InternationalJournalofCardiaclmaging 12: 305-310, 1996. © 1996KluwerAcademic Publishers. Printed in the Netherlands.

305

Neuronal dysfunction in heart failure assessed by cardiac 123-iodine metaiodobenzyiguanidine scintigraphy G. A e r n o u t S o m s e n 1, Ernst E. v a n der W a l l 2, B o b v a n V l i e s 3, J u d o c u s J.J. B o r m 4 & E r i c A. v a n R o y e n 4 1 Department of Cardiology, Academic Medical Centre, Amsterdam; 2 Department of Cardiology, University Hospital Leiden; 3 Department of Cardiology, Elisabeth Gasthuis Haarlem; 4 Department of Nuclear Medicine, Academic Medical Centre, Amsterdam, The Netherlands Accepted 13 June 1996

Key words: Heart failure, metaiodobenzylguanidine, scintigraphy, sympathetic neuronal function

Abstract

In patients with chronic heart failure, increased sympathetic activity and cardiac sympathetic neuronal dysfunction are present and have been related to unfavourable clinical outcome. Modification of these alterations with the objective to improve prognosis has become an important aim of pharmacological therapy for these patients. A noninvasive technique to assess sympathetic neuronal function at the cardiac level may be valuable in evaluating newly developed therapeutic strategies. 123-iodine metaiodobenzylguanidine can be used to visualize cardiac sympathetic nerve function and activity. Single photon emission computerized tomographic is preferred to planar scintigraphy since it does not depend on superposition of other anatomical structures and may allow assessment of regional cardiac 123-iodine metaiodobenzylguanidine uptake. Although the quantitation of cardiac uptake in these tomographic images has several limitations, the use of the left ventricular cavity as a reference, calibrated by the 123-iodine activity in a blood sample drawn at the time of acquisition, may have clinical applications, with respect to the evaluation of therapeutical intervention in patients with heart failure.

Abbreviations: BS - blood sample; CD - count density; dP/dt - change in pressure over time; [123I] - 123-iodine; Km- affinity constant; M I B G - metaiodobenzylguanidine; M B q - mega Bequerel; SPECT- single photon emission computerized tomography; Vm - capacity constant Introduction

Increased sympathetic activity in patients with chronic heart failure has been related to an unfavourable prognosis [1]. Evidence is accumulating that counteracting this neurohormonal compensation mechanism may improve functional capacity and left ventricular function in these patients [2,3]. The use of a noninvasive technique to visualize the effect of pharmacologic intervention on the sympathetic nervous system may therefore be of clinical value. The aim of the present review is to discuss the use of 123-iodine metaiodobenzylguanidine ([123I]-MIBG) scintigraphy in the assessment of the cardiac sympathetic nervous function in patients with heart failure. Nuclear imag-

ing techniques such as planar imaging and single photon emission computerized tomography (SPECT) are addressed. In addition, various methods to quantitate the cardiac uptake of the radioligand are discussed.

Metaiodobenzylguanidine In the 1960s guanethidine was found to be a potent neuron-blocking agent that acts selectively on sympathetic nerve endings [4]. By the modification of this compound into metaiodobenzylguanidine, the affinity for neuronal uptake sites was increased. MIBG was labelled with [123I] to enable scintigraphic visualization of the sympathetic nervous system in humans.

306 OH

~ HO"

-~NH

2

"~

OH Noradrenaline NH 2

[123i]_metaiodobenzylguanidine

Figure 1. Molecular structures of noradreualine and [1231]metaiodobenzylguanidine.

The first clinical application of [Iz3I]-MIBG was the imaging of the adrenal medulla and neoplasms originating from the neural crest, such as pheochromocytoma and neuroblastoma [5,6]. [123I]-MIBG scintigraphy also showed a striking uptake in the heart, which is a densely sympathetic innervated organ. In 1980, the potential use of [123I]-MIBG in myocardial imaging was first suggested [5]. However, at that time no information was available on the physiology of cardiac MIBG uptake and its metabolic fate in humans under different pathological conditions.

Neuronal uptake and metabolism of MIBG Much work has been done to elucidate the mechanism by which the sympathetic nerve endings take up MIBG. It has been shown that MIBG and noradrenaline have similar molecular structures and that both utilize the same uptake and storage mechanisms in the sympathetic nerve endings (Figure 1) [71. Neuronal uptake is mainly achieved through the sodium dependent type-1 uptake mechanism, which is characterized by a temperature dependency, a high affinity (Kin (#molair) of 1.22 i 0.12 for MIBG and 1.41 4- 0.50 for noradrenaline) and a low capacity; (V,~ (pmol/106 cells/10 rain) of 64.3 ± 3.3 for MIBG and 36.6 4- 7.2 for noradrenaline) [7]. In addition, this uptake mechanism has been shown to be energydependent [8].

