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Chapter 18. Echocardiographic determination of respone to cardiac resynchronization therapy

Chapter 18. Echocardiographic determination of respone to cardiac resynchronization therapy

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Figure 18.1 Apical view with imaging of left ventricular outflow tract and placement of pulsed Doppler sample volume (a) and

the corresponding spectral Doppler velocity tracing over time (b) for estimation of stroke volume.

stroke volume in situations where the crosssectional area through the aortic valve is not

represented by the cross-sectional area of the

measured aortic annulus in low-flow states

where the valve leaflets do not separate fully.

Accordingly, the pulsed Doppler method may

be advantageous in the assessment of heart failure patients with diminished stroke volume. The

relative advantages and disadvantages of pulsed

versus continuous-wave Doppler become less

important when patients are assessed before and

acutely after CRT, where one assesses changes

from baseline and individual patients serve as

their own controls. Another important factor is

the presence of heart rate changes that may

affect results. Acute increases in Doppler measures of stroke volume following CRT have been

predicted by the presence of longitudinal dyssynchrony by tissue Doppler velocities and also radial

dyssynchrony by either tissue Doppler or speckle

tracking measures of radial strain.5–7 In a group of

29 patients studied by longitudinal color-coded

tissue Doppler – known as tissue synchronization

imaging – CRT was associated with acute favorable effects on LV function for the entire study

group: stroke volume by pulsed Doppler

increased from 56 ± 12 ml to 63 ± 12 ml (p < 0.001).5

The presence of an opposing wall delay in the

time to peak velocity ജ 65 ms was predictive of

favorable response. In a separate study, small

but significant increases in stroke volume from

31 ± 16 ml to 35 ± 16 ml (p <0.001) occurred following CRT, and radial dyssynchrony ജ130 ms

by speckle tracking of radial strain predicted

an acute response with 91% sensitivity (95% confidence interval (CI) 76–97%) and 75% specificity

(95% CI 51–90%).7 Increases in LV ejection fraction (LVEF) can be detected in these same

patients with an acute response to CRT.

However, these changes are usually subtle in

individual patients – perhaps due to variability in

tracing LV volumes by the biplane Simpson’s

rule. For example, small but significant acute

increases in LVEF were observed from 24% ± 6%

to 26% ± 6% (p < 0.005) in the tissue Doppler

study mentioned above5 and from 26% ± 7% to

29% ± 7% (p < 0.0005) in the speckle tracking

radial strain study in patients studied the day

after CRT.7

Acute improvements in stroke volume, as

assessed by Doppler echocardiography, have

been correlated with acute improvements in

dyssynchrony following CRT. In a study of

33 patients with measures of stroke volume and



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radial dyssynchrony by tissue Doppler strain

before and the day after CRT, changes in radial

dyssynchrony correlated with acute changes in

stroke volume (r = 0.83, p < 0.0001).6 Changes in

stroke volume correlated with the degree of

baseline dyssynchrony until 200 ms (r = 0.93,

p < 0.0001); thereafter, a plateau was observed,

similar to the pattern observed by Bax et al8 with

longitudinal velocities. It appears that reductions in LV end-systolic volume (LVESV) and

improvements in LVEF associated with reverse

remodeling are preferred for determining

long-term or chronic response to CRT. Although

Doppler estimates of stroke volume are very

useful in determining acute responses, they are

difficult to obtain in the electrophysiology laboratory at the time of implantation because of

logistical difficulties with the sterile field and

fluoroscopy equipment, which may limit access

to the patient’s echocardiographic windows.

Accordingly, these acute non-invasive hemodynamic studies can be done more easily in the

echocardiography laboratory or at the patient’s

bedside following CRT implantation. An alternative method to assess acute changes in LV

function following CRT is to estimate dP/dt

using continuous-wave Doppler assessment of

the mitral regurgitant jet.9


Echocardiography is an important means to

follow the clinical progress of patients with heart

failure. Accordingly, it is an important means to

quantify response to CRT. Clinical trials have

used clinical endpoints to determine clinical

response, but several trials have included measures of LV volumes and LVEF as part of their

protocol. CRT appears to exert favorable effects

on LV structure and function that are known as

reverse remodeling. This was demonstrated in

the MIRACLE trial, where 453 patients who had

a device successfully implanted were randomized either to the control group of 225 with

biventricular pacing turned off or to the CRT

group of 228 with biventricular pacing turned on.10

Quantitative echocardiography preformed by an

expert core laboratory revealed a significant

decrease in LV end-diastolic volume (LVEDV)

