congestive heart failure ( chf ) remains a major health problem worldwide , despite considerable progress in its management .
the incidence and prevalence of this disease continues to increase due to an aging population , which , in part , is related to the use of new pharmacologic and non pharmacologic therapies .
an estimated 67 million people have chf in the united states and europe , and approximately 1 million patients are diagnosed with chf every year ( 1 , 2 ) . the cost involved in the management of this problem is enormous and continues to climb . despite a progressive prognosis improvement
thanks to the therapy with ace - inhibitors ( 3 , 4 ) , beta - blockers ( 5 ) and spironolactone ( 6 ) , the quality of life in patients with advanced heart failure remains poor and mortality , due to risks for ventricular arrhythmias and sudden cardiac death , can increase .
patients with advanced heart failure frequently have conduction disturbances ( atrioventricular , inter- or intraventricular conduction delay with qrs interval > 120 ms ) that play an important role in worsening cardiac systolic function and in increasing risk of death ( 7 , 8) . in recent years a new therapeutic approach , biventricular pacing ( bivp ) , has been introduced as an adjunctive therapy to pharmacological treatment in patients with severe chf and intraventricular conduction delay .
biventricular pacing stimulates the right atrium and both the ventricles simultaneously to resynchronize their action .
many studies have demonstrated that bivp in patients with advanced chf significantly improves ventricular hemodynamics , quality of life , exercise capacity and reduces mortality and hospitalization rates ( 911 ) .
little is known yet about the influence of cardiac resynchronization therapy on the heterogeneity of ventricular repolarization ( 11 , 12 ) , which represents the arrhythmogenic substrate of dilatative cardiomyopathy and is identified on the electrocardiogram by qt dispersion ( qtd ) , jt dispersion ( jtd ) and transmural dispersion of repolarization ( tdr ) .
the aim of our study was to evaluate the effect of biventricular pacing on electrocardiographic parameters of heterogeneity of ventricular repolarization , both spatial ( qtd , jtd ) and transmural ( tdr ) .
the study population consisted of fifty patients ( 43 male , 7 female , aged 60.2  3.1 years ) suffering from congestive heart failure ( n = 39 nyha class iii ; n = 11 nyha class iv ) as a result of coronary artery disease ( n = 19 ) or of dilated cardiomyopathy ( n = 31 ) .
all patients were in sinus rhythm and demonstrated a left bundle branch block ( qrs duration > 130 ms ; mean qrs duration > 156  21 ms ) in the standard 12-lead electrocardiogram .
all patients included in the evaluation showed an ejection fraction < 35 and left ventricular end - diastolic diameter > 55 mm .
all patients were taking heart failure medications ( ace - inhibitors , beta - blockers , diuretics , spironolactone ) , which remained unchanged during the previous six weeks before the permanent biventricular dddr pacemaker implantation .
the atrial lead was placed high in the right atrium , the right ventricular lead was placed in the right ventricular apical endocardium , and the left ventricular lead was placed in an epicardial posterolateral vein via coronary sinus access similar to the methods described by daubert et al ( 13 ) .
the pacemakers were triple - output devices that made use of standard dualchamber technology , with built - in adapters to synchronize the pacing of the two ventricles .
results of the implantations were assessed from the positions of the leads on chest x - ray films and from changes in the width of the qrs interval on 12-lead surface electrocardiogram .
each patient underwent a twelve - lead surface electrocardiogram , recorded at a speed of 50 mm / sec and performed before pacemaker implantation and at the end of follow - up period , twelve months after the procedure .
the ecg recording was performed during sinus rhythm ( sr ) , right ventricular endocardial pacing ( rvendop ) , left ventricular epicardial pacing ( lvepip ) and biventricular pacing ( bivp ) .
special attention was paid to eliminate all correctable causes of noise , such as muscle tremor , and to minimize electromagnetic frequency interference generated by electrical sources next to lead array .
