Health to think

1. VentricularDyssynchronyinDilatedCardiomyopathy:TheRoleof
BiventricularPacingintheTreatmentofCongestiveHeartFailure
JUAN M.ARANDA,JR.,M.D.,RICHARD S.SCHOFIELD,M.D.,DANA LEACH,R.N.,JAMIE B.CONTI,M.D.,JAMES A.HILL,M.D.,
ANNE B.CURTIS,M.D.
UniversityofFloridaHealthScienceCenter,DivisionofCardiovascularMedicine,Gainesville,Florida,USA
Summary: Despite advances in pharmacologic therapy, the
prognosis of patients with advanced congestive heart failure
(CHF) remains poor. Many of these patients have cardiac
conductionabnormalities,suchasleftbundle-branchblockor
interventricular conduction delays, that can lead to ventricu-
lardyssynchrony(abnormalventricularactivationthatresults
indecreasedventricularfillingandabnormalventricularwall
motion). Biventricular pacing is an alternative, nonpharma-
cologictherapyunderactiveinvestigationforthetreatmentof
CHF. Resynchronization devices with transvenous leads in
the right atrium, right ventricle, and left ventricle (via the
coronary sinus) have been implanted in patients to provide
atrial triggered biventricular pacing. The use of such devices
has been associated with improvement in ejection fraction,
dP/dt,strokework,andfunctionalclass.Theproposedmech-
anisms involved in improving ventricular function with
biventricular pacing include improved septal contribution to
ventricular ejection, increased diastolic filling times, and re-
duced mitral regurgitation. This article reviews the patho-
physiologyofventriculardyssynchronyandexamineinsights
from clinical trials that are evaluating cardiac resynchroniza-
tion therapy for CHF.
Keywords:heartfailure,pacing
Introduction
Congestiveheartfailure(CHF)secondarytoleftventricular
(LV) systolic dysfunction afflicts more than 4 million patients
intheUnitedStates,withsome400,000to700,000newcases
developing each year.1, 2 Despite advances in pharmacologic
therapy with angiotensin-converting enzyme inhibitors and
beta blockers, the prognosis of patients with New York Heart
Association (NYHA) class III and IV symptoms remains
poor.3 Currently, heart transplantation is the preferred treat-
ment for end-stage CHF that is not amenable to further phar-
macologictherapyorsurgicalintervention,althoughthisther-
apy is limited by the available donor pool. Long-term results
with implantable LV assist devices and cardiomyoplasty are
notknownatthistime.Therefore,thesearchcontinuesforoth-
ertreatmentsforthesepatients.
Permanent pacing has been proposed as one such alterna-
tive. In the early 1990s, short-term studies using dual-cham-
ber atrioventricular (AV) sequential pacing with “optimized”
AV intervals showed improvement in ejection fraction and
functionalclass.4–6 OptimalAVintervalswereobtainedusing
Dopplerechocardiographytolookatthehighestmaximalve-
locity and the greatest velocity time integral over the aortic
valve during a paced ventricular rhythm. Patients with pro-
longedintrinsicPRintervalsseemedtobenefitmostfrompac-
ing.7 With a long PR interval, atrial contraction begins and
ends before the onset of ventricular contraction. There is loss
of the “atrial kick” as well as functional mitral regurgitation
when atrial pressure declines below ventricular pressure dur-
ingatrialrelaxation.WithprogrammingoftheoptimalAVde-
lay, studies found an increase in cardiac output, a decrease in
mitralandtricuspidregurgitationwithanincreaseinventricu-
larfillingtime,andanincreaseinexercisetime;4,6 however,it
should be noted that these studies were small and lacked con-
trols.Subsequentstudiesthatassessedtheuseofconventional
AVsequentialpacemakersforpatientswithdilatedcardiomy-
opathydidnotsubstantiatetheresults.8,9
While AV conduction is normal in the majority of patients
with CHF, many have prolonged QRS durations. Such under-
lyingcardiacconductionabnormalitiescanleadtoventricular
dyssynchronyorabnormalventricularactivationthatresultsin
decreased ventricular filling and abnormal ventricular wall
motion. To correct ventricular dyssynchrony, atrial-sensed
biventricularpacinghasbeenproposedasapotentialtherapy.
Inthisreview,weexplaintheconceptofventriculardyssyn-
chrony, demonstrate how it contributes to inefficient cardiac
function, explore how correction with biventricular pacing
Clin. Cardiol. 25, 357–362 (2002)
Address for reprints:
Juan M. Aranda, Jr., M.D.
