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Chapter 25. Cardiac resynchronization therapy in mildly symptomatic heart failure

Chapter 25. Cardiac resynchronization therapy in mildly symptomatic heart failure

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296 CARDIAC RESYNCHRONIZATION THERAPY



and a concurrent increase in LV ejection fraction

(LVEF).4,7,16,17 This remodeling, along with coordinated contraction of the papillary muscles, can

lead to decreased mitral regurgitation, which has

also been a finding in randomized trials.3,4,7,16,18

Improvements in LV structure and function

together with improved neurohormonal status,

lead to improved symptoms of heart failure.

For example, in the MIRACLE trial, the CRT

group (vs the control group) had an average

6-minute walk distance 29 meters greater

(p = 0.005), Minnesota Living with Heart Failure

(MLWHF) score 9 points lower (p = 0.001), and

peak oxygen consumption (VO2max) 0.9 ml/

kg/min greater (p = 0.009), with benefits occuring as early as 1 month after randomization.4

Also, in CARE-HF, the NYHA class in the CRT

group was 0.6 lower than in medical therapy

(p < 0.001), and the MLWHF score was 10 points

lower (p < 0.001).8 In the COMPANION trial,

6 months after randomization, the CRT-only

group had an average increase in 6-minute walk

distance of 40 meters (p < 0.001) and a decrease

in MLWHF score of 25 points (p < 0.001), and

61% experienced improvement in NYHA class

(p < 0.001).7

Recent trials have also analyzed the effect of

CRT on mortality. For example, the COMPANION trial randomized 1520 patients to optimal

medical therapy, CRT only (Guidant CONTAKTR), or CRT with defibrillator function (Guidant

CONTAK-CD). After 14–16 months of follow-up,

the COMPANION trial found that the CRT-only

group had a ‘marginally significant’ reduction in

the secondary endpoint of all-cause death

(hazard ratio (HR) 0.76, 95% confidence interval

(CI) 0.58–1.01, p = 0.059). After 12 months of

follow-up, the CRT-only group experienced a

significant reduction in the primary endpoint of

death or hospitalization from any cause (HR

0.81, 95% CI 0.69–0.96, p = 0.014). Subsequently,

in CARE-HF, 813 patients were randomized to

receive either medical therapy or CRT-only

(Medtronic InSync or InSync III). After 29 months

of follow-up, the CRT group was associated

with a significant reduction in death from any

cause (HR 0.64, 95% CI 0.48–0.85, p < 0.002).

The impact of CRT on sudden death is less

clear. In the COMPANION trial, the incidence of

sudden death was not reduced with CRT only



(HR 1.21, 95% CI 0.7–2.07, p = 0.50).19 Similary, in

CARE-HF, the rate of sudden death was 32% in

the medical therapy group and 35% in the CRT

group (no confidence intervals were given).

Before drawing conclusions from this data, it

is worth recalling the ongoing difficulties with

classification of mode of death, especially with

regard to the definition of sudden death.20

The definition used for sudden death in the

CARE-HF trial was not documented, and

in COMPANION, the definition of sudden

death was ‘observed or unobserved, but assumed

to be instantaneous because of the clinical

setting’.

Although sudden death may not be affected

by CRT, this therapy may be beneficial as an

adjunct to implantable defibrillators. For example, in a small trial of 18 patients who had their

ICDs upgraded to CRTs with ICDs, it was

shown that the frequency of ventricular tachycardia was decreased from 0.31 to 0.13 episodes

per patient per month (p = 0.59).21 Likewise, the

frequency of ventricular fibrillation decreased

from 0.083 to 0.004 episodes per patient per month

(p = 0.03). As a consequence, the frequency of

shocks from the ICD decreased from 0.048 to

0.003 episodes per patient per month (p = 0.05).