It should be further noted that sodium-independent neuronal uptake of MIBG has also been reported. This type-2 non-neuronal uptake dominates at higher concentrations of the substrate and is probably the result of passive diffusion [7]. ~i~e relative role of each uptake mechanism is dependent upon the plasma concentration of MIBG [7, 8]. However, neuronal uptake is predominantly determined by type-1 uptake since an extremily small quantity of [123I]-MIBG is injected for diagnostic scintigraphy. Typically one standard dose of 185 MBq contains 6.25 x 10 -9 gr MIBG [7-9]. Sisson et al. demonstrated in animal experiments that the kinetics of [125I]-MIBG mimicked those of [3H]-noradrenaline under different conditions [10]. In these experiments yohimbine, an c¢2- adrenoceptor antagonist, was used to increase sympathetic nerve function whereas clonidine was used to induce the opposite effect. In 1986, Mangner et al. extensively studied the metabolism of MIBG in humans [11]. They demonstrated in patients with pheochromocytoma that following intravenous injection of MIBG, the compound was rapidly excreted by the kidneys and that in urine samples, at least 85% of the radioactivity present was unaltered [123I]-MIBG, indicating that MIBG is not appreciably metabolized.

Planar and tomographic imaging of the heart Cardiac uptake of [123I]-MIBG can be visualized noninvasively by scintigraphy. This technique provides information on the distribution of this gamma emitting radioligand in the human heart. Planar imaging has commonly been used to determine cardiac MIBG uptake. However, there are several important limitations to this technique especially with respect to cardiac imaging. First, the superposition of non-cardiac structures such as lung and mediastinum may preclude optimal visualization. Second, even at the cardiac level, superposition of various myocardial segments and motion artifacts interfere with the regional assessment of uptake of the radioligand. To partially overcome these disadvantages, a type of tomography such as SPECT can be applied. A scintillation camera, rotating around the patient acquires images at different angular positions. These data are used to reconstruct tomographic images. Subsequently, these images are reorientated from the transaxial plane to oblique angle slices, perpendicular to the long axis and short axis of the left ventricle. Using this technique, tomographic

307 short axis slices of approximately of 6 mm thickness are obtained. To quantitate the cardiac uptake of the radioligand, the average counts per pixel, or count density, is assessed in a region of interest drawn around the heart. However, for the quantitation of myocardial uptake of a radioligand several confounding factors have to be taken into account. First, the tissue attenuation is nonuniform for intra-thoracic organs since tissue density and therefore the attenuation coefficient varies. Correction for this nonuniform attenuation can be performed theoretically using an iterative reconstruction algorithm or by constructing individual attenuation maps during acquisition using a line source. This is very computerintensive. The clinical utility of such advanced reconstruction techniques for intrathoracic organs remains to be proven. Second, photons that scatter within the patient are often indistinguishable from unscattered (primary) photons with respect to their photon energy. These scattered photons contribute to a further loss of spatial resolution. For [123I]-MIBG SPECT the limiting factor is the number of counts acquired, with respect to the signal-noise ratio. Therefore, dose and acquisition time should be maximized, i.e. using a triple-head camera. Adequate implementation of procedures to limit the effects of the abovementioned factors will improve image quality, i.e. image resolution and contrast. However, it should be noted that each method must be evaluated in terms of accuracy and reproducibility, i.e. data acquired using a suitable phantom of the thorax with a cardiac insert. Quantitation of cardiac [1231]-MIBGuptake To determine the cardiac uptake of MIBG, several methods have been used. Regional cardiac [123I]MIBG uptake can be quantitated relative to the highest uptake in the myocardium in both planar and tomographic images [12,13]. This 'relative scaling' only provides information on localized cardiac pathology and is not suitable in the clinical evaluation of changes in cardiac MIBG uptake caused by therapeutic intervention. To correct for the nonspecific (nonvesicular) [123I]MIBG uptake, the mediastinum is frequently used as a reference for the quantitation of cardiac [123I]MIBG uptake in planar scintigraphy [14-18]. The uptake in the mediastinum is assumed to be constant with age, between subjects, and of a nonspecific

nature. Although the uptake ratio between myocardium and mediastinum in planar studies correlated reasonably with the [123I] activity as determined in a septal endomyocardial biopsy sample in patients with idiopathic dilated cardiomyopathy [15], the assumption of constant nonspecific uptake in mediastinum has never been validated. To avoid this potentially confounding effect, a quantitation method was developed in which the count density (CD) in the left ventricular cavity was used as a reference. Volumes of the myocardium and the left ventricular cavity are reconstructed from SPECT acquisitions. The left ventricular cavity count density was calibrated by the 123I activity in a venous blood sample (BS), drawn at the time of the acquisition. Subsequently, myocardial [123I]-MIBG uptake can be calculated according to the equation: MyocardialI123I]-- MIBGuptake =

