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Cardiac Resynchronization Therapy for the Treatment of Heart Failure

Vikrant Nayar; Peter J Pugh
Expert Rev Cardiovasc Ther. 2010;8(2):229-239.

Abstract and Introduction

Abstract

Heart failure is posing an increasing burden on healthcare systems around the world, a consequence of increased survival from acute coronary syndromes and lifeprolonging medications. Cardiac resynchronization therapy has become a ratified and established therapy for heart failure to reduce both the morbidity and mortality of the
condition. Its prophylactic role in patients who have minimal symptoms to delay future deterioration is a novel development. The indications for this therapy continue to
evolve, mainly as a result of company-sponsored multicenter trial data aimed at broadening its usage. Uncertainty remains on how to accurately identify individuals who
will respond to resynchronization therapy and how best to manage patients following device implant.
Introduction

As more people survive acute coronary syndromes with damaged myocardium, and as pharmacological interventions improve prognosis, the prevalence and economic
burden of chronic heart failure has been increasing and is set to rise further.[13] However, survivors bear a morbidity burden that is associated with a significant reduction
in quality of life, often with a protracted period of deteriorating health and functional limitation prior to death. Beyond drug therapy, further treatments have been sought to
improve quality of life and delay functional deterioration. In the past decade, cardiac resynchronization therapy (CRT) through the implantation of biventricular pacemakers
has been shown to offer significant incremental benefit in optimally medicated patients. In this review, we discuss the applications of this relatively new technology and
discuss possible future directions.

Background & Epidemiology

When normal cardiac conduction is impaired, contraction becomes disorganized, with loss of synchrony between atria and ventricles, between ventricles and within
ventricles. Individuals with bundle branch block (BBB) who have normal contractile function are usually asymptomatic despite attenuated myocardial performance.[4,5]
By contrast, BBB becomes clinically important in patients with impaired contractile function, in whom cardiac efficiency becomes further compromised. This is particularly
important when left BBB (LBBB) is present; the left ventricle (LV) depolarizes after the right ventricle (RV) but, more importantly, the lateral wall of the LV depolarizes and,
thus, contracts later than the septal aspect. This discordance results in smaller stroke volume and lower cardiac output at the expense of greater energy expenditure from
the failing heart.
Conduction disease is common among heart failure patients: PR prolongation of more than 200 ms is observed in 2047% of patients, while QRS above 120 ms is seen in
38% of patients with severe symptoms and 24% of patients with impaired LV function.[6,7] Among patients hospitalized with heart failure in the UK, 12% have LBBB.[8] The
appearance of BBB often occurs as myocardial disease progresses, and both QRS duration and progressive QRS prolongation are strong predictors of early demise.[9]

Implantation Technique
Cardiac resynchronization is achieved by implantation of a pacemaker with leads attached to right atrial and RV endocardium and to LV epicardium via a coronary vein.
This allows stimulation of both ventricles and of opposing walls of the LV to produce simultaneous contraction, restoring atrioventricular (AV), interventricular and
intraventricular synchrony.
The art of accessing the coronary sinus with the LV lead has been made easier through the development of specifically designed sheaths and preshaped catheters. The
guide-catheter is positioned at the os of the coronary sinus and a hydrophilic guidewire is passed into the coronary veins; the guide-catheter is then tracked over the wire.
Contrast venography may be used to delineate the anatomy of the venous system (Figure 1) and allow selection of an appropriate tributary vein, usually overlying the LV
lateral wall (Figure 2). Electrical pulse generation within the vein results in epicardial LV stimulation, allowing the LV to be depolarized from two separate points, that is, the
RV and the epicardial LV pacing site.

Figure 1.

Retrograde venogram of coronary veins. Postero-anterior projection. A balloon-tipped catheter occludes the coronary sinus during contrast injection.

Figure 2.

(A) Posteroanterior and (B) lateral chest radiographs showing postero-lateral position of left ventricular lead.