Therefore, CRT can be viewed as a means of

decreasing the burden of ICD discharges for the

patient.6

PRIOR TRIALS IN MILD HEART

FAILURE PATIENTS

Although most studies to date with CRT have

been in advanced heart failure patients, two

large trials have studied patients with mild heart

failure. The first of these was CONTAK-CD,

which randomized 581 patients with NYHA

class II–IV heart failure, LVEF р35%, and QRS

>120 ms, to CRT-on or CRT-off (Guidant Ventak

CHF or CONTAK-CD).6 In the CONTAK-CD

study, 158 patients with NYHA class II were

included. Between implantation and randomization, the clinicians were allowed to push

aggressive medical therapy for 30 days. As a

result, many of the baseline NYHA groupings

changed before randomization, including 40%

of those initially NYHA class III–IV who

improved to class I–II prior to randomization.



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Also of note, the population in CONTAK-CD

differed from that in other CRT trials in that

there were fewer ischemic etiologies (55% in

CONTAK-CD vs 67% in other trials) and more

beta-blocker use (63% vs 48% in other trials). The

results of the CONTAK-CD trial showed that

there was no difference between the CRT-on

versus CRT-off groups in the composite endpoint

of mortality, hospitalization for heart failure,

and ventricular arrhythmias requiring therapy.

For the NYHA class I–II groups, there was no

improvement in 6-minute walk, MLWHF score,

VO2max, or LVEF. These results may have been

influenced by lack of stability in NYHA groupings, difference in ischemic etiology, and betablocker use. Furthermore, because these patients

had relatively mild symptoms, it may be

difficult to demonstrate significant improvement

in a small subset of patients. Nonetheless, there

was evidence of reverse remodeling, with

small but significant changes in LV end-systolic



and end-diastolic diameters (LVESD and LVEDD)

(Table 25.1). This positive remodeling may not

have resulted immediately in improved symptoms, but may over time have prevented clinical

deterioration. In addition, the duration of

follow-up in CONTAK-CD was possibly too short

to test this hypothesis.

The MIRACLE ICD II trial randomized

186 patients with NYHA class II, LVEF р35%,

LVEDD у55 mm, and QRS у130 ms to receive

CRT-ICD (Medtronic InSync ICD) on or off.22

This trial ran concurrently with the MIRACLE

ICD trial, with separate prespecified endpoints

for the NYHA class II patients. MIRACLE ICD II

showed that CRT improved the secondary

endpoints of NYHA class by 0.18 (p = 0.05),

of LV end-diastolic volume (LVEDV) by 41 ml

(p = 0.04), of LV end-systolic volume (LVESV) by

42 ml (p = 0.01), and of LVEF by 3.8% (p = 0.02).

Furthermore, the composite clinical status score

improved in the CRT-on group vs the CRT-off



Table 25.1 Previous trials of CRT in mild heart failure

Trial



No. of patients



CONTAK-CD6



158



Endpoint



Primary

Composite mortality, hospitalization, VT

Secondary

Increase in 6-min walk

Change MLWHF score

Improvement in VO2max

Change in LVEDDa

Change in LVESDa

Improvement in LVEF

MIRACLE ICD II22

186

Primary

Change in VO 2max

Secondary

Change in 6-min walk

Change in MLWHF score

Change in LVEDV a

Change in LVESVa

Change in LVEFa

Change in mitral regurgitation (cm2)

Change in Ve/VCO2a

Change in NYHA classa

Bold items are significant at a p р 0.05 level.



Results of therapy vs control



Hazard ratio 0.88 (NS)

17 vs 10 (p = 0.55)

-1 vs −4 (p = 0.26)

0.2 vs 0.0 (p = 0.77)

-2.4 vs 0.0 (p = 0.024)

-3.2 vs -0.5 (p = 0.014)

4.7 vs 2.9 (p = 0.16)

0.5 vs 0.2 (p = 0.87)

38 vs 33 (p = 0.59)

-13.3 vs -10.7 (p = 0.49)

-41 vs -16 (p = 0.04)

-42 vs -14 (p = 0.01)

3.8 vs 0.8 (p = 0.02)

-1.7 vs -1.0 (p = 0.25)

-1.8 vs 0.5 (p = 0.01)

-0.18 vs 0.01 (p = 0.05)



MLWHF, Minnesota Living with Heart Failure; VT, ventricular tacharrhythmias requiring device therapy; NS, not-significant; LVEDD, left

ventricular end-diastolic diameter (mm); LVESD, LV end-systolic diameter (mm); LVEDV, LV end-diastolic volume (ml); LVESDV, LV end-systolic

volume (ml); Ve, minute ventilation; VCO2, minute carbon dioxide production.