MyocardialCD ×BS (Bq/ml) CavityCD

Since the left ventricular cavity is contained within the myocardial area the influence of the attenuation is limited. Myocardial uptake has to be corrected for both the physical decay of the isotope and the dose administered. This quantitation method was shown to be reproducible. Furthermore, in experiments with a cardiac phantom this quantitation method showed an accuracy of 81% [19]. Cardiac MIBG uptake in heart failure; clinical use In patients with chronic heart failure, enhanced sympathetic nervous activity is associated with increased cardiac neuronal release and impaired cardiac neuronal uptake of noradrenaline [20-23]. Although MIBG kinetics in patients with heart failure have never been compared to myocardial spillover of noradrenaline, which is a generally accepted standard for measuring neuronal release and uptake of noradrenaline at the cardiac level, changes in [123I]-MIBG washout and uptake in the failing myocardium have been demonstrated (Figure 2). Moreover, the heart to mediastinal uptake ratio of [~z3I]-MIBG in planar images correlated significantly with both the [123I]-MIBG activity and noradrenaline concentration in a septal endomyocardial biopsy sample [,15]. In patients with dilated cardiomyopathy, cardiac [123I]-MIBG uptake is reduced, and washout from the heart is increased compared to normal controls [2426]. Decreased cardiac [123I]-MIBG activity is asso-

3US

Figure 2. Shortaxis reconstructionof cardiac[1231]-MIBGSPECTacquisitionsof a normalperson(A)and of a patientwithchronicheartfailure

accompaniedby left ventricutardilation(B). The yellowand white areas representhigh and very high [t23I]-MIBGuptake, whereasthe red areas representlow [Iz3I]-MIBGuptake. L = left ventricle,R = rightventricle. ciated with a greater heterogeneity in the myocardial uptake in these patients [25,27]. Left ventricular function has been related to cardiac MIBG uptake in patients with heart failure. Yamakado et al. showed a significant correlation between washout rate from the heart and the left ventricular ejection fraction in a small group of heart failure patients suggesting that cardiac MIBG uptake may reflect the severity of the disease [26]. Cardiac [123I]-MIBG uptake on planar images acquired 4 hr after injection using the mediastinum as a reference, also was shown to be positively related to left ventricular ejection fraction [14,15]. Using the same quantitation method, Merlet et al. showed that cardiac [123I]-MIBG uptake was the most accurate prognostic marker in patients with heart failure of various aetiologies when compared to other parameters such as left ventricular ejection fraction, heart-thorax ratio on X-ray and echocardiographic Mmode data [141].This suggests that MIBG scintigraphy may be used to determine prognosis and may help in decision making and timing of cardiac transplantation. In heart failure, it is generally accepted that the increased sympathetic neuronal activity results in a depletion of myocardial noradrenaline and a subsequent /3-adrenoceptor desensitization. This linkage

between pre- and postsynaptic alterations in the failing myocardium has been confirmed by Merlet et al.. They showed a correlation between cardiac [123I]-MIBG uptake and/3-adrenoceptor sensitivity as assessed by measuring the change in left ventricular dP/dt during intracoronary dobutamine infusion in patients with idiopathic cardiomyopathy [28]. This finding indicates that an impaired neuronal uptake mechanism may result in/3-adrenoceptor desensitization and confirms the concept that neuronal uptake is an important mechanism to terminate the effect of noradrenaline on the cardiomyocytes [29]. In the noninfarcted myocardium, apical to the site of a transmurat myocardial infarction, [123I]-MIBG uptake can be diminished due to segmental sympathetic denervation [30, 31]. Whether this area of viable but denervated myocardium is the site of orgin of ventricular arrhythmias in the post infarction period has never been demonstrated convincingly. Although there is no evidence of reinnervation of the infarcted area, a partial reinnervation of the periinfarcted area has been reported 3 :months after myocardial infarction [32]. To date, newly developed pharmacologic therapies aim at the reduction of neurohormonal activation in patients with heart failure. Increased car-

309 diac [123I]-MIBG uptake has been reported in these patients after treatment w i t h / 3 - a d r e n o c e p t o r blockers and angiotensin converting e n z y m e inhibitors [18,33]. This m a y reflect a restoration o f cardiac sympathetic n e r v e function by these drugs.

Conclusion M I B G scintigraphy can be used to noninvasively assess the distribution o f sympathetic nerve endings with a p r e s e r v e d uptake m e c h a n i s m in the intact h u m a n m y o c a r d i u m . T o m o g r a p h i c i m a g i n g is a d v o c a t e d to determine regional m y o c a r d i a l uptake. A c c u r a t e quantitation o f cardiac uptake is not easy to obtain and several conditions should be taken into account. Furthermore, cardiac [123I]-MIBG uptake has b e e n related to prognosis and left ventricular dysfunction in heart failure patients and the use o f [123I]-MIBG m a y also be valuable in the evaluation of therapeutic strategies in these patients. D r u g s w h i c h restore cardiac sympathetic neuronal function m a y be beneficial in the treatment o f patients w i t h heart failure.

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Address for correspondence: G.A. Somsen, MD, Academic Medical Centre, Department of Cardiology, room B2-214, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands