynchronous hearts . expression of some genes and proteins is increased or depressed uniformly , while others show regional differences in expression . examples of uniformly depressed genes and proteins are virtually all potassium channels , several calcium channels and -adrenergic receptors [ 18 , 19 ] . also the foetal gene program and apoptosis - related genes in contrast , the l - type calcium channel and the transient outward potassium current ( ito ) show a more pronounced downregulation in the late - activated regions than in the early - activated ones . in addition , in the late - activated lv lateral wall stress response kinases as well as tnf were upregulated   and the gap junction protein connexin 43 showed lateralisation , the latter being associated with slowing down of conduction velocity ( fig .  1 ; ) . altogether , these global and regional changes lead to a complicated  molecular fingerprint of remodelling in the dyssynchronous heart . these extensive gene expression changes may be compared with the change of the coat of some animals between the seasons , a change that is driven by temperature and sunlight and is effectuated by alterations in gene expression . the observation that crt is able to correct the lbbb - induced abnormalities ( see below ) can then be compared with the recovery of the red squirrel s beautiful summer coat from the grey winter coat . there are indeed quite some studies supporting the myocardial recovery by crt , mentioned above . the primary and immediate aim of crt is to reduce the timing differences in electrical activation as compared with the situation during the conduction abnormality . importantly , crt ( commonly applied by using biventricular pacing ) increases dyssynchrony as compared with normal conduction ( narrow qrs complex ) and does not benefit , but rather harms , patients with narrow qrs complexes [ 23 , 24 ] . these results strongly indicate that crt requires a certain electrical substrate to be effective , the best substrate apparently being lbbb . in connection to the immediate electrical effects of crt , also lv pump function changes in a beat - to - beat fashion , and remains increased as pacing is continued [ 17 , 26 ] . the immediate haemodynamic effect of crt is also used to optimise pacing settings . interestingly , there is no consistency in the findings regarding the relation between the size of the acute haemodynamic and the long - term echocardiographic changes [ 28 , 29 ] . in experimental lbbb models , where heart rate is kept at a physiological level , chronic application of crt almost completely recovered the normal geometry and resolved the asymmetric hypertrophy of the lv , as determined by standard echocardiography ( fig .  2 ; ) . in the tachycardia - induced lbbb heart failure model , three weeks of rapid biventricular pacing created only a minor improvement in overall pump function , yet considerable molecular changes that did point towards recovery . first of all , crt normalised the abnormally distributed expression of l - type calcium channel , camkinase ii , tnf and p38 [ 18 , 31 ] . this normalisation process fits with the idea that the local contraction pattern is a determinant of local gene expression . however , also uniformly depressed genes and proteins such as akt , bad , ik , serca , -mhc recovered . moreover , crt reduced myocardial catecholamine levels , accompanied by increased expression of 1-adrenergic receptor expression . yet , the crt applied at 200  bpm did not result in recovery of ito and several calcium channels , which were all uniformly depressed during dyssynchronous heart failure . are relative changes in ( a ) lv end - diastolic volume ( lv edv ) , ( b ) total lv wall mass , ( c ) septal ( squares ) and lv lateral wall ( circles ) mass in the lbbb ( open symbols ) and lbbb + crt groups ( closed symbols ) . * : p  <  0.05 between lbbb and lbbb + crt group at 16 weeks . + : p  <  0.05 between 8 and 16 weeks within the lbbb + crt group . bvp biventricular pacing , lbbb left bundle branch block , lv left ventricular ( from vernooy et al . ) presented are relative changes in ( a ) lv end - diastolic volume ( lv edv ) , ( b ) total lv wall mass , ( c ) septal ( squares ) and lv lateral wall ( circles ) mass in the lbbb ( open symbols ) and lbbb + crt groups ( closed symbols ) . * : p  <  0.05 between lbbb and lbbb + crt group at 16 weeks . + : p  <  0.05 between 8 and 16 weeks within the lbbb + crt group . bvp biventricular pacing , lbbb left bundle branch block , lv left ventricular ( from vernooy et al . ) the importance and contribution of remodelling processes in the total benefit of crt is also illustrated by the common observation that echocardiographic reverse remodelling ( defined as an increase in lv ejection fraction and/or reduction in lv end - systolic volume ) continues to increase over time , even after years of crt . electrophysiologically , a human study shows a moderate reduction in intrinsic , non - paced qrs duration after longer lasting crt . more pronounced electrophysiological changes appear when observing the t - wave during crt and during temporary halting of crt in patients . doing so , a kind of cardiac memory effects are also known from temporary halting of rv pacing , so inducing dyssynchrony in patients . cardiac memory involves extensive remodelling at the molecular and cellular level , at least partly related to abnormal myocardial stretch   molecular , immunohistochemical and cellular studies on myocardial biopsies show significant reduction in collagen deposition and tnf immunoreaction and reduced cellular apoptotic activity after crt . moreover , patients with effective crt more frequently display chronic enhancement of circulating apelin , a secreted hormone that can block adverse remodelling and has positive inotropic effects . circulating biomarkers of extracellular matrix remodelling also accompany successful crt therapy , including decreases in tenascin - c , and metalloproteinases . chronic crt also has anti - inflammatory effects , reducing monocyte chemoattractant protein-1 , interleukin-8 , and interleukin-6 . the above - mentioned aspects of reversal towards a near - normal myocardial function are to be expected based on the normalisation