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group (49% vs 36%; p = 0.01). However, the

primary endpoint of change in VO2max was no

different between the two groups.

ONGOING RANDOMIZED TRIALS

It is clear from the above discussion that the

experience of CRT in mildly symptomatic heart

failure, although promising, is very limited.

Because of the cost and the small, but not

insignificant, morbidity associated with device

implantation, it is imperative that more data

be obtained. Two large randomized trials are

currently underway that should provide much

more data about the use of CRT in mildly

symptomatic individuals with heart failure

(Table 25.2).

The REVERSE (REsynchronization reVErses

Remodeling in Systolic Left vEntricular

Dysfunction) trial began in the summer of

2004 in over 100 sites in the USA, Canada,



and Europe.23 The expected sample size is

512 patients, who will be followed for 5 years,

with an expected study duration of 87 months.

A combined ICD/CRT device (Medtronic) will

be implanted and then CRT will be activated on

a 2:1 basis in a blinded fashion. LV epicardial

leads will not be allowed, and patients will have

atrioventricular (AV) delay optimization by

echocardiography prior to discharge from their

implant hospitalization. In the USA and Canada,

therapy will be blinded (CRT-on or CRT-off) for

12 months, following which CRT will be activated in all patients. In Europe, therapy will be

blinded for 24 months. Enrollment for REVERSE

was completed in September 2006. Twelve month

follow-up is expected to be completed for all

patients by October 2007.

The primary endpoint of REVERSE will be

a composite endpoint of mortality, hospitalization for heart failure, discontinuation of

double-blind treatment with CRT, or worsening



Table 25.2 Ongoing trials of CRT in mild heart failure



Trial

REVERSE23



Projected

No. of patients

512, with 2:1

CRT-on vs

CRT-off



Study start



Projected

duration



Summer 2004



87 months



Inclusion criteria



LVEF р40%



QRS у120 ms

LVEDD у55 mm

NYHA class I or II

Stable medical regimen

MADIT-CRT27



1820, with 3:2

randomization



December 2004



45 months

LVEF р30%

QRS у130 ms

Sinus rhythm

Ischemic heart disease,

NYHA class I–II

Non-ischemic, NYHA

class II

Stable medical regimen



Endpoint

Primary

Composite of mortality,

hospitalization,

discontinuation of blind

treatment, deterioration

of functional status

Secondary

Increase in 6-min walk

Change in MLWHF score

Change in NYHA class

Change in LVESV

Primary

Death or HF event

Secondary

Change in LVEDV

Change in LVESV

Multiple heart failure

events



MLWHF, Minnesota Living with Heart Failure; LVEDD, left ventricular end-diastolic diameter (mm); LVESD, LV end-systolic diameter (mm);

LVEDV, LV end-diastolic volume (ml); LVESDV, LV end-systolic volume (ml).



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CRT IN MILDLY SYMPTOMATIC HEART FAILURE 299



functional status. There are a number of secondary endpoints that will be evaluated as well,

including LVESV index after 12 months of

blinded therapy, changes in NYHA class, change

in quality-of-life scores, and change in 6-minute

walk distance. The aim of the trial, rather than

focusing on patient improvement, will be to

demonstrate that CRT stabilizes and slows progressive remodeling because patients enrolled in

REVERSE will have little or no symptoms of

heart failure.

Major inclusion criteria for REVERSE were

NYHA class I or II heart failure, QRS duration

у120 ms, LVEF р40%, LVEDD у55 mm (or

2.8 cm/m2 body surface area) and a stable

medical regimen. Major exclusion criteria for

REVERSE were NYHA class III or IV symptoms

within 90 days, admission for heart failure

within 90 days, atrial fibrillation, atrial flutter,

creatinine >3.0 mg/dl, and significant hepatic

abnormalities.

One substudy already planned for REVERSE

will investigate the effect of optimizing interventricular timing. In the CRT-on group, echocardiographic tissue Doppler imaging will be used

to measure the time to peak systolic contraction

of basal septal and basal free walls of the LV.