University of Florida Health Science Center
P.O. Box 100277
Gainesville, FL 32610-0277, USA
e-mail: arandjm@mail-cs.med.ufl.edu
Received: May 18, 2001
Accepted with revision: November 30, 2001

2. Clin. Cardiol. Vol. 25, August 2002
may potentially improve cardiac function and symptoms, and
review the ongoing clinical trials in this area that should help
determinethepotentialvalueofthistherapy.
IncidenceandPrognosisofVentricularDyssynchrony
inHeartFailure
Ventricular dyssynchrony is defined as an abnormality in
electromechanicalcouplingthatoccursinconjunctionwithin-
terventricular conduction block or prolonged QRS duration.
The incidence of prolonged QRS in the CHF population is
substantial. Shamim et al.10 followed 172 patients with CHF
to determine whether interventricular conduction delay pre-
dicted death. Of these, 31% had a QRS duration of 120 ms or
more. Lamp et al.11 reviewed data on 271 patients referred for
heart transplantation. The incidence of a QRS ≥120 ms was
46%.Otherstudieslookingattheprognosticimplicationsofa
wide QRS have reported the prevalence to be between 27 and
53%.12,13 Itisimportanttonotethatthereisnosimplecorrela-
tion between QRS prolongation and ventricular dyssyn-
chrony. Not all patients with QRS prolongation have dyssyn-
chronypresent.Imagingstudiesthatdemonstratewallmotion
characteristics (i.e., tagged magnetic resonance imaging or
Doppler tissue imaging) are required to demonstrate that ven-
tricular dyssynchrony is present, but this problem is more
prevalentasQRSdurationincreases.14,15
Data suggest that patients with CHF with interventricular
conduction block (wide QRS complex) on a 12-lead surface
electrocardiogram (ECG) have a worse prognosis than those
with a narrow QRS complex. Gottipaty et al.16 evaluated the
resting baseline ECGs in patients enrolled in the Effects of
Vesnarinone on Morbidity and Mortality in Patients with
Heart Failure (VEST) Trial. This study assessed the efficacy
of vesnarinone in patients with class II–IV CHF. After re-
viewing some 3,654 ECGs with follow-up of 1 year, cumula-
tive survival was related to QRS duration. The relative risk of
deathinpatientswiththewidestQRSdurationwasfivetimes
greater than in those patients with a narrow QRS. QRS dura-
tion was an independent predictor of mortality in the analysis
of the VEST results. Other published reports have confirmed
these results.10, 12
PathophysiologyofVentricularDyssynchrony
With a 30 to 50% incidence of interventricular conduction
delays in patients with CHF, it is important to understand how
thisfindingcontributestofurtherdeteriorationofcardiacfunc-
tion.Grinesetal.17 studied18patientswithleftbundle-branch
block(LBBB)andnootherunderlyingcardiacdisease.Com-
pared with 10 normal patients, patients with LBBB showed
substantial delays in LV systolic and diastolic events, abnor-
mal interventricular septal wall motion, and loss of the septal
contributiontoglobalejectionfraction.
Themechanismsresponsibleforventriculardyssynchrony
that contribute to deterioration of ventricular function are
complex.InthepresenceofawideQRSorLBBB,thereisde-
layed activation of the left ventricle or, more specifically, the
lateral wall of the heart.14 This results in mechanical disorga-
nization, causing impaired systolic and diastolic function.
Delayedactivationofthelateralwalloftheheartalsoresultsin
delayed contraction of the left posteromedial papillary mus-
cle. This lag creates and prolongs the severity of mitral regur-
gitation.Asaresult,abnormalelectricalconductiongenerates
mechanicaldysfunction.Adequatefunctionoftheventricular
septum is crucial in maintaining interventricular dependence.
The late activation of the lateral wall of the heart leads to
increasing LV systolic pressures well after the interventricu-
lar septum has finished depolarizing, causing not only a de-
creased septal contribution to stroke volume, but also septal
dyskinesis, in which the septum moves away from the LV
wallduringLVcontraction.14
Lateactivationoftheleftventriclecausesdelayintheonset
ofdiastolicfilling,yetatrialactivationexperiencesnosuchde-
lay. As a result, both early passive filling in diastole and atrial
contraction occur simultaneously. Atrial activation during the
earlypassivefillingphasedecreasestotaltransmitralflowand
thusdiminishedpreloadoftheventricle(Fig.1A).Finally,mi-
tralregurgitationisaffectedbythepresenceofaninterventric-
ular conduction delay. Diastolic mitral regurgitation occurs as
358
FIG. 1 Mitral Doppler inflow pattern of a patient with dilated car-
diomyopathyandleftbundle-branchblock.ThereismergerofEand
Awaves,resultingindecreasedearlydiastolicfilling(A).Themitral
Dopplerinflowpatternofthesamepatientafterbiventricularpacing
is shown in (B). There is a separation of E and A waves, leading to
improved preload and increased left ventricular filling times.