Dyssynchrony
The loss of coordinated myocardial contraction that occurs as a result of conduction delay is referred to as dyssynchrony and may be evaluated in a number of ways,
usually involving echocardiography. An assessment of dyssynchrony is usually undertaken prior to CRT in order to identify patients who are likely to improve and avoid

implanting a pacemaker in those unlikely to benefit. Broadly, three different forms of dyssynchrony are assessed.
Atrioventricular dyssynchrony is present when the AV conduction does not promote optimal diastolic filling of the LV. In essence, the PR interval is too long, even if within
the normal range, and allows atrial systole to end well before ventricular systolic contraction. This results in late diastolic mitral regurgitation and abbreviated passive LV
filling. In practice, assessment of AV synchrony alone is insufficient to select patients for therapy but is important postprocedure when optimizing pacing parameters.
Interventricular synchrony is quantified by measuring the delay between systolic contraction of the two ventricles. This is most easily assessed by measuring the time from
onset of the QRS complex to the start of flow across the semilunar valves the aortic and pulmonary pre-ejection periods (A-PEP and P-PEP, respectively).
Interventricular mechanical delay is determined from the difference between A-PEP and P-PEP. Prolonged delay between ventricles is associated with a poorer prognosis
and appears to be an important predictor of response to CRT.[10]
Investigating intraventricular dyssynchrony has developed as an art as much as a science, with a myriad of techniques now described. The most frequently used methods
employ tissue Doppler imaging (TDI) to measure time to peak systolic contraction of two or more LV myocardial segments and to determine the delay between opposing
segments. Numerous variations of this approach have been described, as well as alternative techniques, including M-mode and 3D echocardiography, speckle tracking,
radionuclide imaging and MRI.
The various methods of echocardiographic assessment of dyssynchrony have recently been extensively reviewed.[11] With so many techniques to choose from, it often
seems possible to find segmental dyssynchrony in almost any patient with broad QRS, if only one looks hard enough. It is therefore important to remember that, even
where dyssynchrony is demonstrated, it is only of relevance if it impacts upon cardiac performance. This may be assessed by measuring the 'global markers' of
dyssynchrony, such as A-PEP, the speed of rise in LV pressure (dP/dt) and, most importantly, total isovolumic time and cardiac output.[12] If measurable segmental
dyssynchrony has little impact on cardiac performance, then neither will resynchronization.

The Evidence
The hypothesis that LV function might be improved by restoring a 'normal' QRS interval in a ventricle affected by BBB was first tested in animal studies in the 1980s and
supported by a better understanding of the effect of BBB on the human heart.[13,14] The idea was first translated into clinical practice with the implant of a four-chamber
pacing system in a 54-year-old patient with heart failure and gross disturbance of cardiac conduction.[15]
A large number of studies have now been undertaken to evaluate the clinical effects of CRT in patients with heart failure. The most important of these are summarized in .
The earliest, Pacing Therapies in Chronic Heart Failure (PATH-CHF) was a groundbreaking and hypothesis-generating trial, initially reported in 1999,[16] with long-term
data published in 2002.[17] Among 41 patients, optimum pacing mode was selected for each individual from atrio-biventricular, atrio-univentricular (RV) or atriouniventricular (LV), following initial hemodynamic assessment and then a short crossover period. Pacing was achieved by implant of two separate pacemakers; there was
no inactive treatment arm. The trial was initiated before the advent of transvenous-placed LV leads, which were positioned via thoracotomy (apical to mid-lateral in 27,
anterior in 14). After 12 months, subjects had a significant improvement in exercise capacity from baseline regardless of the selected mode of pacing. Optimum pacing
was biventricular in 12, univentricular (LV) in 13 and univentricular (RV) in four.
Table 1. Inclusion criteria and principal findings of the main clinical trials of cardiac resynchronization therapy.

