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JACC: CARDIOVASCULAR IMAGING
VOL. 4, NO. 1, 2011
© 2011 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 1936-878X/$36.00
DOI:10.1016/j.jcmg.2010.10.005
Iodine-123 mIBG Imaging for Predicting the
Development of Atrial Fibrillation
Yasushi Akutsu, MD,* Kyouichi Kaneko, MD,* Yusuke Kodama, MD,* Hui-Ling Li, MD,*
Jumpei Suyama, MD,† Akira Shinozuka, MD,† Takehiko Gokan, MD,†
Yuji Hamazaki, MD,* Kaoru Tanno, MD,* Youichi Kobayashi, MD*
Tokyo, Japan
O B J E C T I V E S We investigated whether cardiac sympathetic nervous system (SNS) activity mea-
sured by iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging would be associated with both the
occurrence of heart failure (HF) and the transit to permanent atrial fibrillation (AF) in patients with
paroxysmal AF.
B A C K G R O U N D Atrial fibrillation occurs suddenly and transiently and can persist, and results in the
occurrence of HF. An important feature of AF and HF is their propensity to coexist not only because they
share antecedent risk factors, but also because the one may directly predispose the heart to the other.
However, a useful modality for predicting the occurrences of both those has not been established in
patients with paroxysmal AF.
M E T H O D S The 123I-mIBG scintigraphy was performed to evaluate cardiac SNS activity presented as
the heart/mediastinum ratio in 98 consecutive patients (age 66 ⫾ 13 years, 63.3% male) with idiopathic
paroxysmal AF and preserved left ventricular ejection fraction (ⱖ50%).
R E S U L T S During 4 ⫾ 3.6 years of follow-up, the transit to permanent AF was associated with the
occurrence of HF (34.3% in 12 of 35 patients with permanent AF vs. 6.3% in 4 of 63 patients without, p ⬍
0.0001). Lower heart/mediastinum ratio and lower left ventricular ejection fraction were the independent predictors of the transit to permanent AF with adjusted hazard ratios of 3.44 (95% confidence
interval [CI]: 1.9 to 6.2, p ⬍ 0.0001) and 1.04 (95% CI: 1.01 to 1.08, p ⫽ 0.014). Further, these factors and
higher plasma brain natriuretic peptide concentration were the independent predictors of the
occurrence of HF with permanent AF, with adjusted hazard ratios of 5.08 (95% CI: 1.5 to 17.5, p ⫽ 0.011),
1.11 (95% CI: 1.03 to 1.19, p ⫽ 0.004), and 1.004 (95% CI: 1.001 to 1.008, p ⫽ 0.014).
C O N C L U S I O N S Cardiac SNS abnormality was associated with the occurrence of both HF and
permanent AF in paroxysmal AF patients, and 123I-mIBG imaging may be a useful modality for predicting
the development of AF. (J Am Coll Cardiol Img 2011;4:78 – 86) © 2011 by the American College of
Cardiology Foundation
From the *Division of Cardiology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan, and the
†Department of Radiology, Showa University School of Medicine, Tokyo, Japan. All authors have reported that they have no
relationships to disclose.
Manuscript received February 21, 2010; revised manuscript received October 19, 2010, accepted October 20, 2010.
JACC: CARDIOVASCULAR IMAGING, VOL. 4, NO. 1, 2011
JANUARY 2011:78 – 86
A
trial fibrillation (AF) occurs suddenly and
transiently, and can be perpetuated, and
results in the occurrence of heart failure
(HF). AF and HF have emerged as new
cardiovascular epidemics over the last decade (1).
AF facilitates the development or progression of
HF by reduction of cardiac output, which results
from enlargement of left atrial size, rapid ventricular
rate, irregular rate, valvular inefficiency, and left
ventricular dysfunction with tachycardia-induced
cardiomyopathy (2). However, the majority of AF
See page 87
patients with HF do not have a reduced left
ventricular ejection fraction (LVEF) (3,4). An important feature of permanent AF and occurrence of
HF is their propensity to coexist, not only because
they share antecedent risk factors, but also because
the one may directly predispose the heart to the
other. More important, it is widely perceived that
the combination of these conditions carries a worse
prognosis than does either alone. However, the
paroxysmal occurrence of AF does not always result
in the development of permanent AF and HF.
