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B R I E F R E P O R T

Meta-Iodobenzylguanidine Iodine-123 andCardiac Adrenergic Activity in FamilialDilated Cardiomyopathy

Elisabete Martins, MD,* Ana Oliveira, MD,† José Silva-Cardoso, MD, PHD,*§Teresa Faria, MD,† Teresa Pinho, MD,* Manuel Campelo, MD,* Antonio Madureira, MD,‡Orquıdea Ribeiro, BSC,� Isabel Ramos, MD, PHD,‡ Jorge G. Pereira, MD,†Francisco Rocha-Gonçalves, MD, PHD§

Porto, Portugal

amilial dilated cardiomyopathy (FDCM) ischaracterized by genetic heterogeneity, in-complete age-dependent penetrance, and amultifactorial pathogenesis (1). Diagnosis is

still dependent on clinical criteria and familialinvestigation (2). On the other hand, several abnor-malities have been described among asymptomaticrelatives, such as isolated left ventricle (LV) en-largement (3). These abnormalities could assist inidentifying affected relatives, who are potential can-didates for early therapeutic interventions. How-ever, currently not even the presence of such abnor-malities allows inferring carrier state or futureprogression of the disease. We hypothesized that

See page 964

meta-iodobenzylguanidine iodine-123 (123I-mIBG)imaging, a tool for monitoring sympathetic activity,could be useful in the evaluation of family members,as it reflects pathophysiologic mechanisms involved indisease progression (4). This evaluation could provideprognostic data useful in this clinical setting.

We evaluated 45 FDCM members from 23families defined by the European Society of Cardi-ology criteria (2); 25 patients (56%) were male, witha median age of 43 years (interquartile range, 36 toFrom the *Cardiology Department, São João Hospital, Porto, Portugal;†Nuclear Medicine Department, São João Hospital, Porto, Portugal;‡Radiology Department, São João Hospital, Porto, Portugal; §PortoUniversity Medical School, Porto, Portugal; and the �Department ofBiostatistics and Medical Informatics, CINTESIS, Porto UniversityMedical School, Porto, Portugal. This study was supported by a grantfrom Comissão de Fomento da Investigação em Cuidados de Saúde,Ministério da Saúde P.I. n° 64/2007. The authors have reported that theyhave no relationships to disclose.

Manuscript received April 30, 2010; revised manuscript received June 29,2010, accepted July 7, 2010.

51 years). One of the families has the disease locuslocated in chromosome 7q22.3-31.1 (5). All partic-ipants underwent 12-lead electrocardiogram and2-dimensional echocardiogram. Measurementswere done according to the American Society ofEchocardiography. Forty members also underwentcardiac magnetic resonance (CMR) on a 3-Teslascanner (Magneton trio, Siemens AG, Erlangen,Germany). The protocol included contrast-enhanced images, acquired 10 to 15 min afterintravenous administration of gadobutrol (Gadovist[Schering AG, Berlin, Germany]; 0.2 mmol/kg).The 123I-mIBG imaging was performed after intra-venous administration of 370 MBq (10 mCi) of123I-mIBG (4). We used a dual-headed gammacamera (GE Millennium MG, Haifa, Israel),equipped with low-energy, high-resolution,parallel-hole collimators, using a 20% window cen-tered at the 159-keV photo peak. Images wereprocessed with dedicated software (QGS/QPS[Cedars-Sinai Medical Center, Los Angeles, Cali-fornia] on a Xeleris [Paris, France] workstation).No attenuation correction was performed. Anteriorprojection planar thoracic images were obtained 20min and 4 h after tracer injection, and heart/mediastinal (H/M) ratio and myocardial washoutrate (WR) calculated twice by 2 independentblinded observers. The final results were obtainedby the mean of the average of each operator. Ablood sample was obtained for B-type natriureticpeptide (BNP) quantification (Architect system,Abbott, Abbott Park, Illinois) just before 123I-mIBG administration. Heart rate variability param-eters were calculated, using a DigiTrack-Plus Re-