TreatPatients ment
Design
(n)
duration
(n)

Trial

Year

PATHCHF

1999, 41
2002

MUSTIC

MIRACLE

2001

2002

MIRACLE2003
ICD

ContakCD

2003

MIRACLE2004
ICD II

COMP-

58

453

369

490

186

4 weeks
(41)

Crossover

12
months
(29)

Open-label

3
months

6
months

TreatControl
ment

LVEF %
NYHA
Sponsor
entry
class
company
criterion
(n)
(mean)

QRS ms
entry
criterion
(mean)

Echo
evidence Significant
of dystreatment effects
synchrony

CRTP

No
control

Guidant
III/IV
(IN, USA)

120
(175)

No

CRT-P,
no
pacing

ELA
Medical
(France), III
Medtronic
(UK)

Randomized,
CRTsingle-blind,
P
crossover

Randomized,
CRTdouble-blind,
P
parallel

CRT-P,
no
pacing

6
months

Randomized,
CRTdouble-blind,
D
parallel

CRT-D,
no
pacing

3
months
(22)

Randomized, CRTdouble-blind, D
crossover

CRT-D,
no
pacing

6
months
(279)

Randomized,
double-blind,
parallel

6
months

Randomized,
CRTdouble-blind,
D
parallel

16

CRTP
Randomized, (617),

CRT-D,
no
pacing

Medtronic III/IV

NS (21)

<35 (23)

35 (22)

35 (24)

Guidant

35 (21)

Medtronic II

[16,17]

MVO2 1.8
ml/kg/min
6MWD 30 m (8%)

MVO2 8%

Medtronic III/IV

I/II
(63)
III/IV
(227)

End
points un- Ref.
changed

35 (25)

>150
(174)

1320
(1665)

130
(164)

120
(158)

130
(1665)

120

No

6MWD 23%
MLHF 9
Hospitalizations
47%

[18]

No

6MWD 29 m (9%)
LVEF 4.4%
MLHF 9
Hospitalizations
47%

[19]

No

LVEF LV
MVO2 1 ml/kg/min dimensions
Hosp MLHF 6.5
italization
NYHA class
rate

[20]

No

MVO2 0.8
ml/kg/min%
LVEF 2.3%
LVIDS 3.3 mm

No

LVEF 3%
LVESV 28 ml

All-cause

NYHA
MLHF

MVO2,
6MWD

[21]

[46]

ANION

CARE-HF

RETHINQ

2004

2005

2007

1520

813

172

REVERSE 2008, 610

2009

MADITCRT

2009

1820

months

open-label,
parallel

CRTD
(595)

OPT

Guidant

2.4
years

Randomized,
CRTopen-label,
P
parallel

OPT

6
months

Randomized,
CRTdouble-blind,
D
parallel

St Jude
CRT-D,
(MN,
copacing
USA)

Randomized, CRTdouble-blind, P
parallel
(104),
CRTD
(506)

CRT-P,
CRT-D,
no
pacing

12
months
(610)

III/IV

Medtronic III/IV

NS

35 (21)

35 (26)

(160)

120
(160)*

No

Yes (if
QRS <150
ms)

[22]

death/hospitalization
34%

LVEF 3.7%
Death/CV
hospitalization 16%
(HR: 0.63)
Mortality 10%
(HR: 0.64)
LVESVi 18 ml/m2
MLHF 9

[23]

MVO2
III

35 (26)

I/II

40 (27)

<130
(107)
120
(1545)

6MWD
LVEF
LVESV

Yes

No

LVEF
LVESVi 17 ml/m2
Heart failure
hospitalization (HR:
0.47)

2 years
(262)

Heart failure
worsening 15%
6MWD
Heart failure
MLHF
hospitalization/death
(HR: 0.38)

2.4
years

LVEF 8%
Death/health
failure events 8%
(HR: 0.66)
Mortality
Heart failure event
9% (HR: 0.59)
LVESV 39 ml

Randomized,
CRTopen-label,
D
parallel

ICD

Boston
Scientific
(MA,
USA)

I/II

30
(294)

1320
(NS)

No

[27]

[48,49]

[50]

