Cardiac sympathetic activity pre and postresynchronization therapy evaluated by 123I-MIBGmyocardial scintigraphy

Silvana A. D’Orio Nishioka, MD, PhD,a Martino Martinelli Filho, MD, PhD,a

Simone C. Soares Brandão, MD,b Maria Clementina Giorgi, MD, PhD,b

Marcelo L.C. Vieira, MD, PhD,c Roberto Costa, MD, PhD,a

Wilson Mathias, MD, PhD,c and José Cláudio Meneghetti, MD, PhDb

Background. Imaging with 123I-metaiodobenzylguanidine (MIBG) is used for the assessmentof cardiac sympathetic activity (CSA). We analyzed CSA before and after cardiac resynchro-nization therapy (CRT), and correlated these data with CRT response.

Methods and Results. Thirty patients with chronic heart failure and classic indications forCRT were prospectively studied before and at least 3 months after CRT. The variables analyzedwere: QRS width, left-ventricular ejection fraction (LVEF), left-ventricular end-diastolicdiameter (LVEDD), heart/mediastinum MIBG uptake ratio (H/M), and washout rate (WR).After CRT, patients were divided into two groups: group 1 (21 patients), responders improvingto functional class (FC) I or II; and group 2 (9 patients), nonresponders remaining in FC III orIV. After CRT, only group 1 showed favorable changes in QRS width (P � .003), LVEF (P �.01), LVEDD (P � .04), and H/M ratio (P � .003). The H/M ratio and WR were associated withCRT response (P � .005 and P � .04, respectively). The H/M ratio was the only independentpredictor of CRT response (P � .01). Receiver operating characteristic curves showed that theoptimal H/M ratio cutoff point was 1.36 (sensitivity, 75%; specificity, 71%).

Conclusions. Improvement in CSA correlated with a positive CRT response. Lower MIBGuptake before therapy was associated with CRT nonresponse. The H/M ratio could be helpfulin selecting patients for CRT. (J Nucl Cardiol 2007;14:852-9.)

Key Words: Cardiac resynchronization therapy • chronic heart failure • cardiac MIBG

scintigraphy • prognosis

Cardiac resynchronization therapy (CRT) has provenbeneficial in patients with advanced chronic heart failure(HF) and QRS duration greater than 120 milliseconds(ms) in addition to optimal medical therapy.1-4 Much

From the Department of Arrhythmia and Cardiac Stimulation,a Depart-ment of Nuclear Medicine,b and Department of Echocardiography,c

Heart Institute, InCor, University of São Paulo Medical School, SãoPaulo, Brazil.

This study was supported by grants from the Research SupportFoundation of the State of São Paulo, Brazil.

Received for publication June 24, 2007; final revision accepted Aug 6,2007.

Reprint requests: Silvana A. D’Orio Nishioka, MD, PhD, Assistant ofCardiology, Unidade Clínica de Estimulação Cardíaca Artificial doInstituto do Coração do Hospital das Clínicas da Faculdade deMedicina da Universidade de São Paulo, Av. Dr. Enéas de CarvalhoAguiar 44, CEP 05403000 São Paulo, São Paulo, Brazil; silvanadorio@uol.com.br.

1071-3581/$32.00Copyright © 2007 by the American Society of Nuclear Cardiology.

doi:10.1016/j.nuclcard.2007.08.004

852

improvement has been achieved in the pharmacologictreatment of HF.1-6 However, in patients with chronic HFwhose symptoms remain severe, CRT can improveclinical manifestations and quality of life, and reducecomplications and risk of death.4

Despite initial enthusiasm about providing this ther-apy to patients who fulfilled current CRT guidelines,3,6 alack of response was observed in about one third ofpatients who did not benefit clinically or who experi-enced left-ventricular reverse remodeling after biven-tricular stimulation.7 Furthermore, the invasive natureand costs of CRT have highlighted the need to identifyoptimal candidates. Therefore, selection criteria to detectthe most suitable candidates for CRT are crucial.7-11