the pacing sequences were randomly switched between the patients and no effects on the results were observed .
the study was approved by the local ethics committee and written informed consent was obtained from all patients prior to enrolment .
twelve - lead body surface electrocardiograms were recorded at a speed of 50 mm / sec .
qrs duration , qt interval , jt interval and tpeak - end interval measurements were performed with the use of computer software ( configurable measurement system ) using digitizer 34180 ( calcomp , anaheim , california ) .
the standard correlation was 95% ( 95% confidence intervals 6.73 to 6.01 ) . in each electrocardiogram
the leads were excluded from analysis when the end of the t - wave was not clearly distinguishable or the signal quality was too poor for analysis .
the qrs interval was measured from the start of the q wave or , in absence of the q wave , from the start of r wave to the end of s , that is to its return to the isoelectric line .
the qt interval was measured from the initial deflection of the qrs complex to the end of t wave , that is , to the point where t wave returned to the isoelectric line . in case
there was a u wave , the qt interval was measured to the lowest part of the curve between the t and u waves .
the tpeak - end interval was defined as the interval from the maximum t - wave amplitude to the end of the t - wave ( 14 ) .
qt dispersion ( qtd ) was the difference between the maximal and the minimal qt value in all leads ( 15 ) .
the difference between the maximal and the minimal jt value in all leads was defined jt dispersion .
the transmural dispersion of repolarization ( tdr ) was defined as the interval between the peak to the end of the t wave ( 16 , 17 ) , which for our analysis we have considered the mean value .
statistical analysis was done using student s t test for paired data and one - way analysis of variance ( ano - va ) coupled with fisher s lsd test among three or more groups .
the study population consisted of fifty patients ( 43 male , 7 female , aged 60.2  3.1 years ) suffering from congestive heart failure ( n = 39 nyha class iii ; n = 11 nyha class iv ) as a result of coronary artery disease ( n = 19 ) or of dilated cardiomyopathy ( n = 31 ) .
all patients were in sinus rhythm and demonstrated a left bundle branch block ( qrs duration > 130 ms ; mean qrs duration > 156  21 ms ) in the standard 12-lead electrocardiogram .
all patients included in the evaluation showed an ejection fraction < 35 and left ventricular end - diastolic diameter > 55 mm .
all patients were taking heart failure medications ( ace - inhibitors , beta - blockers , diuretics , spironolactone ) , which remained unchanged during the previous six weeks before the permanent biventricular dddr pacemaker implantation .
the atrial lead was placed high in the right atrium , the right ventricular lead was placed in the right ventricular apical endocardium , and the left ventricular lead was placed in an epicardial posterolateral vein via coronary sinus access similar to the methods described by daubert et al ( 13 ) .
the pacemakers were triple - output devices that made use of standard dualchamber technology , with built - in adapters to synchronize the pacing of the two ventricles .
results of the implantations were assessed from the positions of the leads on chest x - ray films and from changes in the width of the qrs interval on 12-lead surface electrocardiogram .
each patient underwent a twelve - lead surface electrocardiogram , recorded at a speed of 50 mm / sec and performed before pacemaker implantation and at the end of follow - up period , twelve months after the procedure .
the ecg recording was performed during sinus rhythm ( sr ) , right ventricular endocardial pacing ( rvendop ) , left ventricular epicardial pacing ( lvepip ) and biventricular pacing ( bivp ) .
special attention was paid to eliminate all correctable causes of noise , such as muscle tremor , and to minimize electromagnetic frequency interference generated by electrical sources next to lead array .
the pacing sequences were randomly switched between the patients and no effects on the results were observed .
the study was approved by the local ethics committee and written informed consent was obtained from all patients prior to enrolment .
twelve - lead body surface electrocardiograms were recorded at a speed of 50 mm / sec .
qrs duration , qt interval , jt interval and tpeak - end interval measurements were performed with the use of computer software ( configurable measurement system ) using digitizer 34180 ( calcomp , anaheim , california ) .
