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Chapter 20. Non-responders and patient selection from an echocardiographic perspective

Chapter 20. Non-responders and patient selection from an echocardiographic perspective

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patient’s criteria for implant. Re-evaluation of

selection criteria must include a search for

reversible causes of heart failure and LV dysfunction (i.e., valve disease, coronary artery disease,

pulmonary disease, and congenital heart disease),

as well as the degree of baseline LV dysfunction,

the presence and degree of intraventricular

mechanical delay, and QRS duration pre-implant.

Patients with borderline LVEF or borderline

QRS durations as well as a QRS morphology

other than left bundle branch block (LBBB)

(i.e., right bundle branch block (RBBB) or intraventricular conduction delay (IVCD)) may be

less likely to demonstrate a positive response as

compared with those with non-ischemic cardiomyopathies, LVEF <35% and a QRS >150 ms,

and LBBB. Precise knowledge of this information may be able to provide insights into why a

patient may have realized a suboptimal response.

Non-responders often present with either symptoms or persistent or worsening LV dysfunction,

or both. Classifying these cases as they present

may be helpful in determining an etiology and

generating a management strategy.

delay has been defined as that which enables

completion of atrial filling prior to ventricular

contraction, thereby allowing for an optimal

diastolic filling time.11 Evidence demonstrating a

clinical benefit or positive impact of AV delay

optimization on outcome, however, is lacking.

Despite this lack of definitive data supporting its

utility, several centers have advocated various

methods for evaluating AV delay and optimizing AV intervals in patients undergoing CRT.

These protocols range from routinely evaluating

hemodynamics with Doppler echocardiography

in all patients undergoing CRT and optimizing

as indicated, to only evaluating AV synchrony

and ultimately optimizing AV delay if the

patient is considered a non-responder. In our

center, we have found it both useful and practical to evaluate diastolic filling parameters

(mitral inflow) by Doppler echocardiography in

all patients undergoing CRT and to proceed

with an AV optimization procedure only if the

hemodynamics are suboptimal9 (Figure 20.1). If

E–A wave reversal is present, there is adequate

separation of the E and A waves, the A wave terminates at least 40 ms after the onset of the QRS


It is typically very clear that these patients have

not experienced the desired effect of CRT, and

therefore investigation must proceed to determine whether a specific reason for this lack of

response can be uncovered and if so whether it

can be corrected. A systematic approach may be

useful in managing these cases – specifically, one

that addresses issues related to intraventricular,

interventricular, and AV synchrony.

Mitral inflow pattern following CRT procedure

Stage I



Stage II or III

pseudonormal or


Mitral E–A reversal,

QA interval > 40 ms,

Pulmonary vein S>D

AV optimization

(Ritter or Iterative)

Maintain baseline

AV delay setting

Target stage I

diastolic filling


Once appropriate patient selection has been

assured, and assuming that the optimal lead

position has been achieved, evaluation of AV

and interventricular (V–V) timing intervals is

recommended. In comparison with the importance and impact of correction of intraventricular dyssynchrony, AV and V–V timing are minor

contributors to the overall impact of CRT.8

However, data clearly demonstrate that, in

selected patients, optimizing the AV delay does

improve hemodynamics.8–10 The optimal AV

Figure 20.1 Recommended algorithm utilizing pulsed Doppler

of mitral inflow to assess diastolic function for approaching

CRT patients being considered for AV optimization. If the

patient presents with stage I diastolic dysfunction or delayed

relaxation abnormality, the QA interval is >40 ms, and the

pulmonary vein flow pattern is systolic > diastolic (S>D), then

the baseline AV delay settings are maintained. If, on the other

hand, pseudonormal (stage II) or restrictive (stage III) physiology is present, then AV optimization is performed.



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Mitral Flow

Pulmonary Vein Flow

40 msec

Figure 20.2 Because the mitral inflow pattern (a) demonstrates E–A reversal, adequate E–A wave separation, and a QA interval

> 40 ms, and the pulmonary vein flow (b) reveals S>D, no further optimization is necessary, as further modifications are unlikely

to improve hemodynamics.

complex, and the systolic flow velocity is greater

than the diastolic flow velocity on pulmonary

vein flow assessment, then the baseline ‘outof-the-box’ setting is maintained (Figure 20.2).

