Biventricular Pacemaker Optimization Guided by Comprehensive ...

CARDIAC RESYNCHRONIZATION THERAPY

From the Non

Cardiovascula

Southern Cali

Reprint reque

Southern Cali

Los Angeles,

0894-7317/$3

Copyright 201

doi:10.1016/j.

Biventricular Pacemaker Optimization Guided byComprehensive Echocardiography—Preliminary

Observations Regarding the Effects on Systolic andDiastolic Ventricular Function and Third Heart Sound

Nima Taha, MD, Jing Zhang, MD, PhD, Rupesh Ranjan, MD, Samuel Daneshvar, MD, Edilzar Castillo, RRT,Elizabeth Guillen, RN, Martha C. Montoya, RDCS, Giovanna Velasquez, and Tasneem Z. Naqvi, MD, FRCP,

FACC, FASE, Los Angeles, California

Background: Doppler echocardiography of mitral inflow or aortic outflow or both has been validated andadvocated to guide biventricular (Biv) pacemaker optimization. A comprehensive and tailored Dopplerechocardiographic evaluation may be required in patients with heart failure to assist with Biv pacemakeroptimization. The third heart sound (S3), an acoustic cardiographic parameter, has been demonstrated tobe a highly specific finding for hemodynamic evaluation in patients with heart failure. The aims of this studywere to evaluate the use of comprehensive Doppler echocardiography as a guide during Biv pacemakeroptimization in patients after cardiac resynchronization therapy and to evaluate the feasibility of S3 intensityto be a cost-efficient parameter for Biv pacemaker optimization compared with Doppler echocardiography.

Methods: Comprehensive Doppler echocardiographic evaluations were performed during Biv pacemakeroptimization in 44 patients referred for pacemaker optimization (mean age, 71 6 12 years; mean left ventricularejection fraction, 34 6 11%). Blinded assessment of S3 intensity was performed simultaneously using acousticcardiography. The correlation and improvement in cardiac hemodynamics were analyzed between themethods.

Results: Echocardiographically guided optimization resulted in significant improvements in the left ventricularoutflow velocity-time integral (15.92 6 4.77 to 18.51 6 5.19 cm, P < .001), ejection time (278 6 40 to 293 6 40ms, P < .001), myocardial performance index (0.57 6 0.19 to 0.44 6 0.14, P < .002), and peak pulmonary arterysystolic pressure (42 6 13 to 36 6 11 mm Hg, P < .04) and decreased S3 intensity from 4.81 6 1.84 at baselineto 3.96 6 1.22 after optimization (P < .02) for the overall study group and from 6.63 6 1.37 to 4.85 6 1.13(P < .001) in the 18 patients with baseline S3 intensity > 5.0. The correlation between echocardiographicand acoustic cardiographic S3 intensity for optimal atrioventricular delay was 0.86 (P < .001) and for optimalinterventricular delay was 0.64 (P < .001). Optimal atrioventricular delay was identical by echocardiographicand acoustic cardiographic S3 intensity in 56%, and optimal interventricular delay was identical in 75% ofpatients. Pacemakers were permanently programmed on the basis of echocardiographic evaluation. In 35patients available for follow up, the mean New York Heart Association class reduced from 2.55 6 0.81 to1.77 6 0.90 (P < .001) and the mean quality-of-life score as assessed by Minnesota Living With Heart FailureQuestionnaire improved from 45 6 28 to 32 6 28 (P = .08) at 2.5 6 2.1 months.

Conclusion: Comprehensive echocardiographically guided Biv pacemaker optimization produces significantimprovement in Doppler echocardiographic hemodynamics, a reduction in S3 intensity, and an improvementin functional class in patients after cardiac resynchronization therapy. (J Am Soc Echocardiogr 2010;23:857-66.)

Keywords: Echocardiography, Doppler, Acoustic cardiography, Biventricular pacemaker, Pacemakeroptimization

Invasive Diagnostic Services and Echocardiography Laboratory,

r and Thoracic Institute, Keck School of Medicine, University of

fornia, Los Angeles, California.

sts: Tasneem Z. Naqvi, MBBS, FRCP, FACC, FASE, University of

fornia, Keck School of Medicine, 1510 San Pablo Street, Suite 322,

CA 90033 (E-mail: [email protected]).

6.00

0 by the American Society of Echocardiography.

echo.2010.04.022

Cardiac resynchronization therapy (CRT) has been effective and stan-dard treatment in patients with drug-resistant heart failure (HF).1

Echocardiographically guided optimization of atrioventricular (AV)delay (AVD) improves left ventricular (LV) filling, and optimized inter-ventricular delay (VVD) leads to further improvement in cardiac out-put in patients with biventricular (Biv) pacemaker.2-7 AdvocatedDoppler parameters include the aortic velocity-time integral(VTI),8,9 diastolic mitral inflow pattern,10 Doppler tissue imaging,2

and Doppler-derived dP/dt.11 Improved LV ejection fraction,6,9,10

857

mailto:[email protected]

Table 1 Pacemaker interrogation

1. Determine percentage Biv pacing. If <95%, determine

mechanisms.

2. Determine patient’s intrinsic AVD. This determines the range of AVDsavailable for programming.

3. Determine backup atrial pacing rate, and turn it up to suppressectopy and down to physiologic levels (60 beats/min) to allow

atrial sensing.