the standard correlation was 95% ( 95% confidence intervals 6.73 to 6.01 ) . in each electrocardiogram
the leads were excluded from analysis when the end of the t - wave was not clearly distinguishable or the signal quality was too poor for analysis .
the qrs interval was measured from the start of the q wave or , in absence of the q wave , from the start of r wave to the end of s , that is to its return to the isoelectric line .
the qt interval was measured from the initial deflection of the qrs complex to the end of t wave , that is , to the point where t wave returned to the isoelectric line . in case
there was a u wave , the qt interval was measured to the lowest part of the curve between the t and u waves .
the tpeak - end interval was defined as the interval from the maximum t - wave amplitude to the end of the t - wave ( 14 ) .
qt dispersion ( qtd ) was the difference between the maximal and the minimal qt value in all leads ( 15 ) .
the difference between the maximal and the minimal jt value in all leads was defined jt dispersion .
the transmural dispersion of repolarization ( tdr ) was defined as the interval between the peak to the end of the t wave ( 16 , 17 ) , which for our analysis we have considered the mean value .
statistical analysis was done using student s t test for paired data and one - way analysis of variance ( ano - va ) coupled with fisher s lsd test among three or more groups .
biventricular pacing resulted in a statistically significant reduction in patient qrs duration ( 132  16 ms during bivp versus 156  21 ms at baseline , n = 50 , p = 0.02 ) .
right ventricular endocardial pacing and left ventricular epicardial pacing , on the other hand , led to a marked prolongation in ventricular activation time ( 183  12.3 ms during rvendop ; 190  15 ms during lvepip versus 156  21 ms at baseline , p<0.05 ) ( fig .
1qrs duration at baseline rhythm ( 15621 ms ) and during left ventricular epicardial pacing ( lvepip ; 19015 ms , p<0.05 ) , right ventricular endocardial pacing ( rvendop ; 18312.3 ms , p<0.05 ) and biventricular pacing ( bivp ; 13216 ms , p<0.02 ) .
qrs duration at baseline rhythm ( 15621 ms ) and during left ventricular epicardial pacing ( lvepip ; 19015 ms , p<0.05 ) , right ventricular endocardial pacing ( rvendop ; 18312.3 ms , p<0.05 ) and biventricular pacing ( bivp ; 13216 ms , p<0.02 ) .
biventricular pacing significantly reduced qt dispersion , compared to sinus rhythm ( 73.93  19.4 ms during bivp vs 91  36.7 at sinus rhythm , n = 50 , p = 0.004 ) .
right ventricular endocardial pacing and left ventricular epicardial pacing both caused a significant increase in qtd value ( rvendop 94  51 ms , p<0.03 ; lvepip 116  71 ms , p<0.02 ) . 

( 9136.7 ms ) right ventricular endocardial pacing ( rvendop , 9451 ms , p<0.03 ) , left ventricular epicardial pacing ( lvepip ; 11671 ms , p<0.02 ) , and biventricular pacing ( bivp 73.9319.4 ms ; p=0.004 ) .
( 9136.7 ms ) right ventricular endocardial pacing ( rvendop , 9451 ms , p<0.03 ) , left ventricular epicardial pacing ( lvepip ; 11671 ms , p<0.02 ) , and biventricular pacing ( bivp 73.9319.4 ms ; p=0.004 ) .
there was no statistically significant effect on jt dispersion during rvendop and lvepip as compared to sinus rhythm , whereas biventricular pacing significantly decreased the jt dispersion ( 73.18  17.16 ms during bivp vs 100.72  39.04 at baseline n = 50 , p = 0.003 ; fig .
( 100.7239.04 ms ) , right ventricular endocardial pacing ( rvendop ; 79.1830.83 ms ; p= ns ) , left ventricular epicardial pacing ( lvepip ; 89.9543.60 ms ; p = ns ) , and biventricular pacing ( bivp 73.1817.16 ms ; p=0.003 ) .
