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Cardiac 123I-MIBG scintigraphy –
why, how and who?
RAD Magazine, 38, 447, 13-14
by Dr Andrew J Marshall
Cardiology specialist registrar
email: [email protected]
Dr Andrew D Kelion
Consultant cardiologist
email: [email protected]
Harefield Hospital Nuclear Medicine
Department, Royal Brompton and Harefield
NHS Foundation Trust
The cardiac sympathetic nervous
system in health and disease
Anatomically the heart, particularly the left ventricular (LV) myocardium, has dense sympathetic
innervation. Postganglionic neurons originate in
the thoracic, stellate and cervical ganglia of the
sympathetic chain, and run alongside the coronary arteries from the base to the apex of the
heart, innervating myocardium and blood vessels
along the way. Sympathetic nerve stimulation
causes rapid release of the neurotransmitter norepinephrine (NE) from presynaptic terminals,
which activates adrenergic receptors (adrenoceptors) on the surface of adjacent cardiac myocytes
(figure 1). This leads to changes in chronotropy,
inotropy and lusitropy (relaxation) via G-proteincoupled intracellular mechanisms.
Abnormal sympathetic function is an important component of the pathogenesis of heart failure. Increased sympathetic tone initially aids the failing cardiovascular system,
raising cardiac output through an increase in heart rate and
myocardial contractility. However, long-term overstimulation leads to increased peripheral vascular constriction and
salt and water retention, increasing afterload and preload on
the heart. There are also direct toxic effects on the
myocardium, with increased risk of arrhythmias, desensitisation of adrenoceptors, and triggering of myocyte death by
apoptosis.
Cardiac sympathetic function can also be disrupted following myocardial infarction, with damage not only to sympathetic neurons innervating the infarcted territory itself,
but also to fibres running through the infarct zone on their
way to innervate more apical regions of the left ventricular
myocardium. This may produce an area of viable and perfused but denervated muscle, which could act as a substrate
for subsequent ventricular arrhythmias.1 Some studies have
also demonstrated abnormal cardiac sympathetic function
in the setting of advanced coronary artery disease without
prior infarction.2
Cardiac sympathetic abnormalities have been implicated
in the pathogenesis of hypertrophic cardiomyopathy. It is
suggested that sympathetic overstimulation produces trophic
factors that contribute to left ventricular hypertrophy, while
excess NE provokes myocyte growth, fibre disarray and scarring.3 This theory could explain why b-blockers are beneficial
in hypertrophic cardiomyopathy.
Principle of cardiac 123I-MIBG scintigraphy
Meta-iodobenzylguanidine (MIBG) is an analogue of NE
with similar pharmacokinetic properties, allowing it to be
used in the assessment of sympathetic function (figure 2).
Following intravenous injection, MIBG is taken up into
presynaptic nerve terminals via the NE transporter membrane protein, and stored in vesicles (figure 1). In contrast
to NE and other endogenous catecholamines, MIBG is not
metabolised by either the monoamine oxidase or catechol
O-methyltransferase enzyme systems. Thus, the uptake of
MIBG within the LV myocardium reflects the anatomical
and physiological integrity of sympathetic nerve terminals.
When labelled with the radionuclide iodine-123, the distribution of MIBG can be imaged scintigraphically with a
gamma camera. This allows non-invasive evaluation of
global and regional sympathetic nerve function using planar or single photon emission computed tomography
(SPECT) imaging respectively.
123
I-MIBG scintigraphy was initially used in humans for
the investigation of catecholamine producing tumours of the
adrenal medulla, such as phaeochromocytoma and neuroblastoma.4-5 Although shown to be feasible more than 20
years ago, cardiac 123I-MIBG imaging has not been widely
used in clinical practice in the UK. Recently there has been
a resurgence of interest, particularly in the setting of heart
FIGURE 1
Representation of sympathetic nerve terminal.
Norepinephrine (NE) is released from storage vesicles, and acts on post-synaptic myocardial adrenoceptors, as well as on pre-synaptic adrenoceptors
which regulate subsequent NE release. Excess NE is
taken back up by the presynaptic terminal via the
membrane NE transporter protein, and is reincorporated into storage vesicles or metabolised. MIBG is
also taken up by the NE transporter, but cannot be
metabolised.