*Median.
6MWD: 6-min walk distance; CARE-HF: Cardiac Resynchronization-Heart Failure; COMPANION: Comparison of Medical Therapy, Pacing and Defibrillation in Heart
Failure; CRT-D: Cardiac resynchronization therapy defibrillator; CRT-P: Cardiac resynchronization therapy pacemaker; CV: Cardiovascular; HR: Hazard ratio; ICD:
Implantable cardioverter defibrillator; LV: Left ventricular; LVEF: Left ventricular ejection fraction; LVESV: Left ventricular end-systolic volume; LVESVi: : Left ventricular
end-systolic volume index; LVIDS: Left ventricular internal diameter in systole; MADIT-CRT: Multicenter Automatic Defibrillator Implantation Trial with Cardiac
Resynchronization Therapy; MIRACLE: Multicenter InSync Randomised Clinical Evaluation; MLHF: Minnesota Living with Heart Failure symptom score; MUSTIC: Multisite
Stimulation in Cardiomyopathies; MVO2: Peak oxygen uptake; NS: Not specified; NYHA: New York Heart Asociation; OPT: Optimal pharmacological therapy; PATH-CHF:
Pacing Therapies for Congestive Heart Failure Study; RETHINQ: Resynchronization Therapy in Heart Failure with Narrow QRS Complexes; REVERSE:
Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction.
The first controlled trial to demonstrate a clinically important effect of CRT was the Multisite Stimulation in Cardiomyopathies (MUSTIC) study, initially reported in 2001.[18]
Undertaken in Europe, this crossover trial randomized 58 patients implanted with CRT to a 3-month period of 'active' pacing followed by 3 months of 'inactive' pacing, or
vice versa. Patients were all optimally treated with ACE inhibitors but only a minority were taking -blockers and spironolactone. A significant increase in 6-min walk
distance was found, as well as improvements in quality of life scores and hospitalizations.
The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) was the first large double-blind, randomized, controlled study of CRT, finding an improvement in
functional capacity and symptoms, and reduced hospitalization.[19] The majority of patients were prescribed -blockers in addition to ACE inhibitors. All study subjects
were implanted with a biventricular pacemaker with the device programmed not to pace the control group during the 6-month follow-up period.
The MIRACLE-Implantable Cardioverter Defibrillator (MIRACLE-ICD) and CONTAK-CD trials compared CRT with defibrillator (CRT-D) with ICD therapy alone, finding
improvements in functional capacity with CRT-D, but without an accompanying reduction in mortality or hospitalization.[20,21] In 2004, the Comparison of Medical Therapy,
Pacing, and Defibrillation in Heart Failure (COMPANION) trial was published comparing the effects of CRT alone (CRT-P) or CRT-D with optimal medical therapy; subjects
were randomized in a 2:2:1 ratio.[22] The majority of patients were receiving modern heart failure medication and most had LBBB. As compared with previous trials, a
greater proportion of patients had ischemic cardiomyopathy. The primary end point was a composite of time to death and hospitalization from any cause. There was a
significant reduction in the primary end point in the CRT-P (34%) and the CRT-D group (40%). A significant 36% reduction in mortality was found with CRT-D, with a
smaller (24%) nonsignificant trend towards mortality reduction with CRT-P (p = 0.06).
The most significant trial of CRT-P to date is Cardiac Resynchronization-Heart Failure (CARE-HF), published in 2005.[23] In this open-label, Europe-based trial, 813
subjects receiving optimal drug therapy were randomized to receive CRT or no additional therapy. Subjects were receiving modern drug therapy and were followed for 2.5
years. Subjects were required to have echocardiographic evidence of dyssynchrony if the QRS was below 150 ms. All subjects were in sinus rhythm without a
conventional indication for a pacemaker. The combined primary outcome of death or hospitalization for a cardiovascular event was 37% lower with CRT, with a 36%
reduction in the secondary end point of death from any cause (absolute risk reduction: 10%). Measures of quality of life and NYHA functional class also demonstrated
significant improvements. There was no notable difference in effect between those patients with and those without ischemic heart disease. Extended follow-up to 37
months found an even greater 40% relative risk reduction in mortality (absolute risk reduction: 13.4%).[24] These results convincingly demonstrate the significant mortality
and morbidity benefits of CRT in patients with heart failure. The investigators concluded that implant of nine biventricular pacemakers prevented one death and three
hospitalizations during the study period.
A systematic review has confirmed the findings of the larger trials (CARE-HF and COMPANION).[25] Of 2601 patients pooled, CRT produced a relative reduction in
mortality risk of 23% compared with no additional treatment. Among 1311 patients, the rate of hospitalization for heart failure was reduced by 49%.