4. Determine heart rate variability, rate response, rate responsesensitivity, and lead thresholds.

5. Evaluate for the presence of sleep apnea.

Abbreviations

AV = Atrioventricular

AVD = Atrioventricular delay

Biv = Biventricular

CRT = Cardiac

resynchronization therapy

EMAT = Electromechanical

activation time

HF = Heart failure

LV = Left ventricular

LVST = Left ventricular

systolic time

MR = Mitral regurgitation

NYHA = New York Heart

Association

PAP = Pulmonary artery

systolic pressure

PW = Pulsed wave

S3 = Third heart sound

VTI = Velocity-time integral

VVD = Interventricular delay

858 Taha et al Journal of the American Society of EchocardiographyAugust 2010

New York Heart Association(NYHA) class,10 and cardiac out-put9 have been reported infollow-up studies. Despite thesedemonstrated benefits, echocar-diographically guided Biv pace-maker optimization is notroutinely performed, given thatit is time, resource, and labor in-tensive. This suggests thatmethods that are simple and ac-curate and that shorten the timeneeded for echocardiographi-cally guided optimization may al-low a wider adoption of Bivpacemaker optimization.

Acoustic cardiography(Audicor; Inovise Medical, Inc,Portland, OR) has been demon-strated to be an accurate phono-cardiographic method forcardiac hemodynamic assess-ment. The assessment of cardiacfunction is achieved by the detec-tion and automated analysis ofsystolic and diastolic heart soundsand their temporal relationshipsto the electrocardiogram. The rel-evant parameters measured by

acoustic cardiography in HF include (1) S3 strength (expressed as0-10 units), which correlates in a linear fashion to LV end-diastolicpressure and has been used to optimize preload in CRT patients12;(2) electromechanical activation time (EMAT), the interval from theonset of the QRS complex to the mitral component of S1, reflectingthe time required for the left ventricle to generate sufficient force toclose the mitral valve; and (3) LV systolic time (LVST), the time fromthe onset of QRS to closure of the aortic valve. EMAT has been shownto correlate with pulsed-wave (PW) Doppler echocardiography of mi-tral inflow or aortic outflow during Biv pacemaker optimization13-15 inpatients with stable HF or those with conduction abnormalities withpreserved heart function who had minimal S3 intensity. In somestudies, acoustic cardiography was not performed concurrently withechocardiographic evaluation.

In clinical practice, patients with symptomatic HF with Biv pace-makers have systolic HF, diastolic HF, elevated filling pressures, andS3 intensity in varying combinations. In these patients, echocardio-graphically guided pacemaker optimization needs to take into consid-eration several other parameters besides LV filling and ejection, suchas mitral regurgitation (MR) severity, the presence or absence of dia-stolic MR, tricuspid regurgitation, pulmonary artery systolic pressure(PAP), atrial filling by pulmonary veins, mechanical dyssynchrony,and the effect of respiration on cardiac hemodynamics.16,17 Thistailored echocardiographic technique has been endorsed by recentguidelines from American Society of Echocardiography18 and resultsin significant improvement in HF.

We hypothesized that a comprehensive Doppler echocardio-graphic evaluation could guide pacemaker optimization in patientswith varying degrees of HF after CRT. In addition, we compared S3

intensity measured by phonocardiography against Doppler parame-ters in guiding pacemaker optimization in a consecutive series ofpatients referred for Biv pacemaker optimization.

METHODS

Subjects

The study protocol was approved by the institutional review board,and all subjects provided written informed consent before enroll-ment. The study group was composed of 50 patients (mean age, 716 12 years) referred to our center by their treating physicians forpacemaker optimization after CRT. All studies were performed asoutpatients except in 3 patients who were hospitalized with HF atthe time of optimization.

Study Protocol

All evaluation was performed after CRT. The pacemaker was inter-rogated using the algorithm shown in Table 1. Underlying intrinsicheart disease, cardiac and valvular function, and cardiac filling pres-sures were evaluated by echocardiography in the left lateral decubitusposition before pacemaker optimization.

Doppler echocardiography and acoustic cardiography were per-formed simultaneously during pacemaker optimization. During pace-maker optimization, echocardiographic (T.Z.N.) and acousticcardiographic evaluation (E.C. and E.G.) was carried out by indepen-dent experts for each method. Two blinded independent investigators(N.T. and J.Z.) performed offline analysis of all echocardiographicdata. Investigators performing offline analysis were blinded to onlineassessments of optimal AVD and VVD settings. Two sonographers(M.C.M. and G.V.) performed imaging. Two investigators (N.T. andS.D.) collected follow-up data.Conventional Doppler Echocardiographic Analysis. LVend-systolic and end-diastolic dimensions, septal and posteriorwall thickness, and left atrial diameter in end-systole were obtainedin the parasternal long-axis view. LV ejection fraction was measuredusing the biplane Simpson’s method.19 Mitral inflow and aorticejection onset and termination were marked using PW Dopplersignals. This allowed the assessment of ejection duration as wellas mitral inflow filling time. Myocardial performance index timewas measured as (A � B)/B, where A is the time from the endof the mitral inflow A wave to the beginning of the next Ewave, and B is the ejection duration. The maximum right ventric-ular–right atrial gradient was obtained with continuous-waveDoppler using a standard method.20 Mitral inflow peak E and Avelocities and E-wave deceleration time were measured usingPW Doppler with the sample volume placed at the tip of the mi-tral leaflets.21 The PW Doppler sample volume was placed 0.5 to 1cm below the aortic valve to obtain the LV ejection duration andaortic VTI. The frame rate was kept above 100 frames/s by usinga single-focus, narrow imaging sector and appropriate depth and

