Biventricular
Pacing in
Congestive Heart Failure
Balbir Singh,
MD,
DM.
Address for correspondence: Balbir
Singh, MD, DM., Consultant Cardiologist, Batra Hospital, New Delhi,
India.Email:
drbalbir@vsnl.com
Congestive heart failure (CHF) is a common,
debilitating and usually lethal condition responsible for enormous
burden on health care. The recent trials have shown improvement in
morbidity and mortality with ACE inhibitors and beta blockers1,2,3. However,
despite this the overall prognosis remains dismal. The other
alternative of cardiac transplantation has several limitations
including the donor organ scarcity. In view of this gloomy prognosis,
several alternative strategies are being explored, one of which has
been pacing for heart failure. In this form of therapy pacing is used
in absence of the conventional bradyarrhthymic indications with
an attempt to lead to optimization of AV delay and co-ordination of
ventricular contraction.
In 1990, Hochleitner et al4 reported
clinical improvement in patients with severe heart failure awaiting
cardiac transplantation with implantation of a physiologic dual-chamber
pacemaker (pacing at right atrium and right ventricle) with a
programmed short atrioventricular (AV) delay. Brecker et al5 in 1992
reported similar observations. However, in a randomized cross over
design,with larger number of patients there was no significant
improvement in the NYHA class or ejection fraction6. Sack et al7 and Guide et
al
reported similar negative results. Consequently, it is difficult to
advocate dual chamber pacing for heart failure management.
The reasons for the discrepancies in the results of these studies is
possibly due to the detrimental effect of pacing induced broadening of
the QRS complex duration in severe ventricular disease resulting from
Right Ventricular (RV) apical pacing offsetting the beneficial effect
of increased ventricular filling time. As a result the focus has now
shifted to Left Ventriuclar (LV) or biventricular (BiV) as opposed to
RV pacing supplemented with the lessons learnt from the optimization of
the AV delay.
Electromechanical Cardiac Synchrony
The association of asynchronous ventricular contraction with
ventricular dysfunction has been recognized for many years. In recent
years the presence of left bundle branch block (LBBB) has been shown to
correlate with decreased LV function, reduced peak dp/dt. LBBB results
in asynchronous ventricular contraction with the LV lateral wall
contracting much later that the inverventricular septum in addition
there is an RV-LV asynchrony with RV contracting earlier than LV.
The presence of conduction disturbances is seen in 20-30% of the
patients with congestive heart failure and contributes to the worsening
of symptoms due to improper co-ordination of LV contraction.
Cardiac
Resyndronisation Therapy (CRT)
CRT aims at 3 different levels (a) AV level (b) intraventricular level
(c) interventricular level. At present this is achieved by pacing or
sensing the right atrium, pacing the right ventricle (near the
interventricular septum) and pacing the left ventricle (using the
coronary venous branches), also called biventricular pacing.
Left
Ventricular Lead Design
The present LV leads have lower profile with preformed curves. Most of
the leads followed the same conventional central–stylet technology,
with curves being fashioned to negotiate the variabilities in cardiac
vein anatomy. Recently over-the-wire lead deployment systems have
been developed (Easytrak – Guidant Corporation, St. Paul, MN) and have
the procedure like an angioplasty. Overall, the success rate for
implantation of left-sided leads ranges from 75 to 93%.
Implantation
Technique
The implantation of biventricular pacing is more technically
challenging than a dual chamber pacing for the reason of placing the LV
pacing lead appropriately. Prior to the introduction of the endocardial
LV pacing leads, surgical implantation of these leads epicardially was
the norm.
It is now possible to pace by entering the cardiac veins which are
approached through the coronary sinus and obtain a reasonable threshold
in one of the cardiac veins. The presence number, location, size and
tortousity of posterior and lateral branches is usually variable. The
coronary veins are
thus studied by contrast injections with a balloon inflated catheter
within
the coronary sinus and subsequently the lead can be placed precisely.
The
posterolateral veins yield the best haemodynamic outcome and are the
ones
targeted for the placement of LV leads.
The findings from the PATH – CHF trial9
suggest that increases in pulse pressures and DP/DT max were maximum at
the mid lateral epicardial pacing sites compared with other regions of
the left ventricle, consequently posterolateral sites are currently
targeted for left
ventricular pacing. Kass et al10 in 1999
demonstrated that LV single site pacing was equal or superior to
biventricular pacing.
Further studies would be needed to demonstrate whether LV pacing is
equivalent.
It is possible that LV pacing may not maintain LV/RV syndrony due to
earlier
pacing of the LV site.
Identifying
patients likely to respond
The primary variable has been the QRS duration – an electrial marker
for spatially dispersed mechanical activation.8 A QRS duration of more than 150ms with class 3
or 4 congestive heart failure and low left ventricular ejection
fraction is an accepted indication for left ventricular pacing. In
presence of QRS
duration of 120-150msec, certain echo – doppler variables must be noted
(such as Q to aortic flow velocity or interventricular dysynchrony – Q
to aortic flow – Q to pulm flow) to obtain the maximum benefit.
Acute Clinical
Studies
Several studies have studied the effects of BiV pacing on the acute
haemodynamics. It has been seen that BiV pacing improves cardiac output
and enhances ventricular systolic function as assessed by maximal rate
of pressure rise and pressure volume loops. Furthermore this
improvement in LV systolic function occurs while concomitantly reducing
myocardial oxygen consumption..
Chronic Clinical
Studies
Three placebo control studies have been completed – the PATH – CHF trial9, the MUSTIC trial11
and
the MIRACLE trial12. In the PATH-CHF
study, patients
were first assigned to four weeks of active pacing (LV or BiV), then
four
weeks of no pacing, then a second four-week active pacing
period-continued for the ensuing year. This was a single-blind study
and required surgically implanted leads and two stimulators.