In patients with chronic HF, various neurohor-monal alterations contribute to the progression of thedisease, and are associated with an unfavorable prog-nosis.5 Increased levels of catecholamines have adirect cardiotoxic effect and are important predictors

of HF mortality and morbidity. Cardiac imaging

Journal of Nuclear Cardiology D’Orio Nishioka et al 853Volume 14, Number 6;852-9 MIBG imaging and cardiac resynchronization therapy

with123I-metaiodobenzylguanidine (MIBG), an ana-logue of norepinephrine, is an important tool fordetecting abnormalities in the myocardial adrenergicnervous system, and has useful prognostic value inpatients with chronic HF.12-15

Some studies showed that the pharmacologic treatmentof HF improves cardiac sympathetic activity, as demon-strated by cardiac MIBG scintigraphy.16-21 A small clinicalstudy also suggested that CRT could induce favorablechanges in the neurohumoral system, as evaluated byplasma brain natriuretic peptide concentration and car-diac MIBG imaging, in patients with HF and a left-ventricular ejection fraction of �35%,22 but no data havedescribed the ability of cardiac MIBG scintigraphy topredict the efficacy of CRT. The aims of the presentstudy were to analyze cardiac sympathetic activity,comparing MIBG imaging before and after CRT, and tocorrelate these data with clinical results after therapy.

METHODS

Study Patients

Thirty patients with symptomatic chronic HF, referred forimplantation of a CRT device, were included in the presentstudy after written, informed consent was obtained. The EthicsCommittee of our institution approved the study protocol. Thisinvestigation conforms to the principles outlined in the Decla-ration of Helsinki.

The mean age of patients was 59 � 12 years (range, 37 to79 years), and 17 (57%) patients were men. Heart failure wasdue to idiopathic dilated cardiomyopathy in 23 (77%) patients,and ischemic heart disease in 7 (23%). Their pharmacologictherapy (Table 1) was unchanged for 6 weeks before CRT andduring a follow-up of at least 3 months. Patients enrolled forCRT had left-ventricular systolic dysfunction with a left-ventricular ejection fraction of �35%, the presence of leftbundle-branch block with QRS equal to or wider than 120 ms,and chronic HF in New York Heart Association (NYHA)functional classes III and IV with optimized clinical treat-ment.3,6 Patients were excluded from the study if they hadatrial fibrillation, an atrioventricular block, a permanent pace-maker, end-stage renal failure, insulin-dependent diabetes mel-litus, or autonomic neuropathy.

Study Protocol

Before and at least 3 months after CRT, patientsunderwent electrocardiography, echocardiography, and car-diac MIBG scintigraphy. Three months after CRT, thesepatients were divided into two groups according to theirresponses to CRT: group 1 (G1), responders who improved tofunctional class (FC) I or II; and group 2 (G2), nonresponders

who remained in FC III or IV.

Electrocardiography

The duration of QRS was measured on a surface 12-leadelectrocardiogram, using the widest QRS complex from the DIIlead. Electrocardiograms were recorded at a speed of 25mm/second, and were evaluated by two observers withoutknowledge of the clinical status of the patient.

Cardiac MIBG Scintigraphy

After thyroid blockade with 100 mg of potassium iodidegiven orally, patients received an intravenous injection of 185MBq of 123I-MIBG. Fifteen minutes (early imaging) and 3hours (delayed imaging) after MIBG administration, a two-million count planar anterior image of the chest was acquiredby using a gamma camera (ORBITER, Siemens MedicalSystems, Hoffmann Estates, Ill) equipped with a low-energy,all-purpose collimator and stored in a 128 � 128 matrix. TheMIBG activity was measured using a manually drawn region ofinterest around the left ventricle (LV) and in the uppermediastinum. Mediastinal and myocardial values were ex-pressed as mean counts per pixel. To evaluate MIBG myocar-dial uptake, the heart/mediastinum count (H/M) ratio wasdetermined from the delayed anterior planar MIBG image. Thewashout rate (WR) was calculated by using the followingformula: [(H/T � M/T) early � (H/T � M/T) delayed]/(H/T �M/T) early � 100(%), where H � mean count per pixel in LV,M � mean count per pixel in the mediastinum, and T � imageacquisition times, with values undergoing correction for 123Iphysical decay.