and LVESV (p <0.001) and an increase in group

mean LVEF by 3.6% in the CRT group versus

0.4% in the control group 6 months after CRT

(p<0.001). These results have been a consistent

finding in several randomized trials of CRT

where improvements in LVESV and LVEF were

observed in the CRT treatment groups.1,2 The

echocardiographic quantitative standard for

determining these chronic changes is application

of the biplane Simpson’s rule, or method of

disks, to the apical four- and two-chamber

views11 (Figure 18.2). Yu et al12 demonstrated a

dramatic dynamic relationship between CRT

and reverse remodeling in a series of 25 patients

in whom CRT was instituted, resulting in

decreases in LVESV and increases in LVEF

followed by a period of time where CRT was

turned off. These beneficial changes in LVESV

and LVEF were lost with cessation of CRT after

4 weeks, followed by return of the favorable

effects on LV function following reinstitution of

CRT. Bleeker et al13 examined the agreement

between clinical and echocardiographic parameters of reverse remodeling following CRT.

In 144 patients following CRT, they observed an

agreement between clinical response (a reduction in ജ1 NYHA class) after 3–6 months of CRT

and echocardiographic response (defined as a

decrease of >15% in LVESV in 76%: 74 patients

(51%) had reductions in NYHA class and LVESV

and 36 patients (25%) had no reductions in

either NYHA class or LVESV. However, clinical

improvement without a >15% reduction in

LVESV was observed in 27 patients (19%), and

7 patients (5%) with no clinical response had

reductions in LVESV. Thus, in 34 patients (24%),

a disagreement between clinical and echocardiographic responses was noted; this disagreement

was mainly due to patients with clinical

responses without echocardiographic responses.

This was hypothesized to be related to factors

other than LV function or to a placebo effect,

which is a common feature of clinical therapeutic trials. Yu et al14 also reported results in

141 patients with advanced heart failure who

had echocardiographic measures of reverse

remodeling, as defined by a decreases in LVESV.

Specifically, they observed a decrease in LVESV

of ജ9.5% to have a sensitivity of 70% and a specificity of 70% in predicting all-cause mortality,

and of 87% and 69%, respectively, in predicting



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Volume = ∑( 14 πD 2)h

Figure 18.2 Apical four-chamber (a) and two-chamber (b) views with computer-assisted tracing of endocardial borders from digital

images for calculation of volumes and ejection fraction using the biplane Simpson’s rule (method of disks). D, diameter of disk;

h, height of disk.

>10% decrease in LVESV



Survival (%)






<10% decrease in LVESV

p < 0001



10 n = 141







Years after CRT

Figure 18.3 Kaplan–Meier survival curve of patients with reductions in left ventricular end-systolic volume (LVESV) of ജ10%

following cardiac resynchronization therapy (CRT), compared with the curve for those who did not demonstrate evidence of

reverse remodeling.



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Clinical parameters











6-min walk

QOL score


Percentage improvement

Percentage improvement


Echocardiographic data

*p < 0.008












Figure 18.4 Comparison of clinical predictors of response to cardiac resynchronization therapy with echocardiographic measures of left ventricular end-diastolic and end-systolic volumes (LVEDF and LVESV) and ejection fraction (LVEF), demonstrating

greater predictive valve of echocardiographic data (b) versus clinical markers of response (a). NYHA, New York Heart Association

functional class; QOL, quality-of-life questionnaire; NS, not significant.

cardiovascular mortality. Accordingly, a decrease

in LVESV of at least 10% was found to be a clinically relevant marker of reverse remodeling,

and to actually predict survival better than routine clinical markers (Figure 18.3). They found

LVESV to be a better predictor of survival and

heart failure events after CRT than NYHA functional class, 6-minute walk distance or qualityof-life score by questionnaire (Figure 18.4). This

supports the important and objective nature of

echocardiographic determination of LVEDV,

LVESV, and LVEF in predicting outcome in

heart failure patients following CRT.

Suffoletto et al15 reported a preliminary experience with examining the relationship of acute

hemodynamic response to chronic reverse remodeling in 33 patients who were studied the day

after CRT and 7 ± 5 months (all > 3 months)

following CRT. An acute hemodynamic response,

defined as ജ15% increase in stroke volume by

Doppler echocardiography, occurred in 22 of

33 patients (67%), 19 of whom (86%) went on to

reverse remodeling 7±5 months after CRT and

whose LVEF increased from 25% ± 7% to

34%±11% (p<0.001). A subset of patients who did

not have an acute hemodynamic response still

went on to demonstrate decreases in LVESV and

increases in LVEF. Baseline dyssynchony by

tissue Doppler was found to be statistically

predictive of both acute hemodynamic response

and later reverse remodeling. A relationship of

acute to chronic response was observed, but

there were patients in whom chronic reverse

remodeling could occur, despite the lack of an

acute response.