Therefore, a recent report from a National Heart,
Lung and Blood Institute workshop has recommended researching noninvasive modalities for
identifying key components of cardiovascular remodeling factors that promote AF (5). As pointed
out in that workshop, the autonomic nervous system plays an important role for both the development of permanent AF from paroxysmal AF (6,7)
and the occurrence of HF (8). Iodine-123 metaiodobenzylguanidine (123I-mIBG) has been the
most widely used imaging agent for studying causes
and effects of cardiac sympathetic nervous system
(SNS) abnormality (9), and has been reported to
predict the mortality of patients with HF independent of its cause. However, these previous studies
using 123I-mIBG imaging have focused on the
occurrence of HF with reduced cardiac function
caused by structural heart disease. We hypothesized
that SNS abnormality measured by 123I-mIBG
imaging would be associated with the occurrence of
HF, with the development to permanent AF in
patients with paroxysmal AF and preserved cardiac
function.
METHODS
Study population. We studied 126 consecutive pa-
tients with a first history of paroxysmal AF at
Akutsu et al.
Sympathetic Function by mIBG and Permanent AF
79
Showa University Hospital. The condition of arrhythmia was diagnosed on the basis of documented AF by ambulance monitoring, 12-lead
electrocardiography (ECG), or Holter monitoring.
They did not have the clinical symptoms of HF
(10). The diagnosis of AF was made when visible
P-waves on all 12 leads of ECG were absent, and an
irregular random-appearing ventricular response
was present (7). The AF was considered paroxysmal
if the fibrillatory process ended spontaneously after
some seconds, minutes, hours, or up to 7 days (7).
The patients who had episodes of AF that were not
self-terminating were considered to have persistent
AF despite sinus rhythm, and were distinguished
from paroxysmal AF. These patients were excluded
from the entry into this study. Left ventricular
ejection fraction (LVEF) and left atrial dimension
(LAD) were measured by 2-dimensional echocardiography before the study. The patients
ABBREVIATIONS
with LVEF ⬍50%, history of valvular
AND ACRONYMS
disease including rheumatic cause, congenital heart disease, ischemic heart disAF ⴝ atrial fibrillation
ease, and cardiomyopathy were excluded
BNP ⴝ brain natriuretic peptide
from this study. Patients were also exCRP ⴝ C-reactive protein
cluded from this study if they had preECG ⴝ electrocardiography
excitation syndrome, supraventricular
HF ⴝ heart failure
tachycardia other than AF, or implanted
H/M ⴝ heart/mediastinum
pacemaker before the study. Patients who
123
I-mIBG ⴝ iodine-123
had autonomic nervous system abnormalmeta-iodobenzylguanidine
ity such as hyperthyroidism, Parkinson’s
LAD ⴝ left atrial dimension
disease, or degenerative cerebral disease,
LVEF ⴝ left ventricular ejection
and patients who had a history of known
fraction
thrombus or vascular events were also
SNS ⴝ sympathetic nervous
excluded from this study.
system
All patients gave written informed consent before this study, and the protocol
was approved by our institutional review board.
Data collected prospectively included demographics, existing medical diagnoses, symptoms, risk
factors for vascular disease, medications, previous
cardiac procedures, and histories of vascular events.
Finally, 123I-mIBG scintigraphy was performed
during stable sinus rhythm to assess SNS activity in
98 patients (mean ⫾ SD; age 66 ⫾ 13 years; 63.3%
male) with paroxysmal AF who did not have
structural heart disease and have preserved cardiac
function. After intravenous injection of 111 MBq
of 123I-mIBG (Dai-ichi Radioisotope Laboratory,
Chiba, Japan), the myocardial planner images were
acquired with 4-h delayed images using a standardfield gamma camera (PRIZM 2000XP, Picker/
Philips Co., Cleveland, Ohio) as shown in a previous study (11). To evaluate the myocardial accu-
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Akutsu et al.