Normal QRS & CRT

As two-thirds of heart failure patients have normal QRS duration, this currently excludes a significant proportion from receiving CRT. However, published reports, based
principally on TDI echo parameters, have suggested a high prevalence of dyssynchrony up to 50% among heart failure patients with normal QRS duration.[26] The
Resynchronization Therapy in Heart Failure with Narrow QRS Complexes (RETHINQ) trial therefore tried to clarify whether CRT would be beneficial in NYHA class III/IV
patients, with normal QRS duration and demonstrable dyssynchrony on echocardiography, but with characteristics otherwise similar to those in CARE-HF.[27] Subjects had
a standard indication for ICD implantation and all received a CRT-D device with CRT inactivated in the control group. At 6 months, there was no difference in the primary
end point of peak oxygen consumption nor in the majority of secondary outcome measures, including LV function.
An important study limitation was the reliance on echo TDI parameters to determine the presence of dyssynchrony, a method that has been found to be unreliable.[28] In
fact, global markers of synchrony were not affected (mean A-PEP: 122 ms). Furthermore, there was no evidence of interventricular dyssynchrony (interventricular
mechanical delay: 9 ms), the most important predictor of response to CRT in CARE-HF.[10] Thus, the investigators inadvertently studied a population with proven interand intraventricular synchrony. The study therefore did not allow for any firm conclusions regarding CRT in this patient group.

Atrial Fibrillation & CRT

As many as half of all patients with heart failure may develop atrial fibrillation (AF), the highest incidence occurring in those with the worst functional class.[29] Most major
randomized trials excluded subjects with AF. However, many small studies of patients in AF have demonstrated either a benefit from CRT compared with RV pacing, or an
equivalent benefit when compared with CRT recipients in sinus rhythm.[3034] Furthermore, subjects in CARE-HF who developed AF had no less degree of benefit from
CRT than subjects who remained in sinus rhythm.[35] Khadjooi et al. found similar improvements in LV ejection fraction, LV dimensions, symptoms and quality of life
among AF patients as those in sinus rhythm.[31] To effect benefit in AF, biventricular pacing must capture over 8590% of ventricular activity.[36] AV node ablation is
therefore often recommended in these patients to ensure consistent biventricular pacing, but not all centers consider this a prerequisite.[37,38] Currently, there is
insufficient data to conclude whether a mortality benefit is derived from CRT in patients with AF.

Right Bundle Branch Block & CRT

Although the major trials of CRT required QRS prolongation for subject inclusion, the type of BBB was not specified. Right BBB (RBBB) was present in a relatively small
proportion (5% in CARE-HF, 11% in COMPANION), making it difficult to draw any useful conclusion regarding these patients.[3941] Furthermore, animal studies and
retrospective analyses suggest a far smaller benefit from CRT, if any at all.[42,43] A recent prospective analysis has shown that intraventricular dyssynchrony, a predictor of
response to CRT, is less common in subjects with RBBB as compared with LBBB.[44] However, current guidelines for CRT do not distinguish between RBBB and LBBB for
patient selection.