(A)
(B)

3. J. M. Aranda et al.: Biventricular pacing in congestive heart failure
aresultofdelayedLVactivationandlateactivationofthepos-
teromedialpapillarymusclecontraction.
The hemodynamic consequences of abnormal ventricular
activation can best be summarized by work from Xiao et al.18
Using continuous-wave Doppler, Xiao analyzed the charac-
teristics of the LV pressure pulse in 50 patients with dilated
cardiomyopathyandvariousQRSdurations.Apositivecorre-
lation was found between QRS duration and overall duration
of LV contraction time. There was a negative correlation with
the peak rate of rise in LV pressure. The data suggest that the
widertheQRScomplex,thelongertheLVcontractionandre-
laxation times, resulting in poorer LV systolic performance.
Prolongedisovolumiccontractionandrelaxationtimesinduce
aproportionatedecreaseinLVfillingtimeinpatientswiththe
longestQRSdurations.Xiaonotedthatleftaxisdeviationwas
associated with the longest QRS durations and thus more se-
vereelectromechanicalalterations.
Ventriculardyssynchronyhasusuallybeendescribedinpa-
tientswithLBBB,sincetheyhavedelayedactivationoftheLV
freewall.Wilenskyetal.19 reportedrightbundle-branchblock
(RBBB) to be rare in a group of patients with dilated car-
diomyopathy (9%). However, it was associated with left-axis
deviationintwothirdsofcases,indicatingaprobableassocia-
tionwithleftanteriorfascicularblock.Thus,thepossibilityex-
ists that patients with RBBB and left-axis deviation also may
experiencesomedegreeofventriculardyssynchrony.
Given the abnormal cardiac function that can be demon-
strated as a result of interventricular conduction delay and the
poorprognosisassociatedwithit,therehasbeeninterestinus-
ingbiventricularpacingtoresynchronizecardiacactivationas
apotentialtreatmentforCHF.
CardiacResynchronizationTechnology
Cardiacresynchronizationinvolvessensingoftherightatri-
um followed by simultaneous pacing of the right and left ven-
tricles. Standard atrial and ventricular pacing leads are placed
in the right atrium and the right ventricle. An active fixation
ventricular lead is often used in the right ventricle so that right
ventricular (RV) sites other than the apex can be used for pac-
ing, if such alternative sites will allow optimal separation be-
tweentheRVandLVleads.Initially,epicardialLVleadswere
necessary to pace the left ventricle. More recently, special
leadshavebeendesignedthatareadvancedintoabranchofthe
coronarysinustopacetheleftventricle(Fig.2).
Unfortunately, coronary venous anatomy is not as predic-
table as the coronary arterial anatomy. To visualize the coro-
naryvenousanatomy,acoronarysinusvenogramisperformed
prior to placement of the lead. Using a specially designed
sheathtoaccessthecoronarysinus,aballoon-tippedcatheteris
advanced into the os of the coronary sinus, and the balloon is
inflated. Contrast is injected in both the left anterior oblique
and right anterior oblique projections to define the venous
anatomy so the operator can decide in which location to best
placethelead.ItisofimportancetoplacetheLVleadinoneof
the cardiac veins that supplies the LV free wall. Butter et al.20
have reported improved hemodynamic outcomes when stim-
ulatingtheLVfreewallcomparedwithstimulatingtheLVan-
teriorregion.Thisisconsistentwiththehypothesisthatstimu-
lation of a delayed LV region can restore synchronous LV
contraction and thus improve systolic function. Venogram
complications include coronary sinus dissection, perforation,
and thrombosis, as well as the inherent risks of using intra-
venous contrast. In addition, access to the coronary sinus can
bedifficulttoachieveinpatientswithdilatedcardiomyopathy,
giventhedistortedanatomy.