Table 2 Clinical characteristics of study subjects at baseline(n = 44)

Variable Value

Age (y) 71 6 12

Men/women 33(75%)/11(25%)

NYHA class 2.55 6 0.81

I 2 (5%)

II 20 (45%)

III 14 (32%)

IV 8 (18%)

Journal of the American Society of EchocardiographyVolume 23 Number 8

Taha et al 859

frame rate. Parallel Doppler beam alignment to myocardial seg-ments and color Doppler was used for all Doppler data acquisition.An electrocardiogram was displayed on the ultrasound system,and 5 cardiac cycles were used for each data acquisition forpatients in sinus rhythm. For patients in atrial fibrillation or thosewith atrial or ventricular ectopic beats, 10 beats were acquired ineach view. Raw data were stored digitally as Digital Imaging andCommunications in Medicine cine loops of $5 cardiac cyclesand transferred for offline analysis to a customized dedicated work-station equipped with custom-built software (EchoPAC PCDimension version 6.0.1; GE Vingmed Ultrasound AS, Horten,Norway) via the Internet.

Rhythm

Sinus 39 (89%)

Atrial fibrillation/flutter 5 (11%)

CardiomyopathyIschemic 32 (73%)

Nonischemic 12 (27%)

Other clinical conditions

Hypertension 30 (68%)

Diabetes mellitus 14 (32%)

MedicationsDiuretics 34 (77%)

b-blockers 35 (80%)

ACE inhibitors 24 (55%)

Amiodarone 19 (43%)

Echocardiographic findings

LV diastolic diameter (cm) 6.05 6 1.14

LV systolic diameter (cm) 5.08 6 1.18

LV ejection fraction (%) 33.77 6 11.12

LA diameter, superior to inferior (cm) 6.13 6 1.19

LA diameter, anterior to posterior (cm) 4.98 6 0.88

ACE, Angiotensin-converting enzyme; LA, left atrial.

Echocardiographically Guided Optimization

For all patients, AVD optimization was performed first. Broad prin-ciples of PW Doppler echocardiography during pacemaker optimiza-tion were followed on the basis of published recommendations,21 aswell as using a previously described algorithm.19 Care was taken toensure that echocardiographic sample volume and transducer werein the same position for each testing delay to reduce sampling error.AVDs of 30 to 300 ms were tested if possible, with the majority inan available range of 50 to 250 ms. In patients with native AV conduc-tion (n = 21), echocardiographic and acoustic cardiographic data wereobtained during native rhythm. AVD was lowered until complete Bivcapture was attained to determine the upper limit of AVD. Ritter’smethod was used if feasible to determine the optimal AVD.22 In pa-tients in whom Ritter’s method was not feasible, an iterative methodwas used whereby AVD was changed in increments of 10 to 20 msdepending on native AVD and mitral inflow pattern.8 PW Dopplerof the LV outflow tract was performed and LV ejection duration andpeak velocity were measured at each AVD and VVD. OptimalAVD was selected on the basis of the ‘‘best diastolic LV filling pattern’’and highest LV ejection duration and peak velocity, but in patientswho had diastolic MR or tricuspid regurgitation, significant systolicMR, restrictive pulmonary vein filling patterns, prominent pulmonaryvein atrial reversal, and measureable and elevated PAP, these param-eters were reevaluated at optimal AVD to ensure maximum improve-ment in diastolic MR or tricuspid regurgitation, least restrictivepulmonary vein filling pattern (least S:D reversal, highest D-wave de-celeration time), minimum pulmonary vein atrial reversal, least PAP,and minimum systolic MR along with optimum LV VTI and diastolicfilling pattern. In some patients, mitral filling time had to be compro-mised to minimize pulmonary vein flow reversal, while in others, themitral inflow A wave had to be truncated to avoid diastolic MR. MRwas graded semiquantitatively as MR jet area in relation to left atrialarea23 and averaged in apical 4-chamber, 2-chamber, and 3-chamberviews. LV VTI, myocardial performance index, and mitral inflow VTIwere measured offline.

The optimal AVD was programmed and then VVD was adjusted atthe optimal AVD. Values of LV preexcitation tested ranged from 4 to30 ms, and values of RV preexcitation tested ranged from 10 to 20ms. Mechanical dyssynchrony was assessed by visual assessment ofcolor-coded tissue velocity imaging in apical 4-chamber, 2-chamber,and 3-chamber views.19 Progressively increasing LV or right ventricu-lar preexcitation was tested until maximum LVejection duration wasobtained. In patients with significant posterolateral wall delay on tis-sue velocity imaging or greater than mild MR and measurable PAP,these were reevaluated to ensure minimum values at optimal VVD.Mitral inflow was reevaluated after optimal VVD programming,and AVD was readjusted if required.

Acoustic Cardiography

Proprietary dual-purpose sensors were placed in the V3 or V4 posi-tions on the patient’s chest wall to record digital electrocardiographicand heart-sound data. During echocardiographic evaluation, a com-puterized acoustic cardiographic measurement was performed simul-taneously at each selected pacemaker setting. To avoid interference indata, the sonographer removed the transducer from the chest wallduring acoustic cardiographic data recording The computerizedacoustic cardiography representing 12 cardiac cycles was producedimmediately within 10 seconds of collection, including analysis ofS3 strength, EMAT, and LVST and a timely trend map against thepacemaker testing.