FIGURE 2
Molecular structure of MIBG (right) compared with
norepinephrine (left).
FIGURE 3
Early (left) and delayed (right) anterior planar acquisitions following injection of 123I-MIBG. This patient
had had a left ventricular assist device explanted following recovery from severe left ventricular failure.
Heart and Mediastinal regions of interest are shown;
early H:M ratio was 2.6 with a washout rate of 5%,
both reassuring features.
failure. Quantitative parameters derived using 123I-MIBG
scintigraphy have been shown to be highly reproducible,
with a strong correlation between myocardial 123I-MIBG
uptake and tissue NE content on myocardial biopsy specimens (and also plasma NE concentration).6
Technical aspects of cardiac 123I-MIBG scintigraphy
Following thyroid blockade with oral potassium iodide or
perchlorate approximately one hour previously, 123I-MIBG
(185-400MBq) is injected intravenously at rest. Planar imaging is carried out 10-15 minutes after initial injection, and is
then repeated 3-4 hours later. Images are acquired in an
anterior projection; medium energy collimators are optimal,
but low energy high resolution collimators are also acceptable. Image acquisition typically takes 15 minutes, with the
main energy window for iodine-123 set at 159keV (±10%);
simultaneous acquisition of a 194keV (±10%) window allows
scatter correction. SPECT acquisition can also be performed,
though poor counts in the inferior LV wall are frequently
seen, and uptake in extracardiac organs (liver and lungs)
may limit image quality.
The two sets of planar images can be used to derive quantitative measures of global LV sympathetic function, including the early and late heart-to-mediastinum (H:M) ratio and
the myocardial washout rate (figure 3). Early H:M ratio is
a measure of the density of innervation and NE transporter
function, washout rate assesses sympathetic tone, and late
H:M ratio is a reflection of both. H:M ratios are derived by
manually drawing separate regions of interest (ROIs) around
the entire heart (H) and in the upper mediastinum (M), and
measuring the counts per pixel within the two regions; both
values can be scatter-corrected by subtracting the counts
per pixel obtained from the same ROIs on the 194keV
energy window images. The H:M ratio is simply derived by
dividing the corrected Heart ROI counts per pixel by the
corrected Mediastinal ROI counts per pixel. The upper mediastinal ROI is a suitable background region as there is little
or no sympathetic innervation in that area.
Washout rate quantifies sympathetic tone by measuring
the reduction in myocardial counts from early to delayed
images. The calculation can be refined by subtracting background Mediastinal counts from the Heart counts, and also
by correcting for radioactive decay. The formula used is
given below, adapted from Ogita et al:7
WR = ([H]e – [M]e)/(0.5)(t1/T) – ([H]d – [M]d)/(0.5)(t2/T) x 100
([H]e – [M]e) / (0.5)(t1/T)
[H]e = mean counts per pixel, heart ROI, early acquisition; [H]d = as above,
delayed acquisition; [M]e = mean counts per pixel, mediastinum ROI, early
acquisition; [M]d = as above, delayed acquisition; t1 = time from isotope injection to early imaging; t2 = time from isotope injection to delayed imaging;
T = half-life of 123I-MIBG, 13.3 hours.
SPECT imaging may provide additional information
regarding relative regional sympathetic function. 123I-MIBG
SPECT images can also be viewed alongside those obtained
from conventional myocardial perfusion SPECT in order to
evaluate ‘mismatch’ between innervation and viability/perfusion, which has been hypothesised to be a substrate for
arrhythmias.