Echocardiography

Transthoracic echocardiographic studies were performedbefore and 3 months after CRT, with a Philips HDI-5000 model(Philips, Andover, Mass) equipped with a 2 to 4 MHz trans-ducer, following American Society of Echocardiography rec-ommendations.23 Two experienced, independent observerswho had no knowledge of the clinical data measured the

Table 1. Baseline patient characteristics (N � 30)

Age (y) 59 � 12Male sex, n (%) 17 (57)Cause of CHF – n (%)

Idiopathic 23 (77)Ischemic 7 (23)

Drugs, n (%)ACE inhibitor or ARB 30 (100)Beta-blocker 29 (97)Spironolactone 26 (87)Diuretic 26 (87)Digoxin 18 (60)Amiodarone 7 (23)

ACE, Angiotensin-converting enzyme; ARB, angiotensin receptorblocker; CHF, chronic heart failure.

left-ventricular end-diastolic diameter and the left-ventricular

854 D’Orio Nishioka et al Journal of Nuclear CardiologyMIBG imaging and cardiac resynchronization therapy November/December 2007

ejection fraction. The left-ventricular end-diastolic diameterwas obtained from the parasternal long-axis view, and theleft-ventricular ejection fraction was calculated by using thebiplane method (Simpson’s rule).

Atriobiventricular Device Implantation

Commercially available biventricular pacemakers wereused (Insync III 8042/Medtronic, Minneapolis, Minn; StratosLV/Biotronik, Berlin, Germany; and Frontier/St. Jude Medical,Memphis, Tenn). The right atrial lead was positioned in theright atrial appendix, and the ventricular lead was positioned inthe right ventricular outflow. The LV pacing lead was posi-tioned in a posterior or lateral branch of the coronary sinus inall patients. An atriobiventricular system was used in allpatients.

Statistical Analysis

Data are expressed as the mean � 1 standard deviation.For the comparison of qualitative variables, the chi-square test,the Fisher exact test, and the likelihood ratio chi-square testwere used. For the comparison of parametric variables beforeand after CRT, we used the paired t test and analysis ofvariance for repeated measures. The comparison of parametersbetween groups was analyzed with an unpaired t test, and astepwise logistic model was used to identify predictive param-eters. The sensitivity and specificity of the H/M ratio beforetreatment for predicting response to CRT was determined byreceiver-operating characteristic curves. Statistical significance

Table 2. Clinical and functional changes in relationto CRT

Pre-CRT(N � 30)

Post-CRT(N � 30)

Pvalue

NYHA class (n)I/II 0 13/8III/IV 26/4 8/1

ElectrocardiographyQRS duration (ms) 163 � 22 147 � 26 .0002

EchocardiographyLVEDD (mm) 79 � 11 76 � 16 .07LVEF (%) 0.22 � 0.05 0.27 � 0.09 .02

123I-metaiodoben-zylguanidine

H/M ratio 1.42 � 0.26 1.53 � 0.27 .005WR (%) 44 � 25 42 � 30 .7

NYHA, New York Heart Association; CRT, cardiac resynchronizationtherapy; ms, milliseconds; LVEDD, left-ventricular end diastolicdiameter; LVEF, left-ventricular ejection fraction; H/M ratio, heartto mediastinum count; WR, washout rate.

was defined at P � .05.

RESULTS

Clinical and Functional Follow-Up

Before CRT, 26 (87%) patients were in FC III, and4 (13%) were in FC IV. After CRT, 12 (40%) patientschanged from FC III to FC I, 8 (27%) patients changedfrom FC III to FC II, 1 (3%) patient changed from FC IVto FC I, 6 patients (20%) remained in FC III, 2 (7%)patients changed from FC IV to FC III, and 1 patient(3%) remained in FC IV. After CRT, the QRS widthchanged from 163 � 22 milliseconds to 147 � 26milliseconds (P � .0002), the mean left-ventricularejection fraction increased from 0.22 � 0.05 to 0.27 �0.09 (P � .02), and the mean left-ventricular end-diastolic diameter changed from 79 � 11 mm to 76 � 16mm (P � .07). The H/M ratio increased significantlycompared with the baseline value (from 1.42 � 0.26 to1.53 � 0.27; P � .005), but the change of in WR was notstatistically significant (Table 2).