( 100.7239.04 ms ) , right ventricular endocardial pacing ( rvendop ; 79.1830.83 ms ; p= ns ) , left ventricular epicardial pacing ( lvepip ; 89.9543.60 ms ; p = ns ) , and biventricular pacing ( bivp 73.1817.16 ms ; p=0.003 ) .
the transmural dispersion of repolarization ( tdr ) was significantly increased during rvendop ( 108.1319.94 ms ; p<0.002 ) and lvepip ( 114.71  26.1 ms ; p<0.05 ) , whereas biventricular pacing significantly decreased the transmural dispersion of repolarization ( 93.16  15.60 ms ; p<0.004 ) , as compared to sinus rhythm ( 101.55  19.08 ms ; fig .
4pacing site dependent changes in transmural dispersion of repolarization ( tdr ) values during sinus rhythm ( 101.5519.08 ms ) , right ventricular endocardial pacing ( rvendop ; 108.1319.94 ms ; p<0.002 ) , left ventricular epicardial pacing ( lvepip ; 114.7126.1 ms ; p<0.05 ) , and biventricular pacing ( bivp , 93.16 15.60 ms ; p<0.004 ) .
pacing site dependent changes in transmural dispersion of repolarization ( tdr ) values during sinus rhythm ( 101.5519.08 ms ) , right ventricular endocardial pacing ( rvendop ; 108.1319.94 ms ; p<0.002 ) , left ventricular epicardial pacing ( lvepip ; 114.7126.1 ms ; p<0.05 ) , and biventricular pacing ( bivp , 93.16 15.60 ms ; p<0.004 ) .
in our study , we evaluated the pacing - site dependent change in markers of ventricular repolarization heterogeneity in a population of fifty patients with congestive heart failure .
the ventricular repolarization heterogeneity is an expression of regional ( qtd , jtd ) and transmural ( tdr ) differences in cellular action potential duration and in ventricular recovery time . in heart failure patients , the preferential prolongation of the m cell action potential results in the development of a transmural dispersion of repolarization ( tdr ) , which can be estimated from the electrocardiogram as the interval between the peak and the end of the t wave ( 18 ) .
previous electrophysiological studies ( 1921 ) , have highlighted the role of ventricular repolarization heterogeneity on the genesis of ventricular malignant arrhythmias in heart failure patients . in failing myocardium
, the enhancement of qtd , jtd and tdr values increases the risk for development of malignant ventricular arrhythmias , probably via two mechanisms .
first , it facilitates transmural differences early after depolarization propagation ; second , it could cause intramural functional conduction blocks that predispose to re - entrant polymorphic ventricular tachyarrhythmia ( 22 ) . several studies suggested that tdr and jtd are clinically useful in assessing arrhythmia risk ( 23 , 24 ) , because they are parameters less dependent on ventricular depolarization and reflect better than qtd the ventricular repolarization heterogeneities in patients with intraventricular conduction abnormalities ( 25 , 26 ) .
medina - ravell and coworkers in a recent experimental study have suggested ( 12 ) a potentially harmful influence of cardiac resynchronization therapy on ventricular repolarization .
the authors found that biventricular pacing or left ventricular epicardial pacing prolong qt interval , increase transmural dispersion of repolarization , and may be a potential risk for development of torsade de pointes in a subset of patients .
nevertheless , abraham wt et al and bristow mr et al in two distinct prospective , randomized studies ( 28 , 29 ) did not find any excess mortality due to sudden death in a population with chronic heart failure and biventricular pacing .
however , in the study of medina - ravell , qtd , jtd and tpeak - end was not estimated at baseline and during biventricular pacing . in our opinion , this information is really important . in our study
, differences in various parameters of ventricular repolarization heterogeneity ( qtd , jtd , tdr ) during right endocardial ventricular , left epicardial ventricular and biventricular pacing in heart failure patients have been obtained using a standard 12-lead ecg .