Sympathetic Function by mIBG and Permanent AF
mulation of 123I-mIBG, the heart/mediastinum
(H/M) activity ratio was calculated from the delayed
image (9,11).
Blood samples were obtained before injection of
123
I-mIBG to measure C-reactive protein (CRP).
CRP was assayed by a latex immunonephelometric
method with an assay range of 0.1 to 30 mg/dl
using an automatic analyzer (7350 Clinical Analyzer, Hitachi High-Tech Trading Co., Tokyo,
Japan). The plasma brain natriuretic peptide (BNP)
level was also measured using an immunoradiometric assay (Shionogi RIA, Shionogi Co. Ltd., Osaka,
Japan).
Follow-up. The patients were prospectively followed
up to investigate SNS abnormality as 1 of the
predictive markers. The primary end point of this
study was the transit to permanent AF. All patients
were followed up at least every 4 weeks, and were
examined using 12-lead ECG to observe cardiac
rhythm. Direct-current cardioversion and/or pharmacological therapy were administered to all patients whose AF persisted and was not self terminating for ⬎1 week. The AF was considered
permanent if these patients failed to recover the
condition of sinus rhythm despite those therapies.
The permanent AF was confirmed by the later
ECG change during follow-up to be distinguished
from the persistent AF. The second end point was
the occurrence of HF requiring hospitalization on
the basis of the clinical criterion (the presence of 2
major or 1 major and 2 minor criteria; major criteria
were paroxysmal nocturnal dyspnea or orthopnea,
distended neck veins, rales, radiographic cardiomegaly, pulmonary edema, third heart sound, increased venous pressure, hepatojugular reflux, and
weight loss on diuretic therapy; minor criteria were
ankle edema, night cough, dyspnea on exertion,
hepatomegaly, pleural effusion, pulmonary vascular
redistribution, decrease in vital capacity, and tachycardia) (10,12).
The clinical diagnosis of HF was also confirmed
by dedicated research personnel using a scripted
review of the medical record. Only the time to
occurrence of the permanent AF and/of HF was
used as the end point. The end points were confirmed by an independent committee blinded to the
patient’s clinical history.
Statistical analysis. Continuous variables were presented as mean ⫾ SD. Differences between groups
were tested using an unpaired t test, chi-square test,
or Fisher exact test as appropriate. When the
variances between each group differed considerably,
we used a nonparametric test (Mann-Whitney U
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test). An association between the predictors such as
age, sex, LAD, LVEF, CRP, and BNP, and the
events such as transit to permanent AF and/or
occurrence of HF was formally tested by construction of Cox proportional hazards model with regression analysis. All multivariable analyses employed the forward stepwise methods, with entry
and removal p values set at 0.1. Further, the
likelihood-ratio test was used to estimate the model
fitting. For descriptive purposes, the receiveroperator characteristic analysis was performed to
define thresholds for those factors, and the patients
were divided into 2 groups to perform the log-rank
test using construction of Kaplan-Meier curves.
The statistical analysis was done using SPSS for
Windows Version 11 (SPSS Inc., Chicago,
Illinois).
RESULTS
Factors perpetuating AF. During 4.0 ⫾ 3.6 years of
follow-up (up to 13.9 years), 35 patients with
paroxysmal AF transited to permanent AF finally
(Fig. 1). Of those 35, 14 patients with permanent
AF had a transient process to sinus rhythm (the
condition of persistent AF) produced by the therapies for a while (Table 1). There were no significant differences between the patients with and
without the transit to permanent AF in age, sex,
cardiovascular risk factors, and hemodynamic responses. Risk factors such as obesity or hypertension were controlled by diet, salt restriction, and
medication after the entry into this study. The SNS
activity, LAD, BNP, and LVEF were the factors
that perpetuated AF (Table 2). In multivariable
analysis, after adjustment for 5 potential confounding variables, SNS abnormality was an independently powerful factor perpetuating AF.