At the end of the optimization procedure, the pacemaker was pro-grammed on the basis of the results of the online echocardiographicevaluation. NYHA class and quality of life were assessed using theMinnesota Living With Heart Failure Questionnaire at baseline andby verbal interrogation and via a questionnaire sent out 1 month afteroptimization.

Statistical Analysis

Data are presented as mean 6 SD. All parameters at baseline andafter optimization were compared using paired 2-tailed Student’st test. Pearson’s correlation analysis was performed betweenoptimized AVD and VVD by echocardiography and acoustic cardiog-raphy. P values < .05 were considered statistically significant.

Table 3 Effect of echocardiographically guided Biv pacemaker optimization on cardiac hemodynamics (n = 44)

Method Parameter Baseline After echocardiographically guided optimization Change‡

Echocardiography LVOT VTI (cm) 15.92 6 4.77 18.51 6 5.19† 17%

LV ET (ms) 278 6 40 293 6 40 5.4%

MI VTI (cm) 20.08 6 8.78 21.09 6 9.7* 4.46%ET (ms) 277.75 6 41.01 292.44 6 40.12† 5.5%

FT (ms) 421.71 6 110.81 432.01 6 108.91 3.35%MPI 0.57 6 0.19 0.44 6 0.14† �21%

MR 2.1 6 4.7 1.18 6 0.9† �15%PAP (mm Hg) 41.88 6 12.72 36.2 6 10.9† �14%

E wave (cm/s) 0.93 6 0.32 0.82 6 0.29 �11%DT (ms) 203 6 76 228 6 85 17%

Acoustic cardiography S3 intensity 4.81 6 1.84 3.96 6 1.23† �12%EMAT (ms) 159.99 6 32.09 146.67 6 27.07* �6%

LVST (ms) 330.14 6 34.95 337.6 6 38.55 2.47%

DT, Deceleration time; ET, ejection time; FT, LV filling time; LVOT, LV outflow tract; MI, mitral inflow; MPI, myocardial performance index.Valve regurgitation grade: 0 = none, 0.5 = trace, 1 = mild, 1.5 = mild to moderate, 2 = moderate. P = .06 for E wave versus baseline and P = .08 for DT

versus baseline.

*P < .01 versus baseline.†P < .001 versus baseline.

‡(After optimization � baseline)/baseline.


RESULTS

Fifty patients were evaluated. All had >85% Biv pacing at baseline.The mean time since CRT was 13.8 months. Six patients in whomadequate-quality acoustic cardiographic data could not be obtainedwere excluded. Twenty patients had Medtronic devices (MedtronicInc, Minneapolis, MN), 13 had Boston Scientific devices (BostonScientific Corporation, Natick, MA), and 11 had St Jude devices (StJude Medical, St Paul, MN). Five patients had atrial fibrillation at thetime of optimization, and 1 had atrial flutter. AVD could thereforebe optimized in 38 patients. Nine patients had prior mitral valvesurgery with annuloplasty rings or valve replacements. Twenty-fourpatients had atrial pacing, and 14 had atrial sensing. Because of devicecharacteristics, VVD could be optimized in 41 patients. The baselineclinical characteristic of the study population at the time of pacemakeroptimization are shown in Table 2. Patients had significant LVenlarge-ment and impaired LV ejection fractions. Fifty percent of patientswere in NYHA class III or IV at baseline. The majority were ondiuretics, and as many as 43% were on amiodarone, thus indicatingsignificant cardiac dysfunction despite CRT.

The mean short AVD tested was 70 6 35 ms, and the mean lon-gest AVD tested was 225 6 65 ms. In 21 patients, the intrinsicAVD was tested at 253 6 74 ms. Optimization led to a significant im-provement in systolic and diastolic Doppler echocardiographic as wellas acoustic cardiographic parameters, as shown in Table 3. The effectsof optimization on LV VTI, S3 intensity, EMAT, and LVST at baseline,shortest AVD, longest AVD, optimal AVD, and optimal VVD in 33 pa-tients in whom paired data were available are shown in Figure 1.Figure 2 shows the correlation between baseline and optimal S3 inten-sity and LV VTI and between baseline and optimal EMATand LV VTI.S3 intensity also correlated well with Doppler echocardiographic LVejection duration both at baseline (r =�0.46, P < .001) and at optimalAVD (r = �0.43, P < .001). Besides systolic parameters, S3 intensityalso correlated with Doppler echocardiographic filling. Figure 3 showsthe correlation between S3 intensity and diastolic filling parameters atbaseline and after optimization in 35 patients without prior mitralvalve surgery.

Figure 4 shows the effect of pacemaker optimization on acousticcardiographic S3 intensity in a representative patient. In this patient,echocardiographic and acoustic cardiographic techniques deter-mined identical optimal AVD and VVD pacemaker setting. S3

became undetectable, and this was associated with improvementsin LV filling and ejection.