Minimal Symptoms & CRT

Given the impact in patients with severe heart failure, can CRT delay the onset of symptoms and improve prognosis in patients with less advanced disease? Data
addressing this question are emerging. In a retrospective review of a small sample of patients receiving CRT, 50 patients with NYHA class II symptoms derived similar
improvements in LVEF and LV dimensions compared with patients with severe symptoms, with a smaller improvement in functional capacity.[45] Within the CONTAK-CD
trial, 263 patients classified as NYHA class I or II at randomization showed significant improvement in LV dimensions with CRT.[21] The MIRACLE-ICD II trial of NYHA
class II patients also found improvements in symptoms and LV function at 6 months.[46] Furthermore, in the CARE-HF trial, 175 subjects with mild self-rated symptoms,
consistent with NYHA class II (although reported by the researchers as class III), appeared to derive symptomatic and prognostic benefits similar to those with more
severe self-rated symptoms.[47]
In the Resynchronization Reverses Remodeling in Systolic left Ventricular Dysfunction (REVERSE) trial, 610 patients with NYHA class I and II symptoms were implanted
with biventricular pacing devices and randomized to CRT-ON or CRT-OFF.[48] After 12 months, there were significant improvements in LV function and dimensions;
subgroup analysis suggested the effects may have been confined to those in NYHA class II with QRS above 152 ms. In a prespecified 2-year analysis of 262 patients,
CRT significantly improved the composite clinical score (34 vs 19%), with an important 62% reduction in heart failure hospitalization or death.[49] For the first time, a trend
to mortality reduction was seen in this patient group (5.7% CRT-ON vs 8.6% CRT-OFF; hazard ratio: 0.40; p = 0.09).
More recently, the Multicenter Defibrillator Implantation Trial with CRT (MADIT-CRT) study has been published.[50] In this largest study of CRT to date, 1820 subjects with
NYHA class I or II symptoms and an ICD indication (EF 30%; QRS 130 ms) were randomized to receive an ICD or CRT-D. After a mean 2.4 years follow-up, the study
found no impact of CRT on mortality but a 41% reduction in nonfatal heart failure events. Subgroup analysis suggested the effect may have been confined to those with
QRS above 150 ms. CRT also induced positive LV remodeling and increased LV ejection fraction.
The greatest impact of CRT in patients with minimal symptoms is upon LV reverse remodeling. This outcome, rather than the effect on symptoms, appears to be the
important determinant in the prognostic impact of CRT.[51] To date, follow-up of patients with mild heart failure symptoms treated with CRT has been relatively short and
longer surveillance of subjects in the larger trials will be required to determine whether 'prophylactic' CRT offers mortality reduction.

CRT in Less Severe LV Impairment

Although as many as 50% of heart failure patients may have preserved LV systolic function, clinical evaluation of CRT has, thus far, been confined to patients with severe
LV impairment. However, in a recent re-evaluation of the PROSPECT trial of CRT, which found significant improvements in a composite clinical score among patients with
NYHA class III/IV symptoms, QRS above 130 ms and poor LV function, subjects' baseline echo data were remeasured.[52] Of 361 subjects with available data, 86 were
found to have an ejection fraction above 35% (mean: 43%). These subjects with milder LV impairment experienced improvements similar to those with an ejection fraction
of 35% or less. Despite the highly dubious nature of these preliminary data, they are likely to prompt further investigation of the role of CRT in the substantial number of
heart failure patients with mild or moderate LV systolic dysfunction.

Guidelines
A number of bodies, including arrhythmia societies, heart failure societies and government-sponsored groups have produced guidance on which patients should be
considered for CRT. shows the criteria of those bodies most relevant to current clinical practice, particularly within the UK. The UK National Institute for Health and Clinical
Excellence guidelines are based largely on the characteristics of patients enrolled in CARE-HF, the trial providing the strongest evidence of benefit.[101] However, the
European and American guidelines acknowledge that published data do not support the use of echocardiography in predicting response to treatment, and evidence of
mechanical dyssynchrony is therefore not required.[53,54] Furthermore, they accept that benefit from CRT is not exclusive to the 'CARE-HF' population.
Table 2. Guidelines for selecting patients for cardiac resynchronization therapy.