Factors resulting in HF with permanent AF. Figure 2
shows the typical 123I-mIBG image examples and
ECG strips. These patients with paroxysmal AF
had the low H/M ratio, which suggests the development of AF. HF occurred in 16 patients during
follow-up, and of those 16, 12 patients were diagnosed as having permanent AF. The transit to
permanent AF was associated with the occurrence
of HF (34.3% in 12 of 35 patients with permanent
AF vs. 6.3% in 4 of 63 patients without, p ⬍
0.0001). The BNP, LAD, SNS activity, LVEF,
and age were the factors resulting in the occurrence
of HF with permanent AF (Table 3). In multivariable analysis, after adjustment for 5 potential
confounding variables, SNS abnormality was an
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Akutsu et al.
Sympathetic Function by mIBG and Permanent AF
Figure 1. Schematic Time Table Regarding the Temporal Sequence of Conversion to Permanent AF
Thirty-five patients with paroxysmal atrial fibrillation (AF) transited to permanent AF finally; of those 35, 14 patients with permanent AF
had a transient process to persistent AF by the conversion. Sixty-three patients with paroxysmal AF remained in sinus rhythm; of those
63, 5 patients had a process of persistent AF by the conversion.
independently powerful predictor resulting in HF
with permanent AF.
An SNS abnormality, defined as H/M ratio ⱕ2.7,
predicted the occurrence of HF with permanent AF in
83.3% (10 of 12 patients) for the sensitivity and 67.4%
(58 of 86 patients) for the specificity (Fig. 3), and was
a powerful predictor of events (log-rank chi-square ⫽
15.4, p ⬍ 0.0001) (Fig. 4). The higher BNP (⬎75
pg/ml) and lower LVEF (ⱕ60%) were also powerful
predictors of the events.
DISCUSSION
Our major finding is that SNS abnormality was an
independently powerful factor for predicting not
only the transit to permanent AF but also the
occurrence of HF with permanent AF in patients
with paroxysmal AF and preserved cardiac function.
SNS abnormality for predicting transit to permanent AF.
The most frequent histopathologic changes in AF
are atrial fibrosis and loss of atrial muscle mass (7).
These changes contribute to a biological phenomenon known as “remodeling,” which makes increasingly irreversible electrical and structural properties
of the atrial tissue and cardiac cells. These changes
are important causes of perpetuated AF. Other than
old age, the established risk factors for promoting
AF include cardiac conditions such as HF, valvular
disease, myocardial infarction, and cardiovascular
risk factors (5,6); and subclinical markers indicating
increased AF risk include increased arterial stiffness
(13), LAD enlargement, left ventricular hypertrophy, and left ventricular dysfunction (14). Recently
identified novel markers associated with increased
risk for AF include the inflammatory and neurohumoral biomarkers (15,16). However, despite hundreds of publications regarding predictors of developing AF, it is still difficult to determine an
individual patient’s risk of developing AF.
Clinical observations suggest that the onset of an
AF episode is often related to variations in autonomic tone (17). Altered autonomic tone may be an
important mechanism underlying the association of
nocturnal oxygen desaturation occurring in patients
with sleep apnea and incident AF (16). Preliminary
studies suggest that the modulation of autonomic
tone is 1 of the possible beneficial effects of
omega-3 fatty acids in the prevention of AF (18).