The optimum interventricular timing for each

patient will be identified by testing each offset

from −20 (right ventricular (RV) lead first by

20 ms) to +20 (LV lead first by 20 ms), searching

for the setting that produces the shortest delay

between time to peak systolic contraction of

the LV walls. The large, randomized trials

completed so far have not optimized the interventricular timing of the CRT devices, because

of lack of this feature in devices and lack of

uniformity in the procedure. Interventricular

timing has been shown to improve stroke

volume, dP/dt, and exercise capacity, so the

standardized use of this technique in the

REVERSE trial may produce a more impressive

response.1,24–26

The other ongoing large trial for mild heart

failure patients is MADIT-CRT (Multicenter

Automatic Defibrillator Implantation Trial).27

In this trial, the recruitment goal is 1820 patients.

Patients will be randomized 3:2 to receive

CRT-ICD or ICD only, and the follow-up will

average 20–33 months, continuing until a



common study termination date. All devices

implanted for this study will be manufactured

by Guidant Corporation, and the study will be

administered by the University of Rochester.

The primary endpoints of MADIT-CRT are

death or heart failure event (e.g., acute decompensated heart failure requiring hospitalization

or outpatient treatment with intravenous diuretics, inotropes, or nesiritide). Deaths will be classified according to cause, such as sudden death.

Secondary endpoints will include LVESV (measured by echocardiography while CRT is turned

off) at 12 months, LVEDV (also measured while

CRT is turned off), and the rate of multiple heart

failure events.

Major inclusion criteria for MADIT-CRT

include ischemic heart disease and NYHA class I

or II symptoms for the previous 3 months, or

non-ischemic heart disease and NYHA class II

for the previous 3 months. Patients must also

have LVEF р30% within 14 days prior to randomization, QRS у130 ms, sinus rhythm, and

stable optimal pharmacologic therapy. Major

exclusion criteria are NYHA class III or IV symptoms in the previous 3 months, coronary artery

bypass grafts or intervention in the previous

3 months, and non-ischemic cardiomyopathy

with NYHA class I symptoms. As of June 2006,

approximately 630 patients had been enrolled in

MADIT-CRT. Enrollment has been rather slow

in this study – perhaps because clinicians may

prefer not to risk the randomization of their

patients with a wide QRS to the group which

receives on ICD without CRT therapy.

CRT FOR MILDLY SYMPTOMATIC PATIENTS

CRT has so far been a therapeutic option for

patients with moderate heart failure despite

optimal medical management. In these patients,

CRT has the potential to improve symptoms

and reduce mortality. It is known that even

asymptomatic patients with reduced LVEF have

increased mortality.28 Since one of the benefits of

CRT is reverse remodeling and improved

systolic function, it may be of benefit in these

less symptomatic patients. This hypothesis is

supported by the MIRACLE ICD II and

CONTAK-CD trials, in which CRT produced

reverse remodeling in a period as short as



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6 months. These trials were limited by several

factors, one of which was that NYHA class II

patients were analyzed primarily as a subgroup

of the more symptomatic patients. Also, the

major benefit of CRT in NYHA class I and II

patients has been reverse remodeling, but only

over some time will the reduced chamber volumes, improved LVEF, and decreased mitral

regurgitation translate to improved outcomes.

This may explain the lack of clinical efficacy in

the small trials so far – the follow-up has been

too short to detect clinical improvement, despite

positive remodeling.

The ongoing trials are specifically targeting

NYHA class I–II patients, and are incorporating

new techniques such as interventricular timing

optimization. The two large trials currently

underway should be expected to meet secondary endpoints such as reverse remodeling.

However, the primary endpoints may be more

difficult, since the event rate in NYHA class I

and II patients in REVERSE and MADIT-CRT

(all of whom have defibrillators) should be quite

low. In SCD-HeFT, mortality in those with ICDs

was only 5.8% per year.10 In a recent report,

Parkash et al29 found a 1-year mortality rate in

low-risk patients (NYHA class I–II, normal renal

function, age < 80 years, and sinus rhythm) of

<5%. Thus, the challenge will be to follow

such patients for a sufficiently long period to

demonstrate prolonged clinical stability rather

than improved symptoms. On the positive side,

these studies will be much longer than previous

trials, with the REVERSE trial having a follow-up

of 12 months for patients in the USA and Canada

and 24 months for European patients, and

MADIT-CRT a follow-up of 20–33 months.