corder (Philips Medical Systems, Andover,

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Massachusetts) and a Philips ZymedHolter, Model 1810 Plus Software (Phil-ips Medical Systems). All statistical anal-yses were performed with SPSS for Win-dows (version 16.0; SPSS Inc, Chicago,Illinois). Categorical data were comparedusing Fisher exact test. Student t andMann-Whitney U tests were used to com-pare continuous variables. The Spearmancorrelation was used to evaluate associa-tions in continuous variables with asym-metric distribution, such as LV mass indexand LV ejection fraction (EF).

Twenty-nine familial members (64%) had EF50% (DCM patients), and 16 had EF �50%,

ncluding 6 with reverse remodeling (previous LVystolic dysfunction) and 10 asymptomatic relatives.n expected difference between both groups wasbserved in CMR-indexed LV end-diastolic vol-mes (134 ml/m2 [range 100 to 161] vs. 85 ml/m2

range 73 to 95]; p � 0.001), LVEF (30% [range5% to 45%] vs. 55% [range 55% to 64%];� 0.001), right ventricular EF (48 � 10% vs. 55 �

%; p � 0.017), late hyperenhancement (8 patientss. none; p � 0.035), plasma BNP (104 pg/mlrange 18 to 354 pg/ml] vs. 10 pg/ml [range 10 to

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Figure 1. Comparison Between FDCM Patients and Relatives Ac

(A) Cardiac magnetic resonance (CMR) left ventricular (LV) end-diasdelayed hyperenhancement, (D) plasma B-type natriuretic peptide (washout rate (WR), (F) 123I-mIBG late heart to mediastinum activity

§Mann-Whitney U test. FDCM � familial dilated cardiomyopathy; LVEF

6 pg/ml]; p � 0.001], myocardial WR (43 � 11%s. 34 � 9%; p � 0.011), and late H/M ratio (1.73

0.26 vs. 1.89 � 0.14; p � 0.027) (Fig. 1). Noeart variability parameter value was distinct be-ween both groups. We did not find significantifferences in WR value and late H/M ratio be-ween members with (47.2 � 11.3% and 1.6 [range.4 to 1.8], respectively) and without (40.2 � 11.3%nd 1.7 [range 1.6 to 1.9], respectively) delayedyperenhancement on CMR (p � 0.16 and p �.22, respectively). The majority (55%) of DCMatients were in New York Heart Associationunctional class I, and 90% were treated witheta-blockers. In this group, WR was higher than0% (�2 SDs) in 24 (83%), and late H/M wasnferior to 1.7 in 11 patients (38%). Myocardial

R and late H/M ratio were both correlated withNP (r � 0.595, p � 0.01; r � �0.622, p � 0.01)

Fig. 2), LVEF (r � �0.668, p � 0.01; r � 0.685,� 0.01), LV diastolic (r � 0.677, p � 0.01; r �0.584, p � 0.01), and systolic (r � 0.743, p �

.01; r � �0.660, p � 0.01) indexed volumes andV indexed mass (r � 0.638, p � 0.01; r �0.471, p � 0.05) on CMR imaging. In the groupith normal LV systolic function, we found an

bnormally high myocardial WR (�30%) in 11

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ardiomyopathy

/M � heart/mediastinal

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� left ventricular ejection fraction.

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Figure 2. Relationship of Plasma BNP to Cardiac 123I-mIBG Scintigraphy Data

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Correlations between plasma BNP levels and (A) myocardial I-mIBG WR and (B) late H/M. Abbreviations as in Figure 1.