These studies propose that SNS activity itself plays
an important role in both initiation and/or the
maintenance of AF (19). Further, when the compensatory support is needed to meet the demands of
organ perfusion due to hemodynamic overload, the
cardiac adrenergic system becomes maladaptive to
the heart and may cause the change that increases
susceptibility to persistent AF. However, the significance of autonomic factors for promoting AF
are poorly understood because there are no effective
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Table 1. Patient Characteristics
Transit to
Permanent AF
(n ⴝ 35)
Variable
No Transit to
Permanent AF
(n ⴝ 63)
p Value
Age, yrs
68 (10)
65 (14)
0.09
Female
15 (42.9%)
21 (33.3%)
0.35
History of diabetes mellitus
6 (9.5%)
0.14
18 (51.4%)
7 (20%)
34 (54%)
0.81
History of hyperlipidemia
8 (22.9%)
17 (27%)
0.65
History of obesity*
1 (2.9%)
4 (6.2%)
0.45
History of hypertension
Resting hemodynamics
Resting HR, beats/min
75 (21)
77 (19)
0.64
Resting systolic BP, mm Hg
135 (22)
129 (18)
0.21
Resting diastolic BP, mm Hg
76 (14)
74 (13)
0.41
Electrocardiogram in sinus rhythm
PQ interval, ms
170 (29)
166 (35)
0.55
QRS wave duration, ms
100 (21)
107 (22)
0.14
QTc interval, ms
438 (22)
489 (48)
0.53
Medications
Use of angiotensin-converting enzyme inhibitor
16 (45.7%)
27 (42.9%)
Use of beta-blocker
11 (31.4%)
20 (31.7%)
0.79
0.97
Use of calcium-channel antagonist
13 (37.1%)
17 (27%)
0.3
0.44
Use of sodium-channel blockers
8 (22.9%)
19 (30.2%)
Use of digoxin
1 (2.9%)
4 (6.3%)
0.45
Occurrence of persistent AF
14 (40%)
5 (7.9%)
⬍0.0001
Occurrence of HF
12 (34.3%)
4 (6.3%)
⬍0.0001
Data are presented as the mean (SD) or n (%). *Obesity was defined as body mass index ⱖ30 kg/m2.
AF ⫽ atrial fibrillation; BP ⫽ blood pressure; HF ⫽ heart failure; HR ⫽ heart rate.
noninvasive methods capable of defining or monitoring autonomic function (5). Recent studies demonstrate the significance of 123I-mIBG imaging as a
marker of SNS activity in patients with structural
heart disease and reduced left ventricular function
(9). Mabuchi et al. (20) first reported using 123ImIBG scintigraphy that SNS abnormality was associated with AF in 13 patients with permanent AF
and valvular disease. Recently, we also demonstrated, using 123I-mIBG imaging, that a combination of SNS abnormality and high inflammatory
markers was associated with vascular events in 71
patients with paroxysmal AF (21). We show in the
present study that SNS activity was associated with
the transit to permanent AF from the paroxysmal
occurrence.
Table 2. Risk of Transit to Permanent Atrial Fibrillation According to Univariable and Multivariable Analyses
Regression
Analysis
Univariable Analysis
Multivariable Analysis
p Value
Hazard Ratio
(95% CI)
Wald
Chi-Square
p Value
Likelihood-Ratio
Test p Value
(Chi-Square)
⬍0.0001
3.44 (1.90–6.21)
16.70
⬍0.0001
⬍0.0001 (17.18)
1.04 (1.01–1.08)
6.08
0.014
⬍0.0001 (21.48)
Variable
Coefficient
(Beta)
Hazard Ratio
(95% CI)
Wald
Chi-Square
H/M ratio, for each decrease
⫺1.141
3.13 (1.80–5.43)
16.4
LAD, mm, for each increase
⫹0.072
1.08 (1.03–1.13)
9.69
0.002
Plasma BNP, pg/ml,
for each increase
⫹0.003
1.003 (1.001–1.004)
7.0
0.008
LVEF, %, for each decrease
⫺0.040
1.04 (1.01–1.08)
5.59
0.02
Age, yrs, for each increase
⫹0.027
1.03 (1.00–1.06)
3.16
0.08
BMI, kg/m2, for each increase
⫹0.034
1.04 (0.94–1.14)
0.53
0.47
CTR, %, for each increase
⫹0.015
1.02 (0.96–1.07)
0.31
0.58
Serum CRP, mg/dl,
for each increase
⫹0.088
1.09 (0.55–2.15)
0.07
0.80
BMI ⫽ body mass index; BNP ⫽ brain natriuretic peptide; CI ⫽ confidence interval; CRP ⫽ C-reactive protein; CTR ⫽ cardiothoracic ratio; H/M ⫽ heart/mediastinum; LAD ⫽ left atrial dimension;
LVEF ⫽ left ventricular ejection fraction.