Regardless of a given institution’s preference

in routinely evaluating AV delay settings, it is

clear that AV delay is worth interrogating in the

non-responder population. Several Doppler

methods for optimization have been described

in the literature, all of which utilize a Doppler

parameter of either systolic or diastolic function

to determine functional response to various AV

delay settings. The two most commonly reported

Doppler parameters are pulsed-wave Doppler

assessment of mitral inflow and continuouswave Doppler assessment of aortic outflow

(stroke volume estimate).12 Also reported to be

useful in this setting is the Tei index,10 which

evaluates both systolic and diastolic function.

The utility of mitral inflow assessment is based

upon the ability to time the termination of the

atrial contribution to filling with the onset of

ventricular contraction, in addition to its ability

to assess diastolic function. This was initially

proposed to be useful in this context by Ritter

et al.13 The Doppler assessment of aortic flow is

a systolic parameter and is an estimation of

stroke volume. In our experience, mitral inflow

assessment has been more robust in regard to

ease of acquisition, interpretation, and prognostic value relative to the aortic flow parameter.

Utilizing the Doppler mitral inflow method as

a parameter to assess myocardial function and

the relationship between the termination of the

atrial contribution to filling and the onset of

ventricular systole, the optimal AV delay can be

determined using either an iterative or a Ritter

method. The iterative method simply attempts

to target stage I diastolic filling or early relaxation, which is an optimal diastolic function

status in a heart failure population. The AV delay

is set to an abnormally prolonged setting while

maintaining BiV capture if conduction is presumed to be relatively normal at baseline, and the

mitral inflow is sampled. The AV delay intervals

are decreased in 20 ms increments, with the mitral

inflow being sampled at each stage. Optimal AV

delay is achieved when E–A reversal is present,

adequate separation of an A wave is appreciated, and the A wave terminates at least 40 ms

after the onset of the QRS complex, representing

minimum electrical–mechanical delay. If there is

evidence of intraatrial or AV conduction delay

at baseline, the AV delay can be adjusted in

increasing increments, again targeting delayed

relaxation abnormality, stage I diastolic dysfunction (Figure 20.3). The Ritter method achieves

this same endpoint by initially setting the AV

delay to an inappropriately short setting,

sampling mitral inflow, measuring the QA interval (QRS onset to A-wave termination) and comparing this measure with the QA interval at an



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Figure 20.3 This patient was a 69-year-old male with ischemic cardiomyopathy and s/p aortic valve replacement, atrial fibrillation, ventricular tachycardia, and heart failure who had recently undergone implantation of a biventricular (BiV) pacemaker. At a

baseline setting of 110 ms, there was no discernible A wave (a). The AV delay was then extended to 280 ms while maintaining

BiV capture (c). At an AV delay of 280 ms, the termination of the A wave fell before QRS onset, resulting in suboptimal diastolic

filling and the potential for diastolic mitral regurgitation. The AV delay was then empirically decreased to 230 ms, where a more

physiologic relationship between the end of the A wave and QRS onset could be realized. The AV delay setting was therefore

maintained at 230 ms.

inappropriately long AV delay setting. The optimal AV delay is then calculated from the difference of the QA intervals at each setting plus the

short AV delay setting.

Data from our institution suggests that

most patients (60%) exhibit optimal diastolic

filling or delayed relaxation (stage I) at an outof-the-box setting of approximately 100–140 ms.

Furthermore, approximately 10% of patients

with suboptimal diastolic filling hemodynamics (stage II or III) will exhibit improved diastolic filling with optimization of the AV delay

(Figure 20.4). The predictors of a longer than

normal (optimal) AV delay include a paced

rhythm, AV block, and an enlarged left atrium

(LA) (Figure 20.5), suggesting that intraatrial

conduction delay necessitates an abnormally

prolonged AV delay in order to optimize diastolic filling.9 Although there are no known

data supporting the utility or impact of AV optimization on outcome, data from several centers

experienced in performing these procedures

suggest that this intervention may positively

impact a segment (albeit small) of the nonresponder group.9,14 Because conduction times

may vary over time – likely related to reverse

remodeling – regular interrogation at 6- to

12-month intervals seems prudent.15



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Figure 20.4 Using an iterative method for AV delay optimization, the AV delay was extended in this 69-year-old male with known

underlying conduction disease. There is no effective late diastolic filling (no A wave) at the baseline AV delay setting of 100 ms (a),

which was set in the laboratory during the CRT procedure. At an AV delay of 150 ms (b), the Doppler mitral inflow pattern has

improved, as an A wave is unmasked, whereas optimal diastolic filling is realized only when the AV delay is prolonged to

250 ms. Notably, at this prolonged AV delay setting of 250 ms (c), the A-wave termination falls clearly after the QRS onset – hence,

a relatively physiologic electrical–mechanical delay can be assumed.