1. Abraham WT, Fisher WG, Smith AL, et al. MIRACLE

Study Group. Cardiac resynchronization in chronic heart

failure. N Engl J Med 2002;346:1845–53.

2. Cleland JG, Daubert JC, Erdmann E, et al. Cardiac

Resynchronization–Heart Failure (CARE-HF) Study

Investigators. The effect of cardiac resynchronization on

morbidity and mortality in heart failure. N Engl J Med

2005; 352:1539–49.

3. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with

dilated cardiomyopathy and ventricular conduction

delay. Circulation 1999;99:1567–73.

4. Lewis JF, Kuo LC, Nelson JG, Limacher MC,

Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical

validation of two new methods using the apical window.

Circulation 1984;70:425–31.

5. Gorcsan J III, Kanzaki H, Bazaz R, Dohi K, Schwartzman D.

Usefulness of echocardiographic tissue synchronization

imaging to predict acute response to cardiac resynchronization therapy. Am J Cardiol 2004;93:1178–81.



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6. Dohi K, Suffoletto MS, Schwartzman D, et al. Utility of

echocardiographic radial strain imaging to quantify left

ventricular dyssynchrony and predict acute response to

cardiac resynchronization therapy. Am J Cardiol


7. Suffoletto M, Dohi K, Cannesson M, Saba S, Gorcsan J.

Novel speckle-tracking radial strain from routine black

and white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation 2006;113:960–8.

8. Bax JJ, Bleeker GB, Marwick TH, et al. Left ventricular

dyssynchrony predicts response and prognosis after

cardiac resynchronization therapy. J Am Coll Cardiol


9. Heist E, Taub C, Fan D, et al. Usefulness of a novel

‘response score’ to predict hemodynamic and clinical

outcome from cardiac resynchronization therapy. Am J

Cardiol 2006;97:1732–6.

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

Multicenter InSync Randomized Clinical Evaluation

(MIRACLE) Study Group. Effect of cardiac resynchronization therapy on left ventricular size and function in

chronic heart failure. Circulation 2003;107:1985–90.

11. Lang RM, Bierig M, Devereux RB, et al. Recommendations

for chamber quantification: a report from the American

Society of Echocardiography’s Guidelines and

Standards Committee and the Chamber Quantification

Writing Group. J Am Soc Echocardiogr 2005;18:1440–63.

12. Yu CM, Chau E, Sanderson JE, et al. Tissue Doppler cardiographic evidence of reverse remodeling and

improved synchronicity by simultaneously delaying

regional contraction after biventricular pacing therapy

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

13. Bleeker GB, Bax JJ, Fung JW, et al. Clinical versus

echocardiographic parameters to assess response to

cardiac resynchronization therapy. Am J Cardiol


14. 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.

15. Suffoletto MS, Cannesson M, Tanabe M, Saba S,

Gorcsan J. Relationship of tissue doppler dyssynchrony

and acute hemodynamic response to later reverse

remodeling after resynchronization therapy. J Am Coll

Cardiol 2006;47:11A (abst).



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Impact of cardiac resynchronization

therapy on mitral regurgitation

Ole-A Breithardt

Introduction • Pathophysiology of functional mitral regurgitation in heart failure • Effects

of CRT on functional mitral regurgitation • Summary


Functional mitral regurgitation (MR) contributes

significantly to the poor hemodynamic status

of patients with advanced systolic heart failure.