After removal of the balloon-tipped catheter, the coronary
sinus lead is advanced through the sheath and manipulated
into a branch of the coronary sinus. Ideally, a lateral or pos-
terolateral branch is used because these locations allow the
greatest separation of the tips of the LV and the RV leads.
Placement of the lead in the desired location may be limited
by such factors as tortuosity of the coronary venous system,
poor pacing thresholds, diaphragmatic stimulation, or lead
stability. Even with an adequate lead position, lead dislodg-
ment is also a risk when removing the coronary sinus sheath.
HemodynamicEffects
Data regarding the hemodynamic effects of atrial-sensed
biventricularpacinginpatientswithLVdysfunctionandinter-
ventricular block are encouraging. Leclercq et al. studied the
acute benefits of multisite pacing with optimized AV delay
and biventricular pacing in patients with class III–IV CHF.21
Theauthorsstudied18patientswithCHFandmajorinterven-
tricular conduction block (QRS duration 170 ± 37 ms). Using
359
FIG. 2 Lateral chest x-ray of a patient with a biventricular pace-
maker. Pacing leads can be seen in the right atrium (RA), the right
ventricle (RV), and the coronary sinus (CS) leading to a left posteri-
or vein of the heart.

4. Clin. Cardiol. Vol. 25, August 2002
apulmonaryarterycatheter,theymeasuredhemodynamicpa-
rameters in different pacing modalities: atrial pacing (AAI),
RVdualchamber(DDD)pacing,andbiventricularDDDpac-
ing using a transvenous coronary sinus lead to pace the left
ventricle. Baseline data consisted of an average PR interval of
221±51mswithLBBBmorphologyinallcasesandleft-axis
deviation in 14 patients. Biventricular DDD pacing signifi-
cantly reduced QRS duration compared with the reference
mode (AAI pacing) or RV DDD pacing (p<0.01). There also
were significant benefits related to cardiac output, mean pul-
monary capillary wedge pressure, and reduction in V wave
(mitralregurgitation).
Kass et al. looked at aortic and LV pressures in 18 patients
with CHF (QRS duration 157 ± 36 ms) during atrial syn-
chronous ventricular pacing (VDD) at varying sites and AV
delays.22 Left ventricular free wall pacing raised dP/dtMAX by
23.7 ± 19% and pulse pressure by 18.0 ± 18.4% (p<0.01).
Compared with RV pacing, biventricular pacing yielded less
change in dP/dt (+12.8 ± 9.3%) than LV free wall pacing.
Pressure volume loops in a subset of patients revealed in-
creased stroke work and lower end-systolic volumes with LV
free wall and biventricular pacing. With respect to AV delay,
LV end-diastolic pressure and dP/dt declined slightly as AV
delay neared 120 ms and fell further as shorter delays were
programmed.EnhancementofdP/dtfromLVfreewallpacing
andbiventricularpacingwasobservedatAVintervalsbetween
100 and 160 ms. Atrioventricular delay had less influence on
LVfunctionthanpacingsite.
Different RV pacing sites have been analyzed as a way to
correct ventricular dyssynchrony.22, 23 It appears that there is
no hemodynamic advantage in pacing the RV apex versus the
RV septum in patients with CHF and conduction abnormali-
ties.22 Bothleftfreewallpacingandbiventricularpacinghave
demonstratedacutebenefitsoveranyRVpacingsite.
SimilarresultshavebeenreportedbyAuricchioetal.from
the Pacing Therapies for Congestive Heart Failure Trial
(PATH-CHF).24 ThePATH-CHFStudyisasingle-blind,ran-
domized, crossover, controlled trial designed to evaluate the
effects of pacing at different sites in the ventricles on acute
hemodynamic function and to assess long-term clinical ben-
efitinpatientswithmoderatetosevereCHFandinterventric-
ular conduction block. Although the final results from this
study have not been presented, information is available on
acute hemodynamic changes from a subset of patients.
Twenty-seven patients with severe CHF and LV conduction
delay received endocardial pacing leads in the right atrium
and right ventricle and an epicardial lead on the left ventricle.
Patients in normal sinus rhythm were stimulated in the right,
left, or both ventricles (biventricular pacing) at various AV
delays. Maximum LV pressure derivative (dP/dt) and aortic
pulse pressure were measured at baseline and during acute
pacing. Biventricular and LV pacing increased dP/dt and
pulse pressure more than RV pacing (p<0.01), whereas LV
pacing increased dP/dt more than biventricular pacing (p<
0.01). Pulse pressure and dP/dt also increased at a patient-
specificoptimalAVdelayin20patientswithwideQRSdura-
tions (180 ± 22 ms). Short AV delays decreased dP/dt and
pulse pressure in five patients with narrower QRS durations
(128 ± 12 ms).