V–V timing is another parameter that can be

modified in patients undergoing BiV pacing,

especially in the non-responder group. As with

AV optimization, optimization of V–V timing

has little data to support its utility and impact on

outcome measures. Additionally, similar to AV

timing, V–V timing likely contributes relatively

little to the overall impact of CRT. However, in

selected cases, V–V timing may have a significant impact. Preliminary studies have demonstrated improvement in hemodynamics.16–18

It has been speculated that this may in part be

the result of compensation for suboptimal lead

position.19 Sogaard et al,20 for example, suggested that patients with ischemic cardiomyopathies benefit from a right ventricular (RV)

pre-offset, whereas patients with dilated cardiomyopathies benefit from an LV pre-offset.

Furthermore, Porciani et al10 demonstrated that

tailored BiV pacing was advantageous. Bordacher

et al17 demonstrated that V–V optimization

resulted in a significant reduction in mitral regurgitation, whereas Van Gelder et al18 reported that



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Figure 20.5 This patient is a 76-year-old female with ischemic cardiomyopathy, ischemic mitral regurgitation, hypertension, and

paroxysmal atrial fibrillation who was s/p Carpentier–Edwards mitral valve replacement. She had recently undergone CRT and

now presented for an AV optimization procedure. The AV delay was set at 320 ms at the time of the BiV implant. Further investigation revealed that the interatrial conduction times had been measured at time of BiV implant in the endocardial prosthesis

laboratory and found to be very abnormally prolonged (350 ms) as the patient had biatrial enlargement with an LA diameter of

6 cm and an area of 34 cm2. It was decided to modify the AV delay to investigate whether changes in diastolic filling could be

elicited. Mitral inflow is shown at AV delays of 320 ms (a), 150 ms (b), and 250 ms (c). The optimal diastolic filling was confirmed to be at an AV delay of 320 ms.

most patients (83%) benefited from LV-first preactivation in a series of 53 patients. One of the

major challenges, however, is to agree or settle

on the best non-invasive parameter available in

our armamentarium that can be practically

employed to assist in detecting whether simultaneous versus LV pre-offset versus RV pre-offset

is best in a given patient.

Clearly, further investigation is needed to

guide appropriate adjustment of this capability.

However, in the absence of definitive guidelines,

and particularly in patients with a suboptimal

response to CRT, it is certainly reasonable to

optimize hemodynamics utilizing one or more

parameters of cardiac function. The protocol utilized in our laboratory is to measure aortic outflow (stroke volume estimate) and the Tei index

(aortic outflow and mitral inflow by pulsed

Doppler) with simultaneous pacing, and four

LV and four RV pre-offsets at 20 ms intervals.

Simultaneous pacing is maintained in most

cases, and only if both parameters exhibit a consistent positive improvement in function at a

given setting will we recommend modification

of the V–V timing. The evaluation will then be

repeated in 6 months to reassess the patients’

clinical status, as well as the associated hemodynamic parameters.



Once AV and V–V timing has been optimized,

and if no improvement in symptoms or ventricular function has been realized, then a reassessment of intraventricular dyssynchrony using

Doppler tissue imaging could be informative.

Importantly, comparison with baseline or preimplant dyssynchrony information, as well as

precise knowledge of the coronary sinus lead

location, are necessary in order to provide the

greatest possible insight into the impact of BiV

stimulation on ventricular mechanical function.

Evaluating intraventricular dyssynchrony post

implant without pre-implant baseline dyssynchrony data and without precise information on

lead location can be problematic, as residual

dyssynchrony will likely be present (Figure 20.6) –

and, without baseline data, much less meaningful.

Improvement in intraventricular dyssynchrony

may be useful to document but is not necessary

for success of therapy (Figure 6 and 7).