Its presence is an unfavorable prognostic marker

in patients with systolic heart failure and is

associated with worsening clinical symptoms, a

decrease in exercise capacity, and decreased

survival. In a prospective trial including 128

consecutive patients with left ventricular (LV)

dysfunction (LV ejection fraction (LVEF) <50%,

average 31% ± 9%), more than 80% of all patients

presented with more than trace functional MR.1

Another study reported a 30% incidence of

severe MR in patients with severely depressed

LV function.2 The severity of functional MR has

been associated with an adverse outcome in

terms of mortality and hospitalization,2–5 particularly in patients after myocardial infarction.6

This motivated the development of numerous

different therapeutic strategies to reduce the

severity of functional MR, ranging from pharmacologic treatment7 to corrective surgical

measures8 and more recently percutaneous

approaches for mitral annuloplasty.9 Conservative

medical treatment with vasodilator agents

such as angiotensin-converting enzyme (ACE)

inhibitors is of limited success, with a 2-year

survival rate of less than 60% in patients with

severe MR,4 and mainly effective in patients

with arterial hypertension.10 Surgical approaches

to reduce severe functional MR in dilated

cardiomyopathies have focused on downsizing

the mitral annulus, and have been comparatively successful, with 2-year survival rates

ranging between 71% and 85%.11,12 Despite these

promising results, many physicians and patients

refrain from open-heart surgery because of

the significant perioperative morbidity and the

early mortality rate of 5–9%.13 Less-invasive percutaneous approaches are currently under

investigation, but long-term results are still


LV-based pacing might be an alternative

strategy to reduce the severity of functional

MR in selected patients with advanced systolic

heart failure and mechanical LV dyssynchrony.

Already in the very first patients who underwent

‘multisite pacing for end-stage heart failure’ –

nowadays referred to as cardiac resynchronization therapy (CRT) – it was noted that CRT

not only improved the systolic function of the

LV, but, almost as a side-effect, also reduced

the severity of functional MR, as measured

by the mean pulmonary capillary v-wave.14,15

These early observations obtained by right-heart

catheterization were confirmed in many subsequent studies using more direct measures for

quantification of MR severity. All investigators



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consistently reported that CRT is associated with

a significant decrease in functional MR, both

acutely16–18 and in long-term follow-up.19–28 To

understand the mechanisms responsible for this

CRT-related improvement in the severity of

functional MR, it is necessary to take a closer

look at the complex pathophysiology of this




The term ‘functional MR’ implies the presence of

MR in the absence of structural damage to the

mitral valve leaflets. In the presence of systolic

heart failure, the incomplete systolic closure

of the mitral leaflets is provoked by several

contributing factors:

LV remodeling (i.e., spherical dilatation)

regional wall motion abnormalities

depressed LV systolic function

The most frequently cited (and probably

somewhat overemphasized) responsible condition for the occurrence of functional MR is

progressive dilatation of the mitral annulus in

the failing heart. It has been postulated that the

mitral leaflet area is insufficient to compensate

for the dilatation of the mitral annulus in heart

failure patients,29 but anatomic studies have

demonstrated that the actual available mitral

leaflet area is theoretically large enough to




compensate for an amount of annular dilatation

that is usually beyond the degree observed in

heart failure patients.30 Thus, mitral annular

dilatation alone cannot sufficiently explain the

occurrence of functional MR. Simultaneous with

the dilatation of the mitral annulus, the LV

undergoes spherical LV remodeling with a progressively increasing distance between the mitral

leaflets and the papillary muscles. Since the

chordal apparatus is inelastic, the increased distance will in turn lead to an increased tethering

force that drags on the leaflet edges during systole and delays or even completely prevents complete leaflet coaptation during systole (Figure

19.1).31,32 The amount of tethering can be quantified by measuring the outward displacement of

the mitral leaflets, the so-called ‘tenting’ area.31,33

These observations led to the experimental concept of selective chordal cutting to reduce the

tethering forces and thereby the severity of functional MR.34 Furthermore, it has been well documented not only that regional dysfunction in

the area of papillary muscle insertion after

myocardial infarction may cause or aggravate

functional MR,1 but also that an additional

isolated loss of papillary muscle contraction may

paradoxically reduce the amount of MR. While

any regional dysfunction of the myocardium

around the papillary muscle insertion may augment the tethering forces, the additional loss of

contractile function within the papillary muscle

itself will counterbalance the increased tethering





Papillary muscle


Closing force






Figure 19.1 (a) Balance of forces acting on the mitral valve. (b) Left ventricular (LV) dilatation displaces the papillary muscle

(PM) and increases the mitral tethering forces. This restricts complete mitral valve closure and causes functional mitral regurgitation (MR). LA, left atrium. (Reproduced from Otsuji Y, Handschumacher MD, Schwammenthal E, et al. Insights from threedimensional echocardiography into the mechanism of functional mitral regurgitation: in vivo demonstration of altered leaflet

tethering geometry. Circulation. 1997; 96(6):1999–2008.31)

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Chapter 18. Echocardiographic determination of respone to cardiac resynchronization therapy

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