The mean baseline AVD was 150 6 43 ms, and the mean LVoffsetwas 8 613 ms; the mean final AVD was 164 6 55 ms, and the meanLVoffset was 4.5 6 6.7 ms (P = NS vs baseline AVD and VVD). Themean change in optimal AVD was 15 ms. With respect to VVD, 5 pa-tients required RV preexcitation (4 at 10 ms and 1 at 15 ms), and 16required LV preexcitation (3 at <10 ms, 8 at 10 ms, 1 at 15 ms, and 4at 20 ms). The mean baseline and optimal AVDs in A-sensed patientswere 131 6 46 and 114 6 35 ms and in A-paced patients were 1656 38 ms (P < .03 vs A-sensed patients) and 192 6 44 ms (P < .001 vsA-sensed patients), respectively.

There was no significant change in LV ejection time, LV VTI,diastolic filling time, PAP, or S3 intensity at optimal AVD and VVDcompared with optimal AVD alone in the overall study group. In pa-tients with atrial fibrillation, a 14% improvement in LV VTI occurredwith VVD optimization compared with baseline.

Optimal AVD and VVD by Echocardiographic and AcousticCardiographic Methods

There was no significant difference in optimal AVD and VVD be-tween these two techniques. Of the 36 patients with paired echocar-diographic and acoustic cardiographic data, there was completeagreement (ie, a difference of 0 ms in AVD between the twomethods) in 58% (n = 21) for optimal AVD. In 6 patients (17%), therewas a discordance of <20 ms, and in 9 patients (25%), there was a dis-cordance of >20 ms. Optimal VVD was identical by echocardiogra-phy and S3 intensity in 30 patients (75%); in 5 patients (12.5%),there was a discordance of <10 ms, and in 5 patients (12.5%), the dis-cordance was >10 ms. Figure 5 shows the correlation between opti-mal AVD by echocardiography and the AVD at which acousticcardiography showed minimum S3 intensity. As noted in Figure 5,

Figure 1 Effect of Biv pacemaker optimization on LV VTI as measured by PW Doppler echocardiography and S3 intensity, EMAT, andLVST as measured by acoustic cardiographic device at baseline (156 6 40 ms), shortest AVD (63 6 20 ms), longest AVD (228 6 66ms), optimal AVD (166 6 51 ms), and optimal AVD and VVD of�2 6 7 ms in 33 patients in whom paired data were available. P valuesare compared with baseline.

Figure 2 Correlation between S3 intensity measured by acoustic cardiography and LV VTI measured by PW Doppler echocardiog-raphy at baseline AVD and at optimal AVD (top) and between EMAT measured by acoustic cardiography and LV VTI measured by PWDoppler echocardiography at baseline AVD and at optimal AVD (bottom).


Taha et al 861

Figure 3 Correlation between S3 intensity measured by acoustic cardiography and mitral inflow early filling wave (E wave) as well asdeceleration time of E wave measured by PW Doppler echocardiography at baseline AVD in (top) and at optimal AVD and VVD (bot-tom). Patients with prior mitral valve surgery were excluded because of the effect of mitral valve prosthesis on PW Doppler diastolicfilling parameters.

Figure 4 Acoustic cardiographically determined S3 intensity data are shown at baseline (top) and after optimization (bottom). (Left)Electrocardiographic signal and acoustic heart sounds. S1, S2, and S3 are shown at baseline, whereas S1 and S2 waves are shownafter optimization. (Right) Heart sound intensity in 3 dimensions. S1 and S2 are shown as dark red signals. Note the presence of anadditional orange-colored area due to S3 immediately after S2 (in the first and third cardiac cycles in the top panel). This S3 disappearsafter pacemaker optimization (bottom). These data were obtained in a 53-year-old man whose baseline pacemaker settings were anA-sensed AVD of 160 ms and an LV offset of 30 ms. There was complete agreement between optimal echocardiographic and acous-tic cardiographic AVD and VVD settings in this patient.


a wide range of optimal AVDs was present both by echocardiography(50-300 ms) and acoustic cardiography (50-300 ms).

In 31 patients, S3 intensity decreased after AVD optimization. On thebasis of the baseline S3 intensity, we divided patients into two sub-groups, those withS3 intensity $ 5.0 (n = 17) and those withS3 intensity

< 5.0 (n = 27). Figure 6 shows the effect of AVD and VVD optimizationon S3 intensity. In the S3 intensity $ 5.0 subgroup, there was an acutereduction in S3 intensity after AVD optimization and a further reductionafter VVD optimization. In the S3 intensity < 5.0 subgroup, a nonsignif-icant reduction in S3 intensity occurred after AVD optimization.

Figure 5 (Left) Correlation between optimal AVD determined by comprehensive echocardiographic Doppler and S3 intensity byacoustic cardiography in all patients. Correlations between optimal AVD by Doppler echocardiography and S3 intensity in subjectswith baseline S3 intensity > 5 (top right) and between optimal AVD by echocardiography and EMAT in patients with baseline S3 in-tensity < 5 (bottom).

Figure 6 S3 intensity at baseline and best AVD and VVD by echocardiography and acoustic cardiography in the entire study popu-lation (left), in the subgroup with baseline S3 intensity > 5.0 (middle), and in the subgroup with baseline S3 intensity < 5.0 (right). Pvalues are compared with baseline.