If LV function is poor (ഛ 35%), unchanged

from baseline, or worse as compared with baseline, and significant intraventricular dyssynchrony persists, particularly if the segment of

most significant delay does not correspond to



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Figure 20.6 Basal and mid myocardial velocity data pre and post CRT obtained using Doppler Tissue Imaging from a 49 y/o

female with a dilated cardiomyopathy and LBBB who responded favorably with improvement in symptoms and EF from 20% to

30%. The left panel is pre implant and demonstrates significant intraventricular dyssynchrony (opposing wall time to peak velocity difference of 112ms from the apical 4 chamber view). The right panel is post implant and reveals persistent residual intraventricular dyssynchrony (opposing wall time to peak velocity difference of 120ms) despite satisfactory lead placement and a

favorable clinical response to CRT.

the site of the coronary sinus lead placement, then

it would seem reasonable to consider revising

lead placement either transvenously or surgically

with an epicardial lead. The recognition of an

anterior lead location combined with a nonresponder status would also favor proceeding

with lead repositioning (Figure 20.8). When a

clear discordance between lead position and

dyssynchrony data cannot be determined with a


high degree of confidence, attempting an

empiric lead revision should be avoided.

Finally, if no clear explanation of the patient’s

failure to respond can be confidently diagnosed, a

trial of allowing intrinsic conduction by discontinuing pacing therapy should be attempted. Global

ventricular function as well as re-acquisition of

dyssynchrony parameters can be re-evaluated

during intrinsic conduction, along with a clinical


112 ms

Figure 20.7 Base and mid myocardial velocity data pre and post CRT within 3 days of implant of a CRT device obtained using

Doppler Tissue Imaging. The left panel is pre implant and demonstrates significant intraventricular dyssynchrony (opposing wall

time to peak velocity difference of 100 ms from the apical 4 chamber view at the base) with improvement in dyssynchrony (right

panel) as the systolic peaks align nearly perfectly. The patient responded favorably with an improvement in symptoms and

LV function.



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Figure 20.8 Multislice computed tomographic (MSCT) scan of

the heart, and more specifically of the coronary veins. This is

a 65-year-old male who underwent CRT and was designated a

non-responder, as after 3 months and then 6 months, his

LVEF was unchanged and his symptomatology was not

improved. Further diagnostics were performed, including a

MSCT scan to assess precise lead placement. The coronary

sinus lead here is seen traversing the great cardiac vein on

the anterior aspect of the heart, and could well explain the

suboptimal response described clinically.

evaluation for a trial period. Clearly, pacing can

be detrimental to LV function – even BiV pacing

with the RV lead positioned in the RV apex.21



This group of patients may or may not be

categorized as non-responders, depending on

whether or not reverse remodeling is considered

necessary to define success. The placebo effect

may be implicated as an explanation for improvement in this subgroup, and therefore a neutral

effect on ventricular function could be consistent

with this outcome. Yet another possibility, however, is that functional status is in fact truly

improved yet traditional methods of evaluating ventricular function are suboptimal for

measuring a real increase in ventricular contractility. In these cases, demonstrating improved

intraventricular synchrony as described above

by comparing pre- and post-implant dyssynchrony measures may be clinically useful.22

Even though no objective improvement in

ventricular function may be realized when using

standard measures of function such as LVEF, an

assessment of intraventricular dyssynchrony

may be worth documenting. This scenario

would contrast with that of a patient whose ventricular function has clearly improved by twodimensional echocardiographic assessment of

LVEF by volumes and in whom an assessment

of intraventricular dyssynchrony could therefore be considered irrelevant and potentially

even misleading to the uninformed.

The time to peak velocity measurements as

determined by color Doppler tissue imaging

utilizing the opposing-wall method (a standard

measure of intraventricular mechanical dyssynchrony) is recommended as a parameter

that could be collected pre and post implant

for comparison.5,23 It is important to note that

opposing-wall time to peak velocity measurements made in isolation post-implant will have

little meaning unless pre-implant data are readily available for comparison.22,24 As reported by

Yu et al,23 segmental opposing-wall times to peak

velocity (Ts) post BiV implant remain abnormally prolonged (anteroseptum 191 ± 32 ms and

lateral wall 213 ± 44 ms); however, the coefficient

of regional variation relative to pre-implant is

improved as a result of a more synchronized

segmental delay among regions of the LV.