Recommendation NICE
NYHA class
III/IV*
OPT

ESC
NYHA class III/IV
OPT

ACC/AHA/HRS
NYHA clas III/IV
OPT

Class 1

Sinus rhythm
EF 35%
QRS 120
ms

Class 2a

Class 2b

Sinus rhythm
EF 35%
QRS 120 ms
LV dilatation
NYHA class III/IV
EF 35%
LV dilatation
Plus
Atrial fibrillation + indication for AV node
ablation
Or
Bradycardia pacing indication

Sinus rhythm
EF 35%
QRS 120 ms

NYHA class III/IV

EF 35%
Plus
Atrial fibrillation + QRS 120 ms
Or
Frequent dependence on ventricular pacing
NYHA class I/II
EF 35%
Scheduled for pacemaker or implantable cardioverter defibrillator with expected frequent
ventricular pacing

*Current or recent.
Plus echo evidence of mechanical dyssynchrony if QRS < 150 ms.
ACC: American College of Cardiology; AHA: American Heart Association; AV: Atrioventricular; EF: Ejection fraction; ESC: European Society of Cardiology; HRS: Heart
Rhythm Society; NYHA: New York Heart Association; OPT: Optimal Pharmacological Therapy.

Postimplant Considerations
As with bradycardia pacing, a number of recognized complications may arise. A recent systematic review of CRT trials found failure to successfully place the LV lead in 7%
of implants, procedural mortality of 0.3%, 45% mechanical complication at implant, 7% postimplant lead problems, and 12% infection.[25] Early lead problems that may
be encountered include capture of the phrenic nerve by the LV pacing stimulus or loss of LV capture due to lead displacement. It may prove possible to solve these
problems by reprogramming the pacing parameters; however, LV lead repositioning may be necessary. Where transvenous LV lead placement is not possible,
transthoracic lead placement may be an alternative, with the lead tunnelled subcutaneously to the pulse generator. It is helpful to position the pacing system on the left
side in case of this eventuality.
The biventricular pacemaker is often programmed to DDD mode to ensure AV synchrony. However, right atrial pacing can result in delayed left atrial depolarization and
excessively shortened left AV delay. In the extreme, this may result in simultaneous left atrial and ventricular systole, producing marked elevation of left atrial and
pulmonary venous pressure. For this reason, VDD may be the preferred mode in the absence of sinus node disease (either primary or secondary to necessary blockade).
It is common practice to undertake some form of optimization of the pacing intervals (AV and RVLV) to produce maximum cardiac output. A review of the numerous
techniques described and the published data for and against each method is beyond the scope of this article. Furthermore, debate continues regarding how frequent
subsequent optimization procedures should be undertaken if at all.
The effects of CRT will often result in patients requiring fewer diuretics. Careful dose reduction may be necessary to prevent overdiuresis, dehydration and prerenal
impairment.
A significant proportion of patients fail to improve following CRT, with response rates of 6080% in most trials. There are a number of potential explanations, which may
help identify those who are likely to respond poorly, but conflicting data mean it is still difficult to accurately predict who the nonresponders are likely to be. Data from MRI
studies suggest that nonresponders are more likely to have an ischemic cardiomyopathy with underlying scar, which is likely to be less responsive to stimulation from the
LV lead.[55] However, recent retrospective data from the Cleveland Clinic (OH, USA) found no impact of ischemia, hibernation or scar on response rates among 603 CRT
recipients.[56] Another possible factor is the position of the LV lead at implantation; data from the early studies showed that lead position within the lateral and posterolateral branches of the coronary sinus were most likely to be beneficial.[57] A number of relatively small and brief studies have examined the acute effects of different LV
lead positions and the possible impact of targeting the lead at a predicted optimal site, pointing to potential benefit from a tailored approach for each individual. A recent
review of data from the large COMPANION trial, however, found no significant difference in benefit from CRT according to LV lead position.[58]

Uncertainties
Currently, good randomized data to recommend CRT for long-term mortality and morbidity benefits in patients with AF or with narrow QRS duration are lacking.
Nonetheless, it is logical to expect that some patients will derive benefit, and expert individual assessment is required to ensure suitable recipients are not denied CRT.
The role of CRT in patients with RBBB also needs clarifying, especially as this remains an accepted indication. There is considerable overlap between patients who need
to receive CRT and those requiring an ICD; the indications are evolving for both therapies and guidelines will need to take this into account. The best methods of selecting
patients for CRT and device-management postimplant remains unclear despite, and perhaps because of, the large number of small trials and publications examining this
area.