Taha et al 863

Table 4 Effect of echocardiographically guided Biv pacemaker optimization on cardiac hemodynamics in patients in NYHAclasses I and II (Group 1) versus those in classes III and IV (Group 2)

Parameter Baseline After optimization P Change†

LVOT VTI (cm)Group 1 17.5 6 4.9 19.7 6 4.9 <.001 15.2%

Group 2 14.5 6 4.0* 17.33 6 5.1 <.001 19.5%

LV ET (ms)

Group 1 286.3 6 35.7 299.8 6 33.8 <.001 5.1%

Group 2 269.6 6 42.5 285.19 6 43.8 <.001 5.9%

MI VTI (cm)Group 1 19 6 6.5 20.3 6 7.2 .003 6.9%

Group 2 20.9 6 10.3 21.5 6 11.5 .27 1.9%

FT (ms)

Group 1 421.2 6 108.8 424.8 6 105.7 .68 1.5%

Group 2 423.2 6 110.3 438.2 6 109.1 .14 4.6%

MPIGroup 1 0.6 6 0.2 0.45 6 0.1 <.001 �23.9%

Group 2 0.5 6 0.2 0.46 6 0.1 <.001 �18.5%

MR

Group 1 2.5 6 6.5 0.9 6 0.7 .003 �18.6%

Group 2 1.6 6 1.1* 1.5 6 1 .02 �14.2%

PAP (mm Hg)Group 1 36.6 6 13 32.5 6 10.7 .001 �12.5%

Group 2 46.9 6 10.2* 39.8 6 9.9 <.001 �16.6%

E wave (cm/s)

Group 1 0.9 6 0.3 0.7 6 0.2 <.001 �10.8%

Group 2 0.95 6 0.35 0.85 6 0.35 .002 �10.2%

DT (ms)Group 1 200.2 6 55.1 236.8 6 75.1 .02 22.6%

Group 2 203.7 6 91 218 6 91.8 .37 10.9%

DT, Deceleration time; ET, ejection time; FT, LV filling time; LVOT, LV outflow tract; MI, mitral inflow; MPI, myocardial performance index.Valve regurgitation grade: 0 = none, 0.5 = trace, 1 = mild, 1.5 = mild to moderate, 2 = moderate.

*P < .05 versus group 1.

†(After optimization � baseline)/baseline.


We also evaluated baseline echocardiographic findings among pa-tients in NYHAclass I and II versus those in NYHAclass III and IVat base-line (Table 3). As shown, a significant improvement in most Dopplerechocardiographic parameters occurred in both groups of patients.

Follow-Up

One patient in NYHA class IV died, and 1 underwent heart transplan-tation. No follow-up was available in 7 patients. In the remaining 35patients, mean NYHA class improved from 2.55 6 0.81 at baseline to1.77 6 0.90 at follow-up (P < .001), and the quality-of-life score asassessed by the Minnesota Living With Heart Failure Questionnaireimproved from 45 6 28 to 32 6 28 (P = .08). When emotionaland physical components of assessment were separated, a significantimprovement was noted in the physical component of quality of lifefrom 30.4 6 18.2 to 21.9 6 15.5 (P = .04). Fifteen patients were inclass I, 12 patients in class II, 7 in class III, and 1 in class IV atfollow-up. There were no significant changes in NYHA class in 10patients at follow-up.

DISCUSSION

The salient findings of our study are that tailored echocardiographi-cally guided pacemaker optimization causes an acute improvement

in Doppler echocardiographic systolic as well diastolic parametersalong with reductions in S3 intensity and EMAT and leads to an im-provement in functional class after CRT. Patients with high restingS3 intensity ($5.0) derived the greatest acute benefit, with reductionsin S3 intensity into the normal range (<5.0).

The echocardiographic optimization method incorporated bothsystolic as well as diastolic parameters. S3 intensity, a parameter of di-astolic filling and LV end-diastolic pressure, was correlated with bothsystolic and diastolic Doppler echocardiographic variables. It is to benoted, however, that there was lack of concordance for optimal AVDbetween S3 intensity and Doppler echocardiographic variables in25% of patients. It appears from our data that acoustic cardiographi-cally guided optimization could be particularly beneficial in patientswith resting S3 intensity > 5. In such patients, acoustic cardiographymay be helpful to guide pacemaker optimization by selecting AVDsthat lower S3 intensity in the <5 range, thus reducing optimizationtime. EMAT may be helpful in remaining patients, as found in ourstudy as well as in prior studies.14,15

Our study differs from prior echocardiographically guided pace-maker optimization studies in that our patients were clinically re-ferred, and half of our population was in NYHA class >II. Weperformed a comprehensive pacemaker interrogation as well asa comprehensive hemodynamic evaluation by Doppler echocardiog-raphy during AVD and VVD optimization. Although we evaluated


Taha et al 865

multiple Doppler criteria during optimization, in patients without sig-nificant systolic and diastolic MR, systolic and diastolic tricuspid regur-gitation, prominent pulmonary vein atrial reversal or restrictivepulmonary vein filling pattern, mitral inflow and LV outflow PWDoppler were the predominant criteria used for determining optimalAV and VVD. Unlike previous acoustic cardiographic studies thatfound EMAT to be the most sensitive parameter to target during pace-maker optimization, we found S3 to correlate better with Dopplerechocardiographic parameters. The relationship of S3 intensity toDoppler echocardiographic filling and ejection parameters, however,were modest. EMAT also reduced significantly in the overall popula-tion after pacemaker optimization. The relationship of EMAT withDoppler echocardiographic parameters was weaker than that of S3 in-tensity. This may be because EMAT is dependent on onset of QRS,a component that may change significantly during AVD and VVDdelay changes and hence may not accurately reflect changes in LVsystolic mechanical function. LVST incorporates EMAT, isovolumiccontraction time, and LVejection time, parameters that go in oppositedirections during pacemaker optimization.