If at 1–3 months post-implant a patient exhibits no

objective improvement in either symptoms or ventricular function, most clinicians would consider

this to be in the non-responder category. In these

cases, a systematic investigation of possible explanations for the lack of response should be initiated.

After reviewing the baseline data, including the

patient selection criteria to assure appropriate candidacy and to rule out other potential reversible

causes of ventricular dysfunction, procedural

issues (operative notes) should be reviewed and

pacing setting optimization should be considered.

Lead position should be reviewed and confirmed with a postero-anterior and lateral



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chest X-ray. If the lead position is in a location

typically considered suboptimal (i.e., anterior), if

the RV/cardiac sinus lead distance is not maximized, or if intraventricular dyssynchrony can

be confidently determined to be increased or

even unchanged as compared with the preimplant evaluation, then serious consideration

should be given to repositioning the LV lead.

Finally, useful information may be obtained by

re-examining intraventricular mechanical dyssynchrony by color TDI with the pacemaker in

both the off and the on mode and comparing

more acutely the real-time impact of the BiV

pacing therapy on ventricular synchrony and

function. On occasion, it can be determined that

ventricular function and/or intraventricular

dyssynchrony are worsened with BiV pacing.







Improving our understanding of the mechanisms underlying CRT, (which will lead to

improved selection criteria and implantation

technique), will be the basis for minimizing the

non-responder population. However, until this

progress can be realized, evaluation and management of the non-responder population must

be thoughtful, careful, and thorough.

Because of the many limitations and uncertainties clinicians have before them in trying to

identify and problem-solve this population of

patients, it is imperative that they accurately

define the problem with objective data, review

expectations with their patients, and pursue a

redirection of therapy only once definitive diagnosis can be delineated. Additionally, appreciating the utility as well as the limitations of

echocardiography can be extremely valuable in

arriving at a correct diagnosis and ultimately

applying the appropriate corrective therapy –

which may well include no therapy.




Cazeau S, Leclercq C, Lavergne T, et al. ftMSiCS

Investigators. Effects of multisite bi-ventricular pacing in

patients with heart failure and intra-ventricular

conduction delay. N Engl J Med 2001;344:873–80.

Bristow M, Saxon L, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable








defibrillator in advanced chronic heart failure. COMPANION Investigators. N Engl J Med 2004;350:2140–50.

Cleland J, Daubert J, Erdmann E, et al. CARE-HF Study

Investigators. The effect of cardiac resynchronization

on morbidity and mortality in heart failure. N Engl J

Med 2005;352:1539–49.

Bax JJ, Abraham T, Barold SS, et al. Cardiac resynchronization therapy: Part I: Issues before device implantation. J Am Coll Cardiol 2005;46:2153–67.

Yu CM, Bleeker GB, Fung JW, et al. Left ventricular

reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization

therapy. Circulation 2005;112:1580–6.

Young JB, Abraham WT, Smith AL. Multicenter Insync

ICD Randomized Clinical Evaluation (MIRACLE ICD)

Trial Investigators. Combined cardiac resynchronization and Implantable cardioversion defibrillation in

advanced chronic heart failure: the MIRACLE ICD trial.

JAMA 2003;289:2685–94.

St John Sutton MG, Plappert T, Abraham WT, et al.

Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure.

Circulation 2003;107:1985–90.

Auricchio A, Stellbrink C, Block M, et al. Effect of

pacing chamber and atrioventricular delay on acute

systolic function of paced patients with congestive

heart failure: the Pacing Therapies for Congestive Heart

Failure Study Group: the Guidant Congestive Heart

Failure Research Group. Circulation 1999;99:2993–3001.

Kedia N, Ng K, Apperson-Hansen C, et al. Usefulness

of atrioventricular delay optimization using Doppler

assessment of mitral inflow in patients undergoing

cardiac resynchronization therapy. Am J Cardiol 2006;


Porciani MC, Dondina C, Macioce R, et al.

Echocardiographic examination of atrioventricular and

interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol 2005;95:1108–10.

Ronaszeki A. Hemodynamic consequences of the

timing of atrial contraction during complete AV block.

Acta Biomed Lovaniensia 1989;15.

