Introduction

Cardiac sympathetic neuronal function and activity can be assessed noninvasively by the use of 123I-metaiodobenzylguanidine (123I-MIBG), an analogue of norepinephrine [1]. In the past two decades, a large number of investigators have demonstrated decreased myocardial 123I-MIBG uptake in patients with chronic heart failure (CHF) and have shown that those with the lowest uptake tend to have the poorest prognosis [2–12]. There have also been findings suggesting that abnormalities of myocardial 123I-MIBG uptake may be predictive of increased risk of ventricular arrhythmia and sudden cardiac death [13, 14]. One factor that has constrained acceptance of cardiac 123I-MIBG imaging as a clinical management tool in heart failure has been the variability of the technical aspects of the procedure. Although most reports include the heart-to-mediastinum (H/M) ratio as the measure of myocardial uptake, the methods used to obtain this parameter have shown considerable variation. However, the influence of procedural and acquisition parameters on the reproducibility of this measurement technique have only occasionally been considered.

How to use myocardial 123I-MIBG scintigraphy in clinical routine

Planar 123I-MIBG imaging

In order to block thyroid uptake of free radioactive iodide either 500 mg potassium perchlorate or 200 mg potassium iodide (10% solution) is orally administered. After 30 min approximately 185 or 370 MBq of 123I-MIBG is administered intravenously for planar and/or SPECT imaging, respectively. 123I-MIBG is internalized by presynaptic nerve endings of postganglionic neuronal cells through the energy-dependent uptake-1 system. A 15% energy window is usually used, centred on the 159-keV 123I photopeak. Anterior planar scintigraphic images are obtained 10 min (early) and 4 h (late) after injection and stored in a 128×128 matrix. Two SPECT images can be acquired (20 min each) just after early and late planar imaging.

Semiquantitative parameters

The commonly used myocardial 123I-MIBG indices are the H/M ratio and myocardial washout. On anterior planar images regions of interest (ROIs) are drawn over the heart and the mediastinum. The mean count density in each ROI is obtained and the H/M ratio (specific activity/nonspecific activity) is calculated. Myocardial 123I-MIBG washout is calculated as follows:

$$\left\{ {\frac{{\left( {{\text{early}}{{\text{H}} \mathord{\left/{\vphantom {{\text{H}} {\text{M}}}} \right.\kern-\nulldelimiterspace} {\text{M}}} - {\text{late}}{{\text{H}} \mathord{\left/{\vphantom {{\text{H}} {\text{M}}}} \right.\kern-\nulldelimiterspace} {\text{M}}}} \right)}}{{{\text{early}}{{\text{H}} \mathord{\left/{\vphantom {{\text{H}} {\text{M}}}} \right.\kern-\nulldelimiterspace} {\text{M}}}}}} \right\} \times 100\% $$

The early H/M ratio probably reflects the integrity of presynaptic nerve terminals and uptake-1 function. The late H/M ratio combines information on neuronal function from uptake to release through the storage vesicle at the nerve terminals. Myocardial 123I-MIBG washout is an index of the degree of sympathetic drive. This implies that increased sympathetic activity is associated with high myocardial 123I-MIBG washout and low myocardial 123I-MIBG delayed uptake.

Impact of ROI definition

For 123I-MIBG there are several ways to define the mediastinal (size and placement) and myocardial ROIs (i.e. myocardium including the left ventricular cavity vs. myocardium excluding the left ventricular cavity). However, there are limited data on the impact of ROI definition on H/M ratios and myocardial washout. Somsen et al. demonstrated in 25 healthy volunteers that 123I-MIBG semiquantitative parameters using a ROI of the myocardium including the left ventricle showed the lowest interindividual and within-subject variability [15]. In a large retrospective study a uniform analysis with clear definition of the myocardial ROI (variable in size, including the left ventricular cavity) and the mediastinal ROI (fixed size) showed remarkable consistency in interpretation between three blinded image evaluators (Fig. 1) [16]. These findings suggest that rigorous and uniform analysis of cardiac 123I-MIBG semiquantitative parameters minimizes inter- and intraindividual variation.

Fig. 1
figure 1

Example of processing procedure for late planar 123I-MIBG images. The positioning of the mediastinal ROI was standardized in relation to the lung apex, the lower boundary of the upper mediastinum, and the midline between the lungs

Full size image

Influence of collimation

The most well-validated influence on the measured late H/M ratio is the collimator type. In addition to the prime emission of 159-keV photons, 123I emits high-energy photons of more than 400 keV (approximately 2.87%, main contributor 529 keV, 1.28%). These high-energy photons lead to penetration of the collimator septa and cause scatter detected in the 159-keV energy window. Septal penetration affects estimation of the H/M ratio in 123I-MIBG imaging with a low-energy (LE) collimator [17]. Nevertheless, LE collimators are frequently used for imaging 123I-MIBG [12, 18]. Medium-energy (ME) collimators have been shown to provide better quantitative accuracy in 123I studies [17–19]. Therefore, in order to minimize the effects of septal penetration the ME collimator is preferred. However, the use of ME collimation provides relatively low spatial resolution which may hamper accurate estimation of activity in small regions through a partial volume effect. In brain SPECT imaging with 123I-labelled agents, collimation with LE high resolution is preferred. High spatial resolution leads to a more or less homogeneous scatter in head and brain tissue imaging, and the regions are mostly equidistant from the gamma camera. In cardiac scintigraphy with 123I-labelled agents, however, H/M ratios are assessed from counts in relatively large regions, the thorax and abdomen produce inhomogeneous scatter, and the myocardium is not equidistant from the gamma-camera, especially in SPECT imaging. In cardiac scintigraphy with 123I-labelled agents the trade-off between spatial resolution and septal penetration is therefore in favour of low septal penetration. Moreover, as shown by Inoue et al. in a checker phantom, the use of ME collimation in cardiac scintigraphy with 123I showed a contrast accuracy similar to that with 99mTc [19].