Akutsu et al.
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Figure 2.
83
123
I-mIBG Image Examples and ECG Strips
In these examples of iodine-123 meta-iodobenzylguanidine (123I-mIBG) images and electrocardiography (ECG) strips, the ovals indicate
the region of interest on the heart area (H), and the rectangles indicate the region of interest on mediastinum area (M). Cardiac sympathetic nervous system activity was estimated by the value of heart/mediastinum (H/M) ratio. (A) A patient with paroxysmal atrial fibrillation (AF), a 78-year-old man, had 2.7 H/M ratio on 123I-mIBG image, and transited to permanent AF without the occurrence of heart
failure (HF). (B) A patient with paroxysmal AF, a 68-year-old man, had 2.6 H/M ratio. The HF with AF occurred afterward, but the
improvement of HF resulted in the recovery to sinus rhythm from AF. (C) A patient with paroxysmal AF, a 71-year-old man. had 2.5 H/M
ratio, and transited to permanent AF. The HF occurred afterward, and the AF was perpetuated after the improvement of HF. These
patients with paroxysmal AF had significantly lower H/M ratios than normal values (vs. 3.3 ⫾ 0.5).
SNS abnormality for predicting occurrence of HF with
transit to permanent AF. Although the causative
relationship between AF and HF has not been fully
determined, their coexistence can be explained to
some degree by the presence of common risk factors
as age, hypertension, diabetes, and obesity, as well
as valvular, ischemic, and nonischemic structural
heart disease (2). More important, these factors are
Table 3. Risk of Heart Failure With Permanent Atrial Fibrillation According to Univariable and Multivariable Analyses
Regression
Analysis
Univariable Analysis
Multivariable Analysis
p Value
Hazard Ratio
(95% CI)
Wald
Chi-Square
p Value
Likelihood-Ratio
Test p Value
(Chi-Square)
⬍0.0001
1.004 (1.001–1.008)
6.02
0.014
⬍0.0001 (19.67)
Coefficient
(Beta)
Hazard Ratio
(95% CI)
Wald
Chi-Square
Plasma BNP, pg/ml,
for each increase
⫹0.005
1.005 (1.002–1.007)
13.6
LAD, mm, for each increase
⫹0.122
1.13 (1.04–1.23)
8.79
H/M ratio, for each decrease
⫺1.269
3.56 (1.49–8.47)
8.16
0.004
5.08 (1.46–17.5)
6.04
0.011
⬍0.0001 (31.52)
LVEF, %, for each decrease
⫺0.087
1.09 (1.02–1.16)
7.08
0.008
1.11 (1.03–1.19)
8.67
0.004
⬍0.0001 (26.35)
Age, yrs, for each increase
⫹0.068
1.07 (1.003–1.142)
4.22
0.040
CTR, %, for each increase
⫹0.067
1.07 (0.97–1.18)
1.75
0.190
Serum CRP, mg/dl,
for each increase
⫹0.506
1.66 (0.69–4.01)
1.27
0.260
Variable
Abbreviations as in Table 2.
0.003
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Figure 3. ROC Curves for Predicting Occurrence of HF With Permanent AF
The receiver-operator characteristics (ROC) curves for predicting occurrence of heart failure (HF) with permanent atrial fibrillation (AF)
indicate that the sensitivity of cardiac sympathetic nervous system abnormality (heart/mediastinum ratio ⱕ2.7) was 83.3% in 10 of 12
patients, and the specificity was 67.4% in 58 of 86 patients. The sensitivity of higher brain natriuretic peptide (BNP) (⬎75 pg/ml) was
83.3% in 10 of 12 patients, and the specificity was 68.6% in 59 of 86 patients. The sensitivity of lower left ventricular ejection fraction
(LVEF) (ⱕ60%) was 75% in 9 of 12 patients, and the specificity was 67.4% in 58 of 86 patients.