Figure 3. Characterization of Familial DCM Members Using Different Imaging Methods

Illustrative examples of (A) 2-dimensional echocardiogram, (B) cardiac magnetic resonance, and (C) 123I-mIBG scan images of: 1) a patientwith dilated cardiomyopathy (DCM) and late hyperenhancement; 2) a patient with reverse remodeling and left bundle branch block; and3) an identified carrier with preserved left ventricular ejection fraction. 123I-mIBG parameters: 1) late H/M � 1.6, WR � 41.6%; 2) late

H/M � 1.9, WR � 36%; 3) late H/M � 1.8, WR � 40.2%. Abbreviations as in Figure 1.

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articipants (69%), including 5 with reverse remod-ling, 4 of 5 identified carriers, and 2 relatives withormal echocardiograms and unknown carrier stateFig. 3). We did not find correlations betweenyocardial 123I-mIBG WR and LVEF or indexed

olumes or mass. However, 123I-mIBG WR wasorrelated with normalized low-frequency powerr � 0.691, p � 0.01) and low-frequency/high-requency ratio (r � 0.702, p � 0.01) heart rateariability parameters. During 558 days (range 432o 863 days) of follow-up, 6 patients (21%) wereubmitted to heart transplantation. WR was signif-cantly different between DCM patients who did

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ardiac 123I-mIBG Scintigraphy Parameters inbers

tion of scintigraphic parameters according to left ventricularction (EF) of family members. Dilated cardiomyopathy (DCM)lation with occurrence of heart transplantation during follow-up.ith EF �50%: relation with carrier state of asymptomatic mem-vidence of reverse remodeling among patients. (B) Distribution ofEF according to late H/M; relation with the presence of delayedncement in cardiac magnetic resonance. Abbreviations as in

51 � 10%) and did not (41 � 11%) undergo t

ransplantation (p � 0.05), as was the presence ofate hyperenhancement on CMR (p � 0.02) (Fig.). None of those with EF �50% developed or hadorsening of heart failure symptoms in this time

nterval.Our study provides evidence of the heterogeneity

f 123I-mIBG findings between FDCM memberswith known and unknown disease). We did findapid WR in a high percentage of individuals withormal EF, and this may reflect the increaseddrenergic drive related to the cardiac remodelingrocess. This hypothesis was somewhat corrobo-ated by the presence of an elevated WR in indi-iduals with reverse remodeling and in 4 locusisease carriers who, theoretically, have higher riskor DCM development. In relatives with EF

50%, a rapid WR could reflect specific his-opathologic base or particular gene/protein in-olvement that causes major interference with car-iac sympathetic nerve metabolism; alternatively, itould reflect the decreased contractility of cardiacyocytes, eventually detected by other diagnostic

ools. Late H/M ratio, an index of sympatheticenervation, is usually altered with more severeeart failure, so it is not expected to be significantlyhanged at early stages of FDCM. In the preservedystolic function group, we did not obtain correla-ions between WR and LV volumes. This resultould be dependent on sample size or just reflectinghe great heterogeneity of sympathetic drive be-ween individuals, even with identical LV dimen-ions and systolic function. We found a positiveorrelation between WR and 2 heart variabilityndexes related to sympathetic activity only in theroup of patients with EF �50%; this could reflecthanges of the sympathovagal balance throughoutifferent stages of disease, as already pointed out byther investigators.Because of the small number of patients in this

tudy and the short-term follow-up, we cannotvaluate the prognostic value of the 123I-mIBGcintigraphy parameters. These parameters coulddd complementary information to other morpho-unctional imaging studies, guiding the start of earlyedical treatment or the clinical follow-up schedule

f asymptomatic relatives.

eprint requests and correspondence: Dr. Elisabete Mar-ins, Serviço de Cardiologia, Hospital de São João,venida Prof. Hernani Monteiro, 4200-319 Porto, Por-

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(A) Distribuejection frapatients: reRelatives wbers and eWR and LVhyperenha

ugal. E-mail: elisabetemartins09@gmail.com.

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ey Words: dilatedardiomyopathy y familial y

enetic y mIBG.