Faddis MN, Waggoner AD, Sawhney N. AV delay optimization by aortic VTI is superior to the pulsed

Doppler mitral inflow method for cardiac resynchronization therapy. Pacing Clin Electrophysiol 2003;


Ritter P, Padeletti L, Gillio-Meina L, et al. Determination

of the optimal atrioventricular delay in DDD pacing:

comparison between echo and peak endocardial acceleration measurements. Europace 1999; 1:126–30.

Sawhney NS, Waggoner AD, Garhwal S, et al.

Randomized prospective trial of AV delay programming for cardiac resynchronization therapy. Heart

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15. O’Donnell D, Nadurata V, Hamer A, Kertes S,

Mohammed W. Long term variations in optimal programming of CRT devices. Pacing Clin Electrophysiol

2005;(Suppl 1):S27–30.

16. Mortensen PT, Sogaard P, Mansour H, et al. Sequential

biventricular pacing: evaluation of safety and efficacy.

Pacing Clin Electrophysiol 2004;27:339–45.

17. Bordachar P, Lafitte S, Reuter S, et al. Echocardiographic

parameters of ventricular dyssynchrony validation

in patients with heart failure using sequential biventricular pacing. J Am Coll Cardiol 2004;44:2154–65.

18. Van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ,

Pijls NH. Effect of optimizing the VV interval on left

ventricular contractility in cardiac resynchronization

therapy. Am J Cardiol 2004;93:1500–3.

19. Greenberg J, Delurgio DBM, Mera F. Left ventricular

lead location in biventricular pacing with variable

RV–LV timing does not affect optimal stroke volume.

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Electrophysiology (NASPE), 2002:151.

20. Sogaard P, Egeblad H, Pedersen AK, et al. Sequential

versus simultaneous biventricular resynchronization





for severe heart failure: evaluation by tissue Doppler

imaging. Circulation 2002;106:2078–84.

Willkoff BL, Cook JR, Epstein AE, et al. Dual-chamber

pacing or ventricular back-up pacing in patients with

an implantable defibrillator; the Dual chamber And

VVI Implantable Defibrillator (DAVID) trial. JAMA


Gorcsan J, Kanzaki H, Bazaz R, Dohi K, Schwartzman

D. Usefulness of echocardiographic tissue synchronization imaging to predict acute response to cardiac

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improved synchronicity by simultaneously delaying

regional contraction after biventricular pacing therapy

in heart failure. Circulation 2002;105:438–45.

Yu CM, Lin H, Fung WH, et al. Comparison of acute

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Use of devices with both cardiac

resynchronization and

cardioverter–defibrillator capabilities

Arthur M Feldman, Reginald T Ho, and Behzad Pavri

Introduction • Clinical studies • Cost of CRT-D devices • Caveats regarding CRT-D therapy

• Summary


As detailed in other chapters of this textbook, two

unique and distinct devices have been evaluated

for the treatment of patients with congestive heart

failure: implantable cardioverter–defibrillators

(ICD) and cardiac resynchronization devices

(CRT). The development of each of these devices

was based on a unique hypothesis. In the case of

the ICD, investigators hypothesized that because

a large number of heart failure patients died suddenly,1 presumably secondary to a lethal tachyor bradyarrhythmia, the ability of an implanted

device to sense and defibrillate a tachyarrhythmia

or to sense and pace a bradyarrhythmia would be

beneficial. Alternatively, the observation that

nearly 30% of patients with heart failure had

dyssynchronous left ventricular (LV) contraction

and that cardiac dyssynchrony was associated

with worsened ventricular function, increased

myocardial oxygen demand, maladaptive ventricular remodeling, and increased mortality2–5

led investigators to assume that resynchronizing

the pattern of ventricular contraction would have

salutary benefits. Indeed, these assumptions

proved true, as both individual trials6,7 and metaanalysis have demonstrated salutary benefits of

both ICD therapy8 and CRT9 in patients with

heart failure.

Interestingly, the development of both the

ICD and CRT devices was facilitated by similar

advances in engineering that provided miniaturization of the required electronics as well as the

capacity to both detect and transmit electrical

signals across wires that could readily be placed

in contact with the ventricular myocardium.

Furthermore, the utility of the CRT device was

enhanced by the development of techniques and

equipment for reaching the LV myocardium via

a percutaneous approach through the coronary

sinus. Engineers were also able to combine both

the technology for biventricular pacing and

requisite technology for defibrillation into the

same relatively small device, thereby overcoming the problems associated with the device–

device interactions that had plagued separately

implanted pacemakers and defibrillators.