Biventricular pacing not only seems to improve hemody-
namic parameters, but studies suggest it also improves ven-
tricular function. Kerwin et al.25 recently reported the effects
of biventricular pacing on interventricular dyssynchrony and
ventricularfunction.Thirteenpatientswithdilatedcardiomy-
opathy and interventricular conduction delay underwent
multiple gated equilibrium blood pool scintigraphy studies.
Phase image analysis was applied and interventricular RV/
LVsynchronywascomputedinsinusrhythmandduringatri-
al-sensedbiventricularpacing.Thedegreeofinterventricular
dyssynchrony during normal sinus rhythm correlated in-
versely with ejection fraction (r = 0.69, p0.01). During
biventricular pacing, LV ejection fraction improved from
17.2 ± 7.9 to 22.5 ± 8.3% (p0.0001). Coincidentally, with
theincreaseinejectionfraction,therewasanimprovementin
interventricular synchrony during biventricular pacing (r =
0.86, p0.0001).
Themechanismofimprovedhemodynamicsandventricu-
lar function with biventricular pacing is not clear. It has been
suggested that biventricular pacing may improve systolic
function by altering the segmental LV and interventricular
septal contractile sequence in patients with decreased LV
function.26 Thisallowstheseptumtoincreaseitscontribution
tostrokevolumeandventricularfunction.Simultaneousacti-
vation of both ventricles yields longer filling times by allow-
ing the left ventricle to complete contraction and begin relax-
ation earlier. The earlier diastolic filling phase occurs before
atrial contraction, as evidenced by echocardiographic Dop-
pler analysis of transmitral flow. There is separation of E and
Awaveswhenbiventricularpacingisperformed(Fig.1B),as
opposed to merged E and A waves when no pacing is per-
formed in the presence of an interventricular conduction de-
lay (Fig. 1A). This separation improves preload conditions.
Finally, early activation of the lateral wall of the left ventricle
leads to early activation of the papillary muscles, decreasing
presystolic mitral regurgitation.
ClinicalTrials
Itisclearthatacuteatrial-synchronousbiventricularpacing
improves cardiac function in patients with dilated cardiomy-
opathy and interventricular conduction block. The question
that must be asked is whether such pacing improves function-
alcapacity,exerciseoxygenconsumption,andoverallsurvival
intheCHFpopulation.
A small, nonrandomized evaluation of patients receiving
cardiac resynchronization devices has shown improvement in
symptoms and exercise tolerance.27 The INSYNC OUS (out
of the United States) Study is a larger, nonrandomized, pro-
spective, multicenter study conducted in Europe and Canada
thatwasdesignedtoexaminethesafetyandefficacyofamul-
tisite pacemaker with transvenous LV pacing leads placed via
the coronary sinus as a supplemental treatment for refractory
CHF.Preliminarydataon103patientswithclassIII–IVCHF,
360

5. J. M. Aranda et al.: Biventricular pacing in congestive heart failure
ejectionfraction35%,andQRSduration150ms,whoun-
derwent implantation of the INSYNC multisite pacemaker
system, have been published.28 At 1- and 3-month follow-up,
mean NYHA functional class was significantly lower, Min-
nesotaLivingwithHeartFailureQualityofLifequestionnaire
scores were significantly improved, and the distance covered
during the 6-min walk test increased. These favorable results
have been maintained for up to 12 months of follow-up. The
study was not powered to determine a difference in mortality,
buttotalmortalityat6monthswasreportedtobe16.6%.
Results from the Multisite Stimulation in Cardiomyopathy
(MUSTIC)trialwererecentlypublished.29 TheMUSTICtrial
is a single-blind, crossover trial in which 48 patients with
NYHA class III CHF and QRS durations 150 ms were en-
rolled. All patients received biventricular pacing devices and
were randomized initially to atrial-synchronous biventricular
pacingornopacing.After3months,thepatientswerecrossed
over to the other treatment arm for 3 months. After 6 months,
patients were programmed to their preferred pacing mode for
the next year of follow-up. Patients showed significant im-
provement in the distance covered in a 6-min walk test,
NYHA class, quality of life, and peak VO2 during biventricu-
lar pacing. Those who received biventricular pacing were less
likely to be hospitalized than those who did not undergo pac-
ing. It is interesting that at the end of the second crossover pe-
riod(6months),85%ofpatientschosecardiacresynchroniza-
tion(pacingon)astheirpreferredpacingmodality.