Our data suggest significant and comparable improvements inDoppler echocardiographic parameters in patients in NYHA classesI and II versus those with in classes III and IV. Hence, pacemaker op-timization should be offered to most patients after CRT. Studies haveshown and our own data suggests that patients may derive benefitfrom pacemaker programming for a few months before deterioratingand requiring reprogramming. In this setting, acoustic cardiographymay be helpful during follow-up evaluation and optimization duringroutine pacemaker evaluation visit as a stand-alone optimizationmethod.

We tested limited LV and right ventricular offsets in our patients.The reason for this is recent data suggesting that LV offsets of 20 to80 ms do not provide benefit compared with simultaneous pacing.24

Biv pacing in canine models of left bundle branch block have shownthat maximum LV stroke work and dP/dt occurs at small degrees ofLV preexcitation between 0 and 20 ms.25 Occasional patients re-quired small degrees of right ventricular offset, consistent with priorstudies.26 VVD optimization did not improve cardiac hemodynamicsfurther, but there was an improvement of cardiac stroke volume withVVD optimization in those with atrial fibrillation in our study.

Our findings suggest that comprehensive Doppler echocardio-graphic evaluation as well as Doppler echocardiographically guidedBiv pacemaker optimization using patient-specific Doppler echocar-diographic abnormalities can improve cardiac hemodynamics in pa-tients after CRT and results in improvement in NYHA class andshould be an integral part of any HF program. The use of acoustic car-diographic S3 intensity may help identify patients with elevated fillingpressure and may assist in guiding pacemaker optimization by select-ing AVD with reduced S3 intensity. We speculate that when used inconjunction with Doppler echocardiography, acoustic cardiographymay shorten pacemaker optimization time.

Limitations

The Doppler echocardiographic method of pacemaker optimizationwe describe is time intensive. Final pacemaker programming wasbased on Doppler echocardiographic parameters and not acousticcardiography. Steering of AVD and VVD pacemaker settings duringoptimization procedure was based on Doppler echocardiographicevaluation. As a stand-alone procedure, phonocardiography mayhave led to differences in the direction of steering of pacemaker set-tings. Our study sample was small, and our findings need to be con-

firmed in a larger cohort. Our patients’ baseline pacemaker settingswere variable and not out-of-box settings of AVD of about 110 to120 ms. There are limitations to the sensitivity of S3 intensity withrespect to LV end-diastolic pressure.27 The test characteristics ofphonocardiography may vary depending on the cutoff used todesignate a positive S3 or S4 from a computer-generated confidencescore for each heart sound. S3 intensity may be susceptible to motionartifacts, and diagnostic data were not possible in 6 of our patients.Theoretically, an increase in diastolic filling due to improved LVpreload may increase S3 intensity, so intensity may not be very helpfulto guide pacemaker optimization in those with normal resting S3

intensity. Ectopy and labored breathing can influence S3 intensity,so ectopic beats should be excluded, and in those with laboredbreathing, measurements should be made during the same phase ofrespiration.

CONCLUSIONS

Our results suggest that comprehensive echocardiography assess-ment during pacemaker optimization can lead to a significant acutehemodynamic benefit as detected by Doppler echocardiography af-ter CRT, along with a decrease in phonocardiographic S3 intensityas well as a significant improvement in functional class. Our findingsalso indicate significant concordance among echocardiographic andphonocardiographic methods in determining optimal AVD andVVD. The additive clinical impact of the S3 intensity–based optimiza-tion approach over a conventional comprehensive hemodynamic as-sessment using Doppler echocardiographic techniques duringoptimization as a stand-alone method is not clearly apparent andneeds to be addressed in future studies.

REFERENCES

1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al.Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-53.

2. Sogaard P, Egeblad H, Pedersen AK, Kim WY, Kristensen BO, Hansen PS,et al. Sequential versus simultaneous biventricular resynchronization forsevere heart failure. Evaluation by tissue Doppler imaging. Circulation2002;106:2078-84.

3. Porciani MC, Dondina C, Macioce R, Demarchi G, Pieragnoli P, Musilli N,et al. Echocardiographic examination of atrioventricular and interventric-ular delay optimization in cardiac resynchronization therapy. Am J Cardiol2005;95:1108-10.

4. Mortensen PT, Sogaard P, Mansour H, Ponsonaille J, Gras D, Lazarus A,et al. Sequential biventricular pacing: evaluation of safety and efficacy. Pac-ing Clin Electrophysiol 2004;27:339-45.

5. Auricchio A, Stellbrink C, Block M, Vogt J, Bakker P, Klein H, et al. Effect ofpacing chamber and atrioventricular delay on acute systolic function ofpaced patients with congestive heart failure. Circulation 1999;99:2993-3001.

6. Cazeau S, Gras D, Lazarus A, Ritter P, Mugica J. Multisite stimulation forcorrection of cardiac asynchrony. Heart 2000;84:579-81.

7. Bordachar P, Lafitte S, Reuter S, Garrigue S, Sanders P, Roudaut R, et al.Biventricular pacing and left ventricular pacing in heart failure similar he-modynamic improvement despite marked electro-mechanical differences.J Cardiovasc Electrophysiol 2004;15:1342-7.

