Author + information
- Received April 30, 2010
- Revision received June 29, 2010
- Accepted July 7, 2010
- Published online September 1, 2010.
- Elisabete Martins, MD*,* (, )
- Ana Oliveira, MD†,
- José Silva-Cardoso, MD, PhD*,§,
- Teresa Faria, MD†,
- Teresa Pinho, MD*,
- Manuel Campelo, MD*,
- António Madureira, MD‡,
- Orquídea Ribeiro, BSc∥,
- Isabel Ramos, MD, PhD‡,
- Jorge G. Pereira, MD† and
- Francisco Rocha-Gonçalves, MD, PhD§
- ↵*Reprint requests and correspondence:
Dr. Elisabete Martins, Serviço de Cardiologia, Hospital de São João, Avenida Prof. Hernani Monteiro, 4200-319 Porto, Portugal
Familial dilated cardiomyopathy (FDCM) is characterized by genetic heterogeneity, incomplete age-dependent penetrance, and a multifactorial pathogenesis (1). Diagnosis is still dependent on clinical criteria and familial investigation (2). On the other hand, several abnormalities have been described among asymptomatic relatives, such as isolated left ventricle (LV) enlargement (3). These abnormalities could assist in identifying affected relatives, who are potential candidates for early therapeutic interventions. However, currently not even the presence of such abnormalities allows inferring carrier state or future progression of the disease. We hypothesized that 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 in disease progression (4). This evaluation could provide prognostic data useful in this clinical setting.
We evaluated 45 FDCM members from 23 families defined by the European Society of Cardiology criteria (2); 25 patients (56%) were male, with a median age of 43 years (interquartile range, 36 to 51 years). One of the families has the disease locus located in chromosome 7q22.3-31.1 (5). All participants underwent 12-lead electrocardiogram and 2-dimensional echocardiogram. Measurements were done according to the American Society of Echocardiography. Forty members also underwent cardiac magnetic resonance (CMR) on a 3-Tesla scanner (Magneton trio, Siemens AG, Erlangen, Germany). The protocol included contrast-enhanced images, acquired 10 to 15 min after intravenous administration of gadobutrol (Gadovist [Schering AG, Berlin, Germany]; 0.2 mmol/kg). The 123I-mIBG imaging was performed after intravenous administration of 370 MBq (10 mCi) of 123I-mIBG (4). We used a dual-headed gamma camera (GE Millennium MG, Haifa, Israel), equipped with low-energy, high-resolution, parallel-hole collimators, using a 20% window centered at the 159-keV photo peak. Images were processed with dedicated software (QGS/QPS [Cedars-Sinai Medical Center, Los Angeles, California] on a Xeleris [Paris, France] workstation). No attenuation correction was performed. Anterior projection planar thoracic images were obtained 20 min and 4 h after tracer injection, and heart/mediastinal (H/M) ratio and myocardial washout rate (WR) calculated twice by 2 independent blinded observers. The final results were obtained by the mean of the average of each operator. A blood sample was obtained for B-type natriuretic peptide (BNP) quantification (Architect system, Abbott, Abbott Park, Illinois) just before 123I-mIBG administration. Heart rate variability parameters were calculated, using a DigiTrack-Plus Recorder (Philips Medical Systems, Andover, Massachusetts) and a Philips Zymed Holter, Model 1810 Plus Software (Philips Medical Systems). All statistical analyses were performed with SPSS for Windows (version 16.0; SPSS Inc, Chicago, Illinois). Categorical data were compared using Fisher exact test. Student t and Mann-Whitney U tests were used to compare continuous variables. The Spearman correlation was used to evaluate associations in continuous variables with asymmetric distribution, such as LV mass index and LV ejection fraction (EF).