Characteristics of Groups

After CRT, patients were classified into two groups:G1, 21 (70%) patients in FC I or II; and G2, 9 (30%)

Table 3. Baseline characteristics of patientsaccording to CRT response: Group 1 (responders,improvement to functional class II or I) or group 2(nonresponders, remaining in class III or IV)

Group 1(N � 21)

Group 2(N � 9)

Pvalue

Age (y) 57 � 11 64 � 15 NSMale sex (%) 57 43 NSCause of CHF, n (%) NS

Idiopathic 17 (81) 6 (67)Ischemic 4 (19) 3 (33)

NYHA class, n (%)III 20 (95) 6 (67)IV 1 (5) 3 (33)

Drugs, n (%)ACE inhibitor or

ARB21 (100) 9 (100) NS

Beta-blocker 21 (100) 8 (89) NSSpironolactone 19 (90) 7 (78) NSDiuretic 18 (86) 8 (89) NSDigoxin 12 (57) 6 (67) NSAmiodarone 4 (19) 3 (33) NS

ACE, Angiotensin-converting enzyme; ARB, angiotensin receptorblocker; CHF, chronic heart failure; CRT, cardiac resynchronizationtherapy; NS, not significant; NYHA, New York Heart Association.

patients in FC III or IV. There were no differences in age,

Journal of Nuclear Cardiology D’Orio Nishioka et al 855Volume 14, Number 6;852-9 MIBG imaging and cardiac resynchronization therapy

sex, cause of cardiomyopathy, and medical treatmentsbetween groups. The baseline characteristics of bothgroups and medical treatments are shown in Table 3.

Comparison of Findings Between Groups

The QRS width, left-ventricular ejection fraction,left-ventricular end-diastolic diameter, H/M ratio, andWR data are given in Table 4. Before CRT, the meanQRS width was 163 � 20 milliseconds in G1 and 166 �28 milliseconds in G2 (P � NS). After CRT, it decreasedsignificantly to 142 � 20 milliseconds in G1 (P � .003)but not in G2, at a mean of 160 � 33 milliseconds (P �NS). Before CRT, the mean left-ventricular end-diastolicdiameter was 78 � 11 mm in G1 and 83 � 13 mm in G2(P � NS). After CRT, the mean left-ventricular end-diastolic diameter decreased to 72 � 14 mm in G1 (P �.04) but not in G2, at a mean of 85 � 16 mm (P � NS).Before CRT, the mean left-ventricular ejection fractionwas 0.24 � 0.06 in G1 and 0.22 � 0.06 in G2 (P � NS).After therapy, it increased to 0.29 � 0.10 (P � .01) inG1, but did not change significantly in G2. Before CRT,the H/M ratio was significantly better in G1 than in G2(1.50 � 0.23 vs 1.22 � 0.23; P � .005). After CRT, themean H/M ratio increased in G1 (1.64 � 0.21; P � .003),but not in G2 (1.27 � 0.23; P � NS; Figure 1). Before

Table 4. Changes in electrocardiographic, echocardioand post-CRT in relation to group

Pre-C

Group 1(N � 21)

ElectrocardiographyQRS width (ms) 163 � 20

EchocardiographyLVEDD (mm) 78 � 11

LVEF (%) 0.24 � 0.06

123I-metaiodobenzylguanidineH/M ratio 1.50 � 0.23

WR (%) 38 � 20

CRT, Cardiac resynchronization therapy; LVEDD, left-ventricular endto mediastinum count; WR, washout rate; NS, not significant.All parameters, pre-CRT and post-CRT, in group 2 did not change*Difference between group 1 and group 2 (pre-CRT).†Difference between pre-CRT and post-CRT in group 1.