Intuitively, the combination of an ICD and a

CRT device seemed logical because each would

be expected to interact with different physiologic pathways in the ventricular myocardium

and thus provide salutary benefits through

different mechanisms. However, the combined

use of an ICD and a CRT device has not been

without controversy. Indeed, the recent

American College of Cardiology/American

Heart Association (ACC/AHA) Guidelines note

that the balance of risks and benefits of ICD

implantation in an individual patient is complex,

particularly in patients with advanced heart failure or other comorbidities, in whom the survival

benefit obtained with an ICD implantation



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The first prospective multicenter study to evaluate an implantable CRT device was reported in

2002.13 The InSync study enrolled patients who

met indications for implantation of an ICD

because of symptomatic sustained ventricular

tachycardia (VT) and/or survival of a cardiac

arrest. Patients were required to have an LV ejection fraction (LVEF) <35%, an LV end-diastolic

diameter >55 mm, and a QRS duration >130 ms.

In comparison with baseline measures, the

81 patients in whom the LV lead was successfully

implanted demonstrated an improvement in

6-minute walk time, classification of New York

Heart Association (NYHA) symptoms, and LV

fractional shortening, as well as decreases in

both end-systolic and end-diastolic dimensions.

Of 81 patients, 26 experienced a total of 472

episodes of spontaneous sustained VT, with all

episodes being successfully terminated (with the

exception of 16 episodes in a single patient who

had incessant VT). Although interpretation of

the study was limited because of the lack of a

control arm, it was the first to demonstrate in a

modest-sized population of heart failure

patients that an ICD and a CRT could be used

together with favorable clinical outcomes.

QRS interval ജ120 ms. Because the patients

enrolled in the study had an immediate need for

an ICD, the total system was implanted but the

patient was not randomized to CRT or no CRT

until after a period of at least 30 days. The study

began as a crossover study after a period of

3 months, but was then changed to a parallel

design because of regulatory concerns. A total of

501 patients were implanted with the device

system, although 11% of patients received the

device via a transthoracic intervention. Patients

were then randomized to either CRT or control

for up to 6 months, with the primary endpoint

being heart failure progression as defined by

the combination of all-cause mortality, hospitalization for heart failure, and VT/ventricular

fibrillation (VF) requiring device intervention.

Randomization to the active treatment group

was associated with a trend towards an

improvement in heart failure progression, but,

this trend was not statistically significant.

However, patients randomized to CRT demonstrated an improvement in functional capacity, a

reduction in ventricular size, and an improvement in LV function – but not a change in NYHA

symptoms. Patients with NYHA class III and IV

symptoms appeared to have the most robust

response to CRT. Importantly, there were no

differences in the incidence or frequency of

ventricular tachyarrhythmias in the two treatment groups, and patients who experienced

spontaneous monomorphic VT were successfully treated in 88% of the episodes. Because of

the relatively short follow-up period of the trial,

investigators could not assess the effect of longterm therapy with CRT-D in this patient population. Nonetheless, it confirmed early studies

demonstrating improvements in functional

capacity in patients with heart failure, as well as

further documenting the safety of combining an

ICD with a CRT.



The CONTAK-CD study was a double-blind,

randomized, controlled study in patients with

symptomatic heart failure who also had indications for placement of an ICD.14 All patients had

typical enrollment criteria, including NYHA

class II–IV symptoms, an LVEF ഛ35%, and a

Similar to CONTAK-CD, the MIRACLE

(Multicenter Insync Randomized Clinical

Evaluation) ICD trial enrolled patients with

LVEF ഛ35%, QRS duration ജ130 ms, and a high

risk of life-threatening ventricular arrhythmias

but who had NYHA class III or IV symptoms.15

might not be evident for several years10–12 or

may be overshadowed by competing causes of

mortality. Therefore, in this chapter, we will

review the available data on the combined use of

an ICD and a resynchronization device (CRT-D),

address some of the ongoing controversies,

including the combined cost of both devices

versus the cost of either device alone, and provide some pragmatic recommendations for the

use of CRT-D.



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Chapter 20. Non-responders and patient selection from an echocardiographic perspective

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