Importantly, exercise performance (e.g., maximal oxygen consumption)
rose significantly only during the two periods of active pacing. This
finding in the third month (after a month of no-pacing) was somewhat
more difficult to ascribe to a placebo effect.
The recently published MUSTIC study11 used
a cross-over design, with patients randomized to three months’
stimulation on or off and the mode then switched for the second
three-month period. In sinus rhythm patients, exercise capacity
improved olnly during active treatment (+23% in 6-min walking distance,
p < 0.001), improved symptoms (32% in quality-of-life questionnaire,
p < 0.001) and increased maximal oxygen consumption (+8%, p <
0.03). Interestingly, this study did not observe a placebo effect. A
separate component of this study evaluated patients with chronic atrial
fibrillation, each patient under-going AV nodal ablation prior to
receiving a BiV stimulation system. Intention-to-treat analysis failed
to reveal significant differences between pacing on and off data,
although limitations due to study design and loss of effective pacing
in several subjects contributed to this. In the subset of subjects in
which
pacing was effectively delivered, the results suggested improvement,
but
this needs more definitive testing.
The recently completed MIRACLE trial12 is
the largest study to date. Preliminary data have been reported and a
full publication is pending. This six-month parallel-design trial
randomized 228 patients to resynchronization therapy and another 225
patients to a placebo control arm. All patients were in normal sinus
rhythm and were stable
NYHA functional class III or class IV. The primary findings showed an
improvement
in the 6-min walk test, quality-of-life score, and NYHA functional
class
(a combined end point was also examined). Secondary end points were
also
assessed in a subset of patients, and the data support a diminished
diastolic
and systolic chamber size in the active resynchronization treatment but
not in the placebo group. Mortality was <10% in both treatment arms
at six months. Rehospitalization rates and number of days hospitalized
were
both significantly and substantially lower in the active treatment
group.
The investigators reported a placebo effect with respect to quality of
life but not for exercise or cardiac-function parameters.
Unresolved
Issues, Future Directions
Clearly, there are major important questions about whether there is a
sustained benefit on morbidity and reduced hospitalization and whether
there is
a favorable effect on overall and cardiac mortality. In this regard, it
is important that the ongoing trails such as COMPANION, which are
addressing these key questions, proceed to completion so that the role
of this therapy can be properly and fully evaluated. The mortality
impact of resynchronization may ultimately be tied in with ICDs,
particularly if the results of ongoing multicenter trials show survival
benefits from such devices in HF.
Another question relates to the prospective identification of
responders. New methods examining regional wall motion hold promise for
generating a dyssynchrony index that could improve on current, more
indirect methods. The optimal method of therapy itself is unresolved.
As noted, questions remain as to whether BiV stimulation is needed,
whether multisite left-heart stimulation would enhance the efficacy,
or, if an RV lead is to be placed, where the optimal location is and
what the best timing delay is between RV and LV stimulation.
A large unresolved question is whether this therapy is going to be
useful in patients with atrial fibrillation. Some studies have
suggested utility, although larger trial data remain inconclusive.
Unlike the sinus rhythm patients, in which there is some degree of
freedom in the AV delay to optimally time a resynchronization effect,
the AV node in atrial fibrillation patients is generally ablated, and
then patients are treated using a BiV pacing mode. This involves
regularization of the heart rate with rate-responsive generators, as
well as activation of both lower chambers. Rate response serves to
simulate normal effects of autonomic tone, but it is not a perfect
replacement for physiologic control. Furthermore, in patients without
an existing conduction delay, BiV pacing may not yield as good a
response as
that with His-Purkinje conduction. More studies are clearly needed in
these
patients.
Finally, the existing evidence indicating deterioration of systolic
function and energetic efficiently with pacing-induced dyssynchrony
suggests that standard RV apex pacing in individuals with cardiac
failure may not be the ideal approach. In patients with
cardiodepression but a narrow QRS complex and normal intraventricular
conduction who need pacing for rate control, a BiV system may prove
superior, but this clearly needs to be tested.
References
1. Flather MD, Yusuf S, Kober L, et al. Long-term
ACE-inhibitor therapy in patients with heart failure or
left-ventricular dysfunction: a systematic overview of data from
individual patients. ACE-Inhibitor Myocardial Infarction Collaborative
Group. Lancet 2000;355:1575-81
2. Bristow MR. Beta-adrenergic receptor blockade
in chronic heart failure. Circulation 2000;101:558-69
3. Cohn J. Structural basis for heart failure:
Ventricular remodeling and its pharmacological inhibition. Circulation
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4. Hochleitner M, Hortnagl H, Ng CK, et al.
Usefulness of physiologic dual-chamber pacing in drug-resistant
idiopathic dilated cardiomyopathy. Am J Cardiol 1990;66:198-202
5. Brecker SJ, Xiao HB, Sparrow J, et al. Effects
of dual-chamber pacing with short atrioventricular delay in dilated
cardiomyopathy. Lancet 1992;340:1308-1312
6. Gold MR, Feliciano Z, Gottlieb SS, et al.
Dual-chamber pacing with a short atrioventricular delay in congestive
heart failure : A randomized study. J Am Coll Cardiol 1995;26:967-937
7. Sack S, Franz R, Dagres N, et al. Can
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selected patients with severe congestive heart failure? Am J Cardiol
1999;83:124D-129D
8. Murkofsky RL, Dangas G, Diamond JA, et al. A
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indicator of left ventricular dysfunction. J Am Coll Cardiol
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Abraham WT. Rationale and design of a
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