8. Sawhney NS, Waggoner AD, Garhwal S, Chawla MK, Osborn J,Faddis MN, et al. Randomized prospective trial of atrioventricular delayprogramming for cardiac resynchronization therapy. Heart Rhythm2004;1:562-7.


9. Kerlan JE, Sawhney NS, Waggoner AD, Chawla MK, Garhwal S,Osborn JL, et al. Prospective comparison of echocardiographic atrioven-tricular delay optimization methods for cardiac resynchronization therapy.Heart Rhythm 2006;3:148-54.

10. Meluzin J, Novak M, Mullerova J, Krejci J, Hude P, Eisenberger M, et al. Afast and simple echocardiographic method of determination of the opti-mal atrioventricular delay in patients after biventricular stimulation. PacingClin Electrophysiol 2004;27:58-64.

11. Morales MA, Startari U, Panchetti L, Rossi A, Piacenti M. Atrioventriculardelay optimization by Doppler-derived left ventricular dP/dt improves 6-month outcome of resynchronized patients. Pacing Clin Electrophysiol2006;29:564-8.

12. Roos M, Toggweiler S, Zuber M, Jamshidi P, Erne P. Acoustic cardiographicparameters and their relationship to invasive hemodynamic measure-ments in patients with left ventricular systolic dysfunction. Congest HeartFail 2006;12(suppl). 19e24.

13. Hasan A, Abraham WT, Quinn-Tate L, Brown L, Amkieh A. Optimizationof cardiac resynchronization devices using acoustic cardiography: a com-parison to echocardiography. Congest Heart Fail 2006;12(suppl):25-31.

14. Toggweiler S, Zuber M, Kobza R, Roos M, Jamshidi P, Meier R, et al.Improved response to cardiac resynchronization therapy throughoptimization of atrioventricular and interventricular delays using acousticcardiography. J Card Fail 2007;13:637-42.

15. Zuber M, Toggweiler S, Tate LQ, Brown L, Amkieh A, Erne P. A compar-ison of acoustic cardiography and echocardiography for optimizingpacemaker settings in cardiac resynchronization therapy. Pacing ClinElectrophysiol 2008;31:802-81.

16. Naqvi TZ, Rafique AM. Novel insights on effect of atrioventricularprogramming of biventricular pacemaker on cardiac physiology in heartfailure—a case series. Cardiovasc Ultrasound 2006;4:38.

17. Naqvi TZ, Rafique AM, Peter CT. Echo-driven V-V optimization deter-mines clinical improvement in non responders to cardiac resynchroniza-tion treatment. Cardiovasc Ultrasound 2006;4:39.

18. Gorcsan J III, Abraham T, Agler DA, Bax JJ, Derumeaux G, Grimm RA,et al., American Society of Echocardiography Dyssynchrony WritingGroup. Echocardiography for cardiac resynchronization therapy: recom-mendations for performance and reporting—a report from the American

Society of Echocardiography Dyssynchrony Writing Group endorsed bythe Heart Rhythm Society. J Am Soc Echocardiogr 2008;21:191-213.

19. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R,Feigenbaum H, et al. Recommendations for quantitation of the left ventri-cle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358-67.

20. Yock PG, Popp RL. Non invasive estimation of right ventricular systolicpressure by Doppler ultrasound in patients with tricuspid regurgitation.Circulation 1984;70:657-62.

21. Nishimura RA, Abel MD, Hatle LK, Tajik AJ. Assessment of diastolicfunction of the heart: background and current applications of Dopplerechocardiography: part II clinical studies. Mayo Clin Proc 1989;64:181-204.

22. Ritter PLT, Lavergne T. Quick determination of the optimal AV delay atrest in patients paced in DDD mode for complete AV block. Eur J CardiacPacing Electrophysiol 1994;4:54.

23. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD,Levine RA, et al. Recommendations for evaluation of the severity of nativevalvular regurgitation with two-dimensional and Doppler echocardiogra-phy. J Am Soc Echocardiogr 2003;7:777-802.

24. Rao RK, Kumar UN, Schafer J, Viloria E, De Lurgio D, Foster E, et al.Reduced ventricular volumes and improved systolic function with cardiacresynchronization therapy: a randomized trial comparing simultaneousbiventricular pacing, sequential biventricular pacing, and left ventricularpacing. Circulation 2007;115:2136-44.

25. Vernooy K, Verbeek XA, Cornelussen RN, Dijkman B, Crijns HJ, Arts T,et al. Calculation of effective VV interval facilitates optimization of AV de-lay and VV interval in cardiac resynchronization therapy. Heart Rhythm2007;4:75-82.

26. Vanderheyden M, De Backer T, Rivero-Ayerza M, Geelen P, Bartunek J,Verstreken S, et al. Tailored echocardiographic interventricular delayprogramming further optimizes left ventricular performance after cardiacresynchronization therapy. Heart Rhythm 2005;10:1066-72.

27. Marcus G, Gerber IL, McKeown BH, Vessey JC, Jordan MV,Huddleston M, et al. The association between phonocardiographic thirdand fourth heart sounds and objective measures of left ventricularfunction. JAMA 2005;293:2238-44.

Biventricular Pacemaker Optimization Guided by Comprehensive ...

Documents