CRT, the mean WR was 38% � 20% in G1 and 59% �

30% in G2 (P � .04). After CRT, the mean WR tendedto decline (32% � 13%) in G1, and tended to increase(70% � 43%) in G2. However, there were no statisti-cally significant changes in either group. Figure 2 showsthe cardiac sympathetic activity in one patient of eachgroup. The patient from G1 had a greater value of H/Mratio before CRT, which improved after therapy. Thiswas not observed in the G2 patient.

Univariate and Multivariate Predictorsof Response to CRT

By univariate analysis, the H/M ratio and WR werevariables of response to CRT (P � .005 and 0.04,respectively). By stepwise logistic regression analysis,the H/M ratio was the only independent predictor ofresponse to CRT (P � .01). Receiver operating charac-teristic (ROC) curves for prediction of the response toCRT showed a greater area under the curves for the H/Mratio before CRT. The optimal cutoff point of the H/Mratio was 1.36, with 75% sensitivity and 71% specificity(Figure 3).

DISCUSSION

The data presented in this study demonstrated that

ic, and 123I-metaiodobenzylguanidine data pre-CRT

Post-CRT

P valueup 2� 9)

Group 1(N � 21)

Group 2(N � 9)

� 28 142 � 20 160 � 33 NS*0.003†

� 13 72 � 14 85 � 16 NS*.04†

� 0.06 0.29 � 0.10 0.21 � 0.04 NS*.01†

� 0.23 1.64 � 0.21 1.27 � 0.23 .005*.003†

� 30 32 � 13 70 � 43 .04*NS†

ic diameter; LVEF, left-ventricular ejection fraction; H/M ratio, heart

graph

RT

Gro(N

166

83

0.22

1.22

59

diastol

.

CRT induced an increase in the H/M ratio and in the

856 D’Orio Nishioka et al Journal of Nuclear CardiologyMIBG imaging and cardiac resynchronization therapy November/December 2007

left-ventricular ejection fraction, and a reduction in symp-toms and QRS width. However, not all patients respondedequally to CRT, and when patients were separated in groupsbased on improvement in NYHA functional class, it be-came evident that an improvement in clinical and functionalparameters was observed only in the responders. Moreover,by multivariate analysis, the only variable at baseline thatwas significantly different between responders and nonre-

Figure 1. (Left) There were favorable chaend-diastolic diameter (LVEDD; P � .04), lefheart/mediastinum count (H/M) ratio (P � .00were no significant changes in all parametersresynchronization therapy.

sponders was the H/M ratio. We found that a cutoff value

�1.36 could predict potential responders to CRT with asensitivity of 75% and a specificity of 71%.

This is the first study to show that the H/M ratio canadd information during the patient-selection process forCRT. This is relevant because, despite the potentialbenefits of this procedure for some patients, othersreceive the therapy but do not improve.

Many studies used hemodynamic parameters,4,14,22-26

n QRS width (P � .003), left-ventricularicular ejection fraction (LVEF; P � .01), andCRT and post-CRT in group 1. (Right) ThereRT and post-CRT in group 2. CRT, cardiac

nges it-ventr3) pre-

pre-C

the left-ventricular ejection fraction, and echocardio-

Journal of Nuclear Cardiology D’Orio Nishioka et al 857Volume 14, Number 6;852-9 MIBG imaging and cardiac resynchronization therapy

graphic data27,28 as prognostic indicators in patients withcongestive HF. It is a common belief that in diseasedhearts, mechanical systolic dyssynchrony is associated

Figure 2. Delayed 123I-metaiodobenzylguanidcardiac resynchronization therapy (CRT). (A) I(H/M) ratio before CRT was 1.66. (B) In this p(C) In this patient of group 2, the H/M ratio bafter CRT, the H/M ratio was 0.98.