Controversy remains over which of the values derived
from 123I-MIBG scintigraphy characterises cardiac sympathetic activity most accurately. Much of the recent literature has focussed on late H:M ratio as the preferred
measure. A pooled meta-analysis of 123I-MIBG imaging studies found that washout rate and particularly late H:M ratio
appeared to be the best predictors of prognosis in patients
with heart failure.8
Cardiac 123I-MIBG scintigraphy and prognosis in
heart failure
Abnormalities of 123I-MIBG uptake and washout on scintigraphy have been demonstrated in patients with ischaemic
heart disease, dilated cardiomyopathy and idiopathic ventricular arrhythmias. Moreover, these abnormalities predict
adverse cardiac events including death and ventricular
arrhythmia: 123I-MIBG uptake is a stronger predictor of
prognosis in heart failure than left ventricular ejection
fraction (LVEF), LV volumes and several other haemodynamic parameters.7,9-12
The recent AdreView Myocardial Imaging for Risk
Evaluation in Heart Failure (ADMIRE-HF) study provides
the most up-to-date insight into the prognostic value of
123
I-MIBG imaging.13 This large prospective international
study recruited 961 patients with predominantly NYHA
class 2 heart failure symptoms and LVEF <35%, on full
pharmacological treatment. The underlying aetiology was
coronary artery disease in 66%. Patients underwent
123
I-MIBG imaging, and were followed for two years to determine the occurrence of adverse events. The composite event
rate was inversely related to late H:M ratio: 15% for a value
≥1.6 (21% of the study population) and 37% for a value <1.6.
The late H:M ratio separately predicted the occurrence of
all cause death, cardiac death, heart failure progression and
life-threatening arrhythmia, and provided information that
was complementary to LVEF and BNP level.
Other studies have demonstrated improvements in
123
I-MIBG imaging parameters with conventional drug therapy for heart failure, including b-blockers, spironolactone
and angiotensin-converting enzyme inhibitors.14-15 Non-pharmacological treatments also produce improvements, including cardiac resynchronisation therapy (CRT) devices and LV
assist devices (LVADs).16, unpublished data
123
I-MIBG and arrhythmia risk
123
I-MIBG scintigraphy provides robust prognostic data in
heart failure, but this may be insufficient to lead to its adoption into routine clinical practice. A relatively expensive
investigation is only likely to be widely used if it can be
shown to guide patient management. One promising area
is the use of 123I-MIBG scintigraphy in the selection of
patients for implantable cardioverter defibrillator (ICD)
devices. ICDs can reduce the risk of death from ventricular
arrhythmia in high risk individuals. Recent trials have progressively extended the indications for ICD implantation to
include not only patients who have suffered a previous
arrhythmic episode (secondary prevention),17-19 but even those
who simply have significantly impaired LV systolic function
whether due to ischaemic heart disease or a dilated cardiomyopathy (primary prevention).20-22 However, many individuals, particularly in the primary prevention group, will
never suffer an arrhythmia requiring therapy from their
device.22 Moreover, there are considerable drawbacks to
device therapy, including the high cost, the risk of periprocedural complications, and the risk of inappropriate shocks
that have been linked to subsequent mortality.23-25 There is,
therefore, much interest in improving the risk stratification
of patients being considered for ICD therapy, to distinguish
between those most likely to benefit and those in whom
device implantation could safely be avoided.
Boogers and colleagues followed 116 patients with
advanced heart failure undergoing ICD implantation, and
demonstrated a significant association between 123I-MIBG
SPECT defect score on delayed imaging and the likelihood of
appropriate ICD discharge.26 Surprisingly, none of the conventional planar MIBG imaging parameters was found to
be predictive, which may reflect technical issues with the
imaging. In our own institution, we have performed
123
I-MIBG scintigraphy prospectively in 27 heart failure
patients prior to ICD implantation for primary prevention.
The risk of subsequent device therapy was significantly associated with both early and late H:M ratio, and 123I-MIBG
SPECT defect score: a summed score threshold of 31 yielded
sensitivity 78%, specificity 77%, and negative predictive
value 86% for significant arrhythmia at 16 months follow-up
(data submitted for publication).
Summary
The cardiac sympathetic nervous system plays an important
role in the regulation of normal cardiovascular physiology,
and may be disrupted in pathological states. Cardiac
123
I-MIBG scintigraphy to assess sympathetic function is easy
to perform, and provides robust prognostic information in
heart failure. 123I-MIBG indices have been shown to improve
with heart failure therapy, and there is preliminary evidence
to support a possible future role for the technique in
the prediction of ventricular arrhythmias in potential
ICD recipients. The number of referrals for cardiac
123
I-MIBG scintigraphic studies may rise significantly over
the coming decade.
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