Expert Commentary
Cardiac resynchronization therapy should be considered for patients in sinus rhythm, with current or recent NYHA class III or IV heart failure symptoms, severely impaired
LV systolic function and broad LBBB. Patients should be counseled as to the likelihood of benefit, with an expectation of greater improvement among those with more
advanced symptoms, poorer LV function and broader QRS specifically, those with the most to gain. Outside of current guidelines, CRT should ideally be undertaken
within the context of a clinical trial. Where trials are lacking, expert clinical opinion should be used to consider biventricular pacing in patients with conditions where right
ventricular pacing may be detrimental, such as those with complete heart block or slowly conducted AF with coexistent heart failure symptoms or impaired LV function. It is
likely that the indication for CRT will expand in the coming years and it is expected that guidelines will be subject to regular review. Cost constraints and the small but finite
risk of adverse events will require further evaluation of methods to accurately identify potential beneficiaries of CRT. The postimplant management of CRT patients is an
area of medicine ripe for research. Institutions will need to develop local protocols for the assessment and follow-up of patients, using those techniques that work well
within their own hospitals, and which can be subjected to scrutiny with audit.

Five-year View
Although studied for over a decade now, it is only in the last few years that CRT has been recommended in guidelines as a standard therapy for a specific subset of
patients with chronic heart failure. Further investigations will seek to determine how far beyond that subset CRT may provide benefit. Large studies are planned to

evaluate new roles for CRT, such as the Echo-CRT trial, sponsored by Biotronik (Berlin, Germany), which will re-assess CRT among patients scheduled for ICD implant
with narrow QRS. Longer-term follow-up of the MADIT-CRT and REVERSE trials will give insight into the potential prognostic benefit of CRT when undertaken earlier in
the disease. Within this, it will be helpful to reconsider at what stage CRT is applied; currently, we wait until medical therapy has been fully optimized, a process that can
take many months, potentially delaying what for some individuals will be the most important aspect of their treatment. It is likely that further data will become available
concerning CRT among patients with less severe LV impairment, as well as those in AF and those with RBBB. Investigations will also look at the role of upgrading existing
pacemakers to CRT systems and, indeed, the role of primary CRT-P implant for patients requiring treatment of bradyarrhythmia. Given the marked rise in CRT implants, it
is hoped that studies will be undertaken to guide the follow-up and management of patients postimplant.

Sidebar
Key Issues

The technology of cardiac resynchronization therapy (CRT) has been incorporated into clinical practice over the past decade for the treatment of heart failure.
Heart failure is associated with dyssynchronous ventricular contraction that contributes to the heart's worsening hemodynamic performance.
CRT produces synchronous contraction of opposing regions of the left ventricle, resulting in improved hemodynamic function and reverse remodeling of the
impaired ventricle.
CRT should be considered for patients with severely impaired left ventricular systolic function who are optimally medicated.
Current guidance recommends its use in patients with a prolonged QRS and New York Heart Association class IIIIV symptoms for improvements in long-term
morbidity and mortality.
There is evidence that patients with either atrial fibrillation or sinus rhythm can benefit to a similar degree.
Minimally symptomatic patients with a prolonged QRS and severe left ventricular impairment benefit through a reduction in future deterioration, but mortality benefit
has not been demonstrated.
Postimplantation follow-up is necessary to ensure optimal functioning of the biventricular pacemaker and to monitor for complications.
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Website
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Papers of special note have been highlighted as:
of interest
of considerable interest
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Expert Rev Cardiovasc Ther. 2010;8(2):229-239. 2010 Expert Reviews Ltd.
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