00,10,20,30,40,50,60,70,8

1 1,2 1,4 1,6 1,8 2

H/M ratio

Pro

bab

ility

Figure 3. Receiver operating characteristiresponse to cardiac resynchronization theracurves showed a greater area under the cur(pre-CRT). The optimal cutoff point of the71%).

with prolonged QRS duration. However, even under

optimally controlled conditions, the baseline QRS dura-tion or QRS narrowing after CRT are not always asso-ciated with hemodynamic, clinical, or echocardiographic

IBG) images were obtained before and afteratient of group 1, the heart/mediastinum countof group 1, the H/M ratio after CRT was 2.01.CRT was 0.99. (D) In this patient of group 2,

1 1,1 1,2 1,3 1,4 1,5 1,6 1,7 1,8 1,9 2

H/M ratiosensitivity specificity

H/M ratio=1.36

es for the prediction of mortality or noRT). The receiver operating characteristicr the heart/mediastinum count (H/M) ratioatio was 1.36 (sensitivity, 75%; specificity,

ine (Mn this patientefore

0

20

40

60

80

100

c curvpy (Cves foH/M r

improvement.8 Therefore, the assessment of cardiac

858 D’Orio Nishioka et al Journal of Nuclear CardiologyMIBG imaging and cardiac resynchronization therapy November/December 2007

sympathetic activity by MIBG scintigraphy may contrib-ute to a more appropriate patient selection and predictionof response to this therapy.

Merlet et al.29 assessed MIBG uptake and othervariables in patients with dilated cardiomyopathy, andverified that MIBG uptake, as assessed with the H/Mratio, was the best predictor of survival. Suwa et al.17

used MIBG imaging to predict the response to bisoprololtherapy, identifying an H/M ratio �1.7 as a goodpredictor. In this study, CRT increased cardiac MIBGuptake in patients who benefited from therapy, reflectingimprovement in the balance of cardiac adrenergic func-tion. Furthermore, one study indicated that MIBG pa-rameters correlate with inflammatory cytokines such asinterleukin.30 Gerson et al.31 showed that using MIBG tofurther classify severe heart-failure patients by risk typecan effectively contribute to establishing indications forheart transplantation.

The degree of sympathetic nervous-system derange-ment measured by MIBG scintigraphy is related tocardiac remodeling during the evolution of HF, reflectingthe degree of cardiac dysfunction. Kasama et al.18 foundgreater values of H/M ratio in a population with conges-tive heart failure and preserved left-ventricular ejectionfraction. It is possible that lower values of H/M ratiosrepresent hearts with more severe myocardial damageand without conditions to improve function despite anytherapeutic approach. Thus, the lowest H/M values insome patients represent advanced and irreversible intra-cellular derangement.

A misbalance of adrenergic function is a hallmark ofchronic HF, and cardiac MIBG imaging seems to be auseful tool in the evaluation of prognosis13-15 and re-sponse to treatment.16-22 To distinguish respondersamong patients at both ends of the HF spectrum repre-sents a major problem. Considering the procedural risks,the use of CRT in end-stage HF is even more trouble-some, because little evidence of HF improvement existsin this population.32,33

We can state that the baseline cardiac sympatheticactivity evaluated by MIBG scintigraphy offers addi-tional information to that of ventricular dyssynchrony,thus leading to a better definition of HF outcome aftertherapy. This assessment is also useful in evaluating thecardiac sympathetic activity response in patients whoundergo CRT.

Limitations

The number of patients in the present study limitsthe power of its findings. The results shown here seem tobe very promising. However, further studies with a large

patient population, using this cutoff value H/M ratio in

the selection of candidates for CRT, will be necessary tovalidate these results.

Another limitation may involve the fact that onlyplanar images were used. Maybe the use of MIBGtomographic images would allow a better separation ofthe heart from other thoracic structures. This couldcontribute to the achievement of a more precise numberof counts in the heart and mediastinum regions of interestand more accurate indices.

Possible interobserver and intraobserver variabilitymay also have interfered with the results, because pa-tients with severe HF have a low cardiac concentration ofMIBG, which increases statistical errors during calcula-tions.

Conclusions

In conclusion, these results show that an improve-ment in cardiac sympathetic activity correlated with apositive response to CRT, and that the H/M ratio ofMIBG uptake could help in selecting patients for CRT. Alow value for cardiac MIBG uptake seems to be a markerof end-stage chronic HF and nonresponse to CRT.

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