Twenty-nine familial members (64%) had EF <50% (DCM patients), and 16 had EF ≥50%, including 6 with reverse remodeling (previous LV systolic dysfunction) and 10 asymptomatic relatives. An expected difference between both groups was observed in CMR-indexed LV end-diastolic volumes (134 ml/m2 [range 100 to 161] vs. 85 ml/m2 [range 73 to 95]; p < 0.001), LVEF (30% [range 25% to 45%] vs. 55% [range 55% to 64%]; p < 0.001), right ventricular EF (48 ± 10% vs. 55 ± 7%; p = 0.017), late hyperenhancement (8 patients vs. none; p = 0.035), plasma BNP (104 pg/ml [range 18 to 354 pg/ml] vs. 10 pg/ml [range 10 to 16 pg/ml]; p < 0.001], myocardial WR (43 ± 11% vs. 34 ± 9%; p = 0.011), and late H/M ratio (1.73 ± 0.26 vs. 1.89 ± 0.14; p = 0.027) (Fig. 1). No heart variability parameter value was distinct between both groups. We did not find significant differences in WR value and late H/M ratio between members with (47.2 ± 11.3% and 1.6 [range 1.4 to 1.8], respectively) and without (40.2 ± 11.3% and 1.7 [range 1.6 to 1.9], respectively) delayed hyperenhancement on CMR (p = 0.16 and p = 0.22, respectively). The majority (55%) of DCM patients were in New York Heart Association functional class I, and 90% were treated with beta-blockers. In this group, WR was higher than 30% (≥2 SDs) in 24 (83%), and late H/M was inferior to 1.7 in 11 patients (38%). Myocardial WR and late H/M ratio were both correlated with BNP (r = 0.595, p = 0.01; r = −0.622, p = 0.01) (Fig. 2), LVEF (r = −0.668, p = 0.01; r = 0.685, p = 0.01), LV diastolic (r = 0.677, p = 0.01; r = −0.584, p = 0.01), and systolic (r = 0.743, p = 0.01; r = −0.660, p = 0.01) indexed volumes and LV indexed mass (r = 0.638, p = 0.01; r = −0.471, p = 0.05) on CMR imaging. In the group with normal LV systolic function, we found an abnormally high myocardial WR (>30%) in 11 participants (69%), including 5 with reverse remodeling, 4 of 5 identified carriers, and 2 relatives with normal echocardiograms and unknown carrier state (Fig. 3). We did not find correlations between myocardial 123I-mIBG WR and LVEF or indexed volumes or mass. However, 123I-mIBG WR was correlated with normalized low-frequency power (r = 0.691, p = 0.01) and low-frequency/high-frequency ratio (r = 0.702, p = 0.01) heart rate variability parameters. During 558 days (range 432 to 863 days) of follow-up, 6 patients (21%) were submitted to heart transplantation. WR was significantly different between DCM patients who did (51 ± 10%) and did not (41 ± 11%) undergo transplantation (p = 0.05), as was the presence of late hyperenhancement on CMR (p = 0.02) (Fig. 4). None of those with EF >50% developed or had worsening of heart failure symptoms in this time interval.
Our study provides evidence of the heterogeneity of 123I-mIBG findings between FDCM members (with known and unknown disease). We did find rapid WR in a high percentage of individuals with normal EF, and this may reflect the increased adrenergic drive related to the cardiac remodeling process. This hypothesis was somewhat corroborated by the presence of an elevated WR in individuals with reverse remodeling and in 4 locus disease carriers who, theoretically, have higher risk for DCM development. In relatives with EF >50%, a rapid WR could reflect specific histopathologic base or particular gene/protein involvement that causes major interference with cardiac sympathetic nerve metabolism; alternatively, it could reflect the decreased contractility of cardiac myocytes, eventually detected by other diagnostic tools. Late H/M ratio, an index of sympathetic denervation, is usually altered with more severe heart failure, so it is not expected to be significantly changed at early stages of FDCM. In the preserved systolic function group, we did not obtain correlations between WR and LV volumes. This result could be dependent on sample size or just reflecting the great heterogeneity of sympathetic drive between individuals, even with identical LV dimensions and systolic function. We found a positive correlation between WR and 2 heart variability indexes related to sympathetic activity only in the group of patients with EF >50%; this could reflect changes of the sympathovagal balance throughout different stages of disease, as already pointed out by other investigators.
Because of the small number of patients in this study and the short-term follow-up, we cannot evaluate the prognostic value of the 123I-mIBG scintigraphy parameters. These parameters could add complementary information to other morphofunctional imaging studies, guiding the start of early medical treatment or the clinical follow-up schedule of asymptomatic relatives.
This study was supported by a grant from Comissão de Fomento da Investigação em Cuidados de Saúde, Ministério da Saúde P.I. n° 64/2007. The authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- B-type natriuretic peptide
- cardiac magnetic resonance
- ejection fraction
- familial dilated cardiomyopathy
- left ventricular
- washout rate
- Received April 30, 2010.
- Revision received June 29, 2010.
- Accepted July 7, 2010.
- American College of Cardiology Foundation
- Burkett E.L.,
- Hershberger R.E.
- Mestroni L.,
- Maisch B.,
- McKenna W.J.,
- et al.
- Baig M.K.,
- Goldman J.H.,
- Caforio A.L.,
- Coonar A.S.,
- Keeling P.J.,
- McKenna W.J.