Currentmultisitepacingtrialsshouldhelpclarifytheroleof
biventricular pacing in CHF. The Multicenter INSYNC Ran-
domized Clinical Evaluation (MIRACLE) is a prospective,
randomized, double-blind trial of biventricular pacing recent-
ly published.30 It is designed to demonstrate the safety and ef-
ficacy of cardiac resynchronization therapy in patients with
CHF. Patients with NYHA class III–IV CHF, QRS durations
≥130 ms, ejection fractions ≤35%, and LV end-diastolic di-
mensions ≥55 mm were eligible for enrollment. All patients
received the resynchronization device, with half randomized
to biventricular pacing and the other half randomized off for
the first 6 months. After the initial study period, all patients
were programmed on and followed. Compared with patients
who were randomized to the “off” mode, patients with biven-
tricular pacing had improvement in 6-min hall walk distance,
NYHAclass,andqualityoflife.Therewasalsoimprovement
insecondaryendpointssuchastotalexercisetime,reductionin
LVdiastolicdiameter,andimprovementinejectionfraction.
Inadditiontothebiventricularpacingtrials,thereareongo-
ing studies of biventricular pacing using implantable cardio-
verterdefibrillators(ICDs),suchastheVentakCHFStudyand
the INSYNC ICD Study. The CONTAK CD/EASYTRAK
Continued Access Study is a prospective, randomized trial to
examine the safety and efficacy of biventricular pacing in pa-
tients with standard indications for an ICD, using a steroid-
eluting,over-the-wiresystem.31,32 Patientsinthestudyhadthe
ICD implanted at the time of initial presentation with an indi-
cation for an ICD. Randomization occurred after a 1-month
stabilizationperiodforCHFtherapy.Primaryendpointsofthe
trial were all-cause mortality, hospitalization for CHF, and re-
currentventriculartachycardia/fibrillationevents.Preliminary
results showed no difference in the primary outcome between
biventricular pacing and RV pacing alone. The study was
probablyunderpoweredfordetectingsignificantdifferencesin
the primary endpoint, particularly because many of the pa-
tientshadimprovedtoclassIIbythetimeofrandomization.In
fact,only58%ofpatientsintheCONTAKCDStudyhadclass
IIICHFcomparedwith90%inMIRACLE.
The Comparison of Medical Therapy, Pacing and Defib-
rillation in Heart Failure (COMPANION) Study, another im-
portantclinicaltrialinprogress,iscomparingmedicaltherapy,
biventricular pacing, and biventricular ICDs in patients with
CHF. The COMPANION trial will attempt to prove that opti-
mal pharmacologic therapy combined with biventricular pac-
ingaloneorbiventricularpacingwithdefibrillationissuperior
to medical therapy alone. This open-label, prospective, multi-
center clinical trial will randomize patients with CHF and
wideQRStomedicaltherapy,medicaltherapywithbiventric-
ular pacing without defibrillation, or medical therapy plus
biventricular pacing therapy with defibrillation. The primary
endpointwillbecombinedall-causemortalityandhospitaliza-
tion for CHF. Potential candidates for this cardiac resynchro-
nizationtrialcannothaveindicationsforpacingorICDs.
Conclusion
Ventricular dyssynchrony is often present in the CHF pop-
ulation and may contribute to deterioration of cardiac func-
tion. Preliminary studies suggest a role for biventricular
pacing in patients with CHF with bundle-branch block or in-
terventricular conduction delays; however, many questions
remain unanswered. Will biventricular pacing improve sur-
vival in the absence of defibrillation? What is the optimal site
for cardiac resynchronization in the left and right ventricles?
What are the long-term hemodynamic consequences and
structural sequelae (i.e., effects on remodeling) of the tech-
nique? Is there the potential to increase the ischemic burden
involvingperi-infarctregionsorchronicallyischemicregions
in patients with ischemic cardiomyopathy with this tech-
nique?Ongoingclinicaltrialswillprovideinsightintothisdif-
ficultproblemfacingpatientswithrefractoryCHF.
Acknowledgments
The authors wish to thank Melanie Fridl Ross, M.S.J.,
E.L.S,foreditorialassistanceandLisaA.Hamilton,M.A.,for
manuscriptpreparation.
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