associated with myocardial cellular and extracellular
alterations and electrophysiological and neurohumoral changes that combine to create an environment that predisposes the heart to both permanent
AF and HF (2). The SNS dysfunction in patients
with HF has been demonstrated as several neurohumoral alterations that are associated with poor
patient prognosis as well as cardiac dysfunction
(22). Depleted norepinephrine stores, desensitized
adrenoreceptors, and functional autonomic imbalance in the myocardium (23), and increased spillover of norepinephrine from the SNS in the skeletal
muscle (24) and heart (8) are related to the increased plasma concentration and depleted stores in
the failing heart. Many previous studies have reported that SNS abnormality that correlated with
severe cardiac dysfunction is predictive of mortality
in patients with HF (25). Recently, Kasama et al.
(26) showed that SNS abnormality correlated with
BNP in patients with HF despite preserved ventricular ejection fraction, suggesting the significance of
SNS abnormality for predicting mortality independent of cardiac function. Similar to their study, our
results also indicate the significance of SNS abnormality independent of structural remodeling represented as LAD enlargement or subsequent severe
cardiac dysfunction.
Jahangir et al. (27) demonstrated that not only
old age but also proarrhythmic effects were the
common factors of development of both permanent
AF and HF in 76 patients with idiopathic paroxysmal AF during follow-up, and they suggested that
electrical remodeling plays an important role for
promoting the development to both permanent AF
and HF rather than structural remodeling in patients with paroxysmal AF and preserved cardiac
function. Surely, in patients with paroxysmal AF,
electrical remodeling of atria occurs before struc-
Figure 4. Kaplan-Meier Survival Curves
Kaplan-Meier survival curves for predicting occurrence of heart failure (HF) with permanent atrial fibrillation (AF). Cardiac sympathetic
nervous system abnormality (heart/mediastinum ratio [H/M] ⱕ2.7), higher brain natriuretic peptide (BNP) (⬎75 pg/ml), and lower left
ventricular ejection fraction (LVEF) (ⱕ60%) were the powerful predictors of the events.
Akutsu et al.
Sympathetic Function by mIBG and Permanent AF
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tural remodeling (28), and the electrical remodeling
prolongs the duration of paroxysmal AF (proarrhythmic effects), which results in HF in patients
with paroxysmal AF (29). It may result from similar
causes that the value of SNS abnormality was
superior to that of large LAD for predicting both
events. The electrical remodeling of atria may
influence SNS activity indirectly by the triggering
of myocardial damage that AF causes, for example,
oxidative stress.
Study limitations. In the present study, the small
patient numbers, low event rates, and the relatively
wide range of hazard ratios on Cox proportional
hazards model are major limitations. In this respect,
a large cohort study given the rarity of the disease,
which was focused on the arrhythmogenic disease,
should be started in the near future. We used
medium-energy collimators in the present study
because the influences on the planer H/M ratios by
scatter or septal penetration were less pronounced
for medium energy. As a result, H/M ratio values
obtained in our study patients were higher compared to those of others (9). It is well known that
there is variability in mIBG distribution, and there
are significant variations regarding H/M values
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from one nuclear medicine center to another in
both healthy patients and patients with heart disease (11). We used H/M ratio as a value of SNS
activity, similar to our previous studies (11), but the
value of washout ratio may also be important for
predicting the prognosis (9).
CONCLUSIONS
Cardiac SNS abnormality was associated with the
occurrence of both HF and permanent AF in
idiopathic paroxysmal AF patients. Imaging studies
with 123I-mIBG imaging may be a useful modality
for predicting the development of AF. Our findings
may have important implications for the management of patients with paroxysmal AF before the
occurrence of remarkable structural remodeling of
atria and subsequent cardiac dysfunction of the left
ventricle caused by AF.
Reprint requests and correspondence: Dr. Yasushi Akutsu,
Division of Cardiology, Department of Medicine, Showa
University School of Medicine, 1-5-8 Hatanodai, Shinagawaku, Tokyo 142-8666, Japan. E-mail: hzn01233@
s02.itscom.net.
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Key Words: atrial fibrillation y
heart failure y scintigraphy y
sympathetic nervous system.