While these results would suggest that semiquantitative cardiac 123I-MIBG imaging might be best performed using ME collimators, there are practical limitations to such a recommendation. Almost all nuclear medicine procedures are now performed on a multihead gamma camera, and many dedicated dual head cardiac cameras are not supplied with ME collimators.

Triple energy window scatter correction

Various methods of scatter correction have been described to improve image quality and quantitative accuracy [20]. The triple energy window (TEW) scatter correction method estimates the scatter component in the prime photopeak from counts in a window just below and above the prime photopeak window [21]. Data on the effect of this TEW scatter correction method in 123I studies on semiquantitative cardiac analysis are limited [17, 19]. Although TEW scatter correction increases all planar ME collimated H/M ratios, TEW scatter correction does not improve the contrast between the ME collimated H/M ratios.

In a clinical setting of heart failure, myocardial count densities are generally low. TEW scatter correction, however, reduces the already low count density which increases the uncertainty in ratio determination. Moreover, the reduction in count density induced by TEW scatter correction hampers the identification of endo- and epicardium and will therefore influence the definition of the myocardial ROIs. This decreases the reproducibility of the ratios. In addition, TEW scatter correction introduces noise, again increasing the uncertainty of the generated ratios.

In addition to theoretical limitations, the TEW method has a limited availability in various gamma camera systems because TEW requires special hardware and software. Rather than try to filter unwanted counts by a post-acquisition scatter correction method, it is preferable to acquire data directly with less scatter. ME collimation without scatter correction is straightforward to implement and is therefore preferred in cardiac 123I scintigraphy.

Acquisition parameters

In a heterogeneous population of patients with heart failure, the most important determinant of cardiac uptake of 123I-MIBG is the degree of impairment of the norepinephrine transporter function in presynaptic adrenergic neurons [2–10]. As such, considerable variation in late H/M ratio would be expected between patients with otherwise similar clinical presentations (NYHA class, LVEF, etc). Nevertheless, a relative small proportion of the variation in the late H/M 123I-MIBG can also be explained by differences in acquisition duration. Of particular interest, factors contributing to this variation differ for different ranges of late H/M ratio [22].

123I-MIBG SPECT

Planar imaging is most commonly used in myocardial 123I-MIBG scintigraphy. Nevertheless, there are known limitations to this technique: superposition of noncardiac structures, and lack of segmental analysis. Although SPECT may overcome these limitations, it must be taken into account that in patients with severe CHF myocardial 123I-MIBG uptake may be severely reduced. This reduced myocardial uptake may hamper adequate image reconstruction (i.e. short-axis, horizontal long-axis and vertical long-axis slices). However, it seems of paramount importance to couple 123I-MIBG SPECT to perfusion imaging in order to understand the real regional myocardial uptake of MIBG in both ischaemic and nonischaemic cardiomyopathy, and therefore the possible pathophysiological mechanism of ventricular tachyarrhythmias.

123I-MIBG and perfusion SPECT imaging

Recently the inducibility of ventricular arrhythmias during electrophysiology (EP) testing in patients with previous myocardial infarction has been explored using both 123I-MIBG and myocardial perfusion scintigraphy [23].

In a multivariable analysis the 4-hour 123I-MIBG SPECT defect score was the only independent predictor of EP results. A 4-hour 123I-MIBG SPECT defect score of ≥37 yielded a sensitivity of 77% and specificity of 75% for predicting the EP results.

The results of this pilot study suggest that the extent of denervated myocardium, as assessed by 123I-MIBG SPECT, is correlated with the inducibility of ventricular tachyarrhythmias during EP testing. Data from two ongoing major prospective trials in the US and Europe may support the additional value of the combined use of 123I-MIBG and myocardial perfusion scintigraphy in patients with heart failure for the prediction of ventricular tachyarrhythmias. The results of these trials are expected in 2009. Furthermore, it is tempting to speculate whether patients with mismatches between perfusion and innervation are more prone to the development of ventricular tachyarrhythmias (Fig. 2). This may imply that those patients with mismatches are especially eligible for implantation of an implantable cardioverter defibrillator.

Fig. 2
figure 2

MIBG and tetrofosmin SPECT studies in a patient with ischaemic cardiomyopathy (inferior myocardial infarction, LVEF 33%) show a mismatch between perfusion (tetrofosmin top panel) and innervation (MIBG bottom panel) in inferior, lateral and apical walls. There is a larger defect in innervation than in perfusion imaging

Full size image

Conclusion

The absence of published guidelines for cardiac 123I-MIBG imaging, makes standardization of procedures among individual users of this radiopharmaceutical even more important. Given the current data, myocardial 123I-MIBG scintigraphy is preferred with adapted collimation without scatter correction, adequate acquisition duration and simple but robust analysis of the semiquantitative parameters and innervation score on 17 LV segments. The use of both myocardial perfusion and myocardial innervation SPECT seems to be promising in identifying those patients with heart failure at risk of developing ventricular tachyarrhythmia.