of contraction patterns . however , there are indications that resynchronisation after a period of dyssynchrony creates an even better condition than a heart that has never experienced dyssynchrony . this is already suggested by the survival curves of lbbb and non - lbbb patients receiving crt . while the activation patterns during crt are expected to be the same in lbbb and non - lbbb , absolute survival tends to be better in crt - treated lbbb patients than in their non - lbbb counterparts . experimentally , dogs subjected to 6 weeks of atrial tachypacing ( synchronous heart failure ) were compared with dogs , in which in week 3 and 4 rapid atrial pacing was replaced by rapid rv pacing , thereby inducing temporary dyssynchrony . myocytes from the latter hearts displayed substantial improvement in function and calcium transients during resting condition as well as during 2-adrenergic stimulation   this improvement appeared to relate to higher expression of negative regulators of gi signalling ( yielding gs - biased 2-adrenergic stimulation ) that was higher than during lbbb and even than during control , thus indicating activation of pathways that are specifically activated during resynchronisation after a period of dyssynchrony . another example of the potential benefit of temporary dyssynchrony comes from a study involving the trans - catheter aortic valve implantation ( tavi)-induced lbbb in patients with aortic stenosis . while the development of persistent lbbb after tavi clearly increases the risk of death compared with those not developing lbbb , patients who developed transient lbbb ( lbbb disappearing within a year ) tended to have a better survival than patients not developing lbbb during tavi [ 43 , 42 ] . pushing a potential therapeutic role for intermittent or temporary dyssynchrony further , vanagt et al . such protection was demonstrated in rabbit and pig hearts , using brief periods of ventricular pacing before ( preconditioning ) or after ( postconditioning ) a period of ischaemia . pacing postconditioning was also applied in a small study in patients with first myocardial infarction , immediately following percutaneous coronary intervention . although the study did not meet its primary endpoint ( enzyme release ) , adjusted late - enhancement magnetic resonance images revealed an approximately 25  % reduction in infarct size ( fig .  3 ; ) . 3infarct size ( % lv ) determined by contrast - enhanced cardiac mri ( ce - cmr ) at 4 days ( n  =  48 ) , 4 months ( n  =  44 ) and 12 months after percutaneous intervention ( n  =  41 ) in control patients and patients who received transient right ventricular pacing immediately following coronary reperfusion . data were adjusted for st - segment deviation , time from symptom onset to hospital admission and affected coronary artery . from waltenberger infarct size ( % lv ) determined by contrast - enhanced cardiac mri ( ce - cmr ) at 4 days ( n  =  48 ) , 4 months ( n  =  44 ) and 12 months after percutaneous intervention ( n  =  41 ) in control patients and patients who received transient right ventricular pacing immediately following coronary reperfusion . data were adjusted for st - segment deviation , time from symptom onset to hospital admission and affected coronary artery . from waltenberger was not mediated by an ischaemic stimulus , nor by g - protein coupled signalling . the hypothesis that pacing postconditioning is mediated by stretch signalling is supported by the finding that protection could also be induced by intermittently raising the preload in isolated working hearts . additional proof came from experiments that showed that disruption of microtubules with colchicine and blocking stretch activated channels with gadolinium abrogated the protective effect of pacing postconditioning . summarising , the aforementioned data indicate that after a period of dyssynchrony , recovery by resynchronisation does not lead to a return exactly back to baseline . rather , while some derangements appear not amenable , some new pathways ( related to sympathetic stimulation and/or myocardial stretch ) appear to be activated that lead to a new , supra - normal state . in this regard a comparison may be made with bone healing after a fracture : the fraction heals , and due to the it is premature to make extrapolations to possible applications of intermittent pacing in the field of crt . however , better understanding the molecular mechanisms of the benefits of intermittent dyssynchrony may lead to novel targets for the treatment of heart failure . evidence is increasing that dyssynchrony can lead to a major and distinctive way of remodelling within the ventricular wall , involving processes that might affect long - term outcome . an important part of that remodelling may be linked to the abnormal contraction pattern rather than to global haemodynamics . this research was performed within the framework of ctmm , the center for translational molecular medicine ( www.ctmm.nl ) , project cohfar ( grant 01c-203 ) , and supported by the dutch heart foundation . jude medical , sorin , biological delivery system ( johnson and johnson ) , msd and proteus medical .
the genesis of cardiac resynchronisation therapy ( crt ) consists of 
 bedside research and  bench studies that are performed in series with each other . in this field , the bench studies are crucial for understanding the pathophysiology of dyssynchrony and resynchronisation . in a way , 
 crt started with the insight that abnormal ventricular conduction , as caused by right ventricular pacing , has adverse effects . 
 out of this research came the ground - breaking insight that 
 simple disturbances in impulse conduction , which were initially considered innocent , proved to result in a host of molecular and cellular derangements that lead to a vicious circle of remodelling processes that facilitate the development of heart failure . 
 as a consequence , crt does not only correct conduction abnormalities , but also improves myocardial properties at many levels . 
 interestingly , corrections by crt do not exactly reverse the derangements , induced by dyssynchrony , but also activate novel pathways , a property that may open new avenues for the treatment of heart failure .