The primary endpoints of both studies will

include death and hospitalizations, but REVERSE

will also include change in functional status

or the need to activate CRT in control patients.

The primary endpoint goal is subtly different –

that fewer patients will worsen with CRT compared with control – whereas most other heart

failure trials have depended on mortality and

hospitalization to drive their clinical endpoints.

Therefore, the chief aim of this trial is not

to improve symptoms but rather to stabilize

patients with LV dysfunction, and hence prevent

disease progression. These two studies will



help determine if positive results with surrogate

endpoints can translate into meaningful clinical

outcomes, such as reduced mortality, hospitalization, or prolonged clinical stability.

In a few short years, CRT has brought a new

realm of therapy to patients significantly limited

by heart failure. On the other hand, this therapy

is expensive, does not always work, and carries

some risk. The two ongoing trials will answer

two important questions. Does the incremental

cost associated with CRT in patients receiving

defibrillators produce clinically significant

results? Can CRT bring about longer clinical

stability than pharmacologic therapy alone?

Our patients and those of us who care for them

anxiously await the results of these landmark

trials.



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reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study. Am Heart J 2006;151:288–94.

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Resynchronization Therapy (MADIT-CRT): design and

clinical protocol. Ann Noninvasive Electrocardiol

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and the development of heart failure in asymptomatic

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26



Cardiac resynchronization therapy in

patients with narrow QRS

Bàrbara Vidal, Marta Sitges, and Lls Mont



Introduction • QRS duration and cardiac resynchronization therapy • Mechanical versus

electrical dyssynchrony • Intraventricular dyssynchrony and response to CRT • Benefit

from CRT in patients with advanced heart failure and narrow QRS • Summary



INTRODUCTION

Several studies have shown that a wide QRS,

mainly with a left bundle branch block (LBBB)

morphology, is a marker of poor prognosis in

patients with advanced heart failure.1,2 There is

a linear correlation between a QRS duration and

age, with worse functional class, worse left ventricular ejection fraction (LVEF), more severe

mitral regurgitation (MR), and shorter diastolic

filling time of the left ventricle (LV). In general

terms, the wider the QRS, the more severe is the

ventricular dysfunction.1,3

QRS DURATION AND CARDIAC

RESYNCHRONIZATION THERAPY

Previous studies have shown that about 30% of

patients with heart failure show a wide QRS

(90% of them with LBBB).4,5 Cardiac resynchronization therapy (CRT) has proven to be effective in improving mortality and exercise

capacity in patients with wide QRS, systolic LV

dysfunction, and advanced heart failure.6–8

The rationale behind CRT is the possibility of

correcting an electrical delay created by a given

conduction disturbance, by pacing areas with

late activation within the LV. It has been taken

for granted that a wide QRS is a surrogate



for electrical dyssynchrony that in turn would

induce mechanical dyssynchrony in the ventricular contraction. Accordingly, established

indications for CRT are based on the QRS

width.9–11

On the other hand, it is well established from

the results of several multicenter international

randomized trials that, using this type of criteria

for candidate selection, there is a constant proportion (approximately 30%) of non-responders

among patients treated with CRT.12,13 It has been

suggested that a percentage of non-responders

may be attributable to the fact that patients may

show a wide QRS but do not have mechanical

dyssynchrony in ventricular contraction, and

therefore CRT is useless simply because there is

no myocardium to resynchronize. Therefore, several authors have underlined the importance of

demonstrating mechanical dyssynchrony by

imaging techniques before implanting a CRT

device, in order to improve the clinical outcomes

after CRT. Imaging techniques, not only can

demonstrate mechanical dyssynchrony, but can

also delineate the extent of the scar tissue not

amenable to resynchronization.14

Due to its wide availability, high temporal

resolution (allowing the study of rapid events

during the cardiac cycle), and low cost, echocardiography has been the most frequently used