our data , in contrast to medina - ravell s findings , showed that biventricular pacing reduced the qtd , jtd and tdr and , with them , the relative risk of malignant ventricular arrhythmias . nevertheless , in accordance with medina - ravell et al findings and those of fish et al , epicardial pacing of left ventricle has been shown to increase the ventricular heterogeneity of repolarization , probably because the physiological ventricular activation was reversed .
normally , ventricular activation starts with endocardium via subendocardial purkinje network and spreads across the ventricular wall .
although the epicardium is activated last , it repolarizes first , producing a repolarization sequence opposite to activation ( 14 ) . furthermore
, our data showed that sole right endocardial ventricular pacing increased qtd and tdr less than left epicardial ventricular stimulation .
qt interval and tpeak - end measurements were conducted in 12-lead ecgs , with the use of computer software and digitizer by an experienced observer . despite all that
, the reliability of the measurements remains uncertain to the extent that the lack of a consensus has as a consequence the absence of indisputable , generally accepted criteria for the definition of the end of t interval .
biventricular pacing causes a stastically significant reduction of all parameters proposed to estimate the heterogeneity of ventricular repolarization ( qtd , jtd , tdr ) , as compared to sinus rhythm , whereas both right ventricular endocardial and left ventricular epicardial pacing cause an increment of heterogeneity of ventricular repolarization . in conclusion our data show that cardiac resynchronization therapy could have an electrophysiologic antiarrhythmic influence on arrhythmogenic substrate of dilatative cardiomyopathy .
further long - term studies have to asses the utility of surrogate parameters of ventricular dispersion of repolarization .
 objective : the aim of our study was to evaluate the effect of cardiac resyncronization therapy ( crt ) on qt dispersion ( qtd ) , jt dispersion ( jtd ) and transmural dispersion of re - polarization ( tdr ) , markers of heterogeneity of ventricular repolarization in a study population with severe heart failure.methods and results : fifty patients ( 43 male , 7 female , aged 60.2  3.1 years ) suffering from congestive heart failure ( n = 39 nyha class iii ; n = 11 nyha class iv ) as a result of coronary artery disease ( n = 19 ) or of dilated cardiomyopathy ( n = 31 ) , sinus rhythm , qrs duration > 130 ms ( mean qrs duration > 156  21 ms ) , an ejection fraction < 35% , left ventricular end - diastolic diameter > 55 mm , underwent permanent biventricular dddr pacemaker implantation . 
 a 12-lead standard electrocardiogram was performed at baseline , during right- , left- , and biventricular pacing and qtd , jtd and tdr were assessed . 
 biventricular pacing significantly reduced qtd ( 73.93  19.4 ms during bivp vs 91  6.7 ms at sinus rhythm , p = 0.004 ) , jtd ( 73.18  17.16 ms during bivp vs 100.72  39.04 at baseline p = 0.003 ) , tdr ( 93.16  15.60 vs 101.55  19.08 at baseline ; p<0.004 ) , as compared to sinus rhythm . 
 right ventricular endocardial pacing and left ventricular epicardial pacing both enhanced qtd ( rvendop 94  51 ms , p<0.03 ; lvepip 116 71 ms , p<0.02 ) and tdr ( rvendop 108.13  19.94 ms ; p<0.002 ; lvepip 
 114.71  26.1 ; p<0.05).there was no effect on jtd during right and left ventricular stimulation.conclusions:biventricular pacing causes a statistically significant reduction of ventricular heterogeneity of ripolarization and has an electrophysiological antiarrhythmic influence on arrhythmogenic substrate of dilatative cardiomiopathy . 
INTRODUCTION
METHODS
Selection of patients
Implantation of pacemaker
Protocol study
Data acquisition and electrocardiogram measurements
Statistical analysis
RESULTS
DISCUSSION
LIMITATIONS
CONCLUSIONS