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304 CARDIAC RESYNCHRONIZATION THERAPY



imaging technique is the investigation of

mechanical dyssynchrony.15 The methodology

used for assessing cardiac dyssynchrony with

echocardiography is not the subject of this chapter

and has been reviewed elsewhere;16 here, we

simply point out that it is based mainly on the

analysis of segmental ventricular motion with

tissue Doppler imaging (TDI) techniques, threedimensional (3D) echocardiography, or, more

recently, 2D velocity imaging. However, no

single parameter is currently considered the

gold standard for defining cardiac mechanical

dyssynchrony. Other techniques, such as magnetic

resonance imaging (MRI), may also play a role

in the study of dyssynchrony and tissue viability. Although some studies are beginning to

clarify what is the most powerful echocardiographic parameter to detect dyssynchrony and

to predict response to CRT,17 the integration

of multimodality cardiac imaging and the global

integration of several echocardiographic parameters to assess dyssynchrony will probably

be necessary in the future for optimal patient

selection.18

MECHANICAL VERSUS ELECTRICAL

DYSSYNCHRONY

The presence of a wide QRS in patients with

dilated cardiomyopathy (DCM) of any etiology

has been considered to be a marker of delayed

electrical activation of some regions of the

myocardium. This delay induces inter- and

intraventricular dysynchronous contraction and

relaxation resulting in less efficient performance

of the LV.19 This concept has been challenged by

the observation that not all patients with a wide

QRS show mechanical dyssynchrony (Figure 26.1),

whereas a proportion of patients with narrow

QRS do. Some authors have suggested that the

presence of extracellular deposits, a loss in

the number of myocytes, or ultrastructural

lesions may induce delayed mechanical contraction without showing electrical changes on the

surface ECG.20

The correlation between QRS width and LV

performance has been studied by Leclerq et al21

in a canine model with LBBB and ventricular

dysfunction. They observed that biventricular

pacing and LV pacing alone induced the same



hemodynamic improvement in dP/dt and aortic

pressure, despite LV pacing producing a wider

QRS. They therefore concluded that there

was no correlation between QRS duration and

mechanical response.

A series of echocardiographic studies have

also analyzed the correlation between QRS

width and the presence of mechanical dyssynchrony (Table 26.1). Several methods have been

used – this may be a limitation, since there is no

single standardized echocardiographic measurement to diagnose inter- and intraventricular

dyssynchrony. Yu et al22 found a high percentage

of intraventricular dyssynchrony in patients

with heart failure and wide QRS (73%) using

tissue Doppler imaging; however, they also

found dyssynchrony in 51% of those patients

with narrow QRS. Breithardt et al23 also performed an echocardiographic study of the cycle

of inward and outward displacement of each

region of the endocardial wall and the presence

of dyssynchrony in patients with advanced

heart failure and wide QRS included in the

PATH-CHF trial. They found that some patients

showed synchronous contraction between the

septal and lateral walls despite a wide QRS, and

that the lack of dyssynchrony (defined as a lack

of correspondence between the phase angles of

the regional displacement curves) was a predictor

of a lack of response.

Ghio et al1 analyzed the presence of dyssynchrony in a series of 158 consecutive patients

with low LVEF (<35%). Patients were classified

into three groups according to QRS width.

Group 1 comprised 61 patients with normal QRS

width, group 2 included 21 patients with LBBB

and a QRS duration of 120–150 ms, and group 3

included 76 patients with QRS >150 ms.

Interventricular dyssynchrony (defined by the

presence of an intraventricular mechanical delay

>40 ms) was present in 12%, 52%, and 72% of

these groups, respectively. Intraventricular dyssynchrony (defined by the presence of one or

more differences >50 ms) among regional preejection periods assessed with TDI velocities

was present in 30% of patients with narrow QRS,

57% of group 2 patients, and 71% of group

3 patients. Therefore, although the proportion of

patients with dyssynchrony is higher in those

with a wide QRS, a significant proportion of



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Chapter 25. Cardiac resynchronization therapy in mildly symptomatic heart failure

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