Cardiac Uptake-1 Inhibition by High Circulating Norepinephrine Levels in Patients with Pheochromocytoma

Abstract

Abstract-Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 mol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[ 18 F]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (Ϸ500 pg/mL), left ventricular myocardial 6-[18 F]fluorodopamine-derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration (rϭϪ0.77, PϽ0.0001). Reduction of plasma norepinephrine levels by treatment of the pheochromocytoma increased myocardial 6-[18 F]fluorodopamine-derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine. Key Words: heart Ⅲ norepinephrine Ⅲ pheochromocytoma Ⅲ radiography N euronal reuptake of the sympathetic neurotransmitter norepinephrine through the membrane norepinephrine transporter 1-3 (also known as uptake-1) is a key determinant of inactivation of norepinephrine in the heart and, therefore, of cardiac sympathetic neuroeffector function. Cardiac sympathetic neuroimaging, using radiolabeled sympathomimetic amines such as 123 I-or 131 I-metaiodobenzylguanidine (MIBG) or catecholamines such as 6-[18 F]fluorodopamine, depends on uptake of the imaging agent into sympathetic nerves through the cell membrane norepinephrine transporter.Pheochromocytoma tumor cells also express the cell membrane norepinephrine transporter. Scintigraphy or singlephoton emission-computed tomography after injection of radioiodinated MIBG or positron emission tomography after injection of 6-[18 F]fluorodopamine aids diagnostic localization of pheochromocytoma. 4 Preclinical studies dating back to the 1960s have demonstrated saturability of uptake-1, with a K m in the range of 0.1 to 1 mol/L. 5,6 Since plasma norepinephrine levels in humans normally average about 3 nmol/L, increasing by at most 10-to 20-fold in extreme situations, one might presume that circulating norepinephrine would exert little impact on the efficiency of uptake-1. Reports that patients with high circulating norepinephrine concentrations due to pheochromocytoma can have decreased myocardial MIBG-derived radioactivity, however, have called this view into question. [7][8][9] In the present study, we show that myocardial 6-[18 F]fluorodopamine-derived radioactivity decreased when plasma norepinephrine levels were markedly elevated in patients with pheoch...

Brown Fat Imaging with 18F-6-Fluorodopamine PET/CT, 18F-FDG PET/CT, and 123I-MIBG SPECT: A Study of Patients Being Evaluated for Pheochromocytoma

“…That stated, a possible explanation could be that the elevated plasma norepinephrine levels may have competed with 18 F-F-DA for norepinephrine transporter, thus reducing the uptake of 18 F-F-DA in BAT. A similar inverse relationship has been found with respect to cardiac uptake of 18 F-F-DA and 123 I-MIBG in the presence of elevated catecholamines (35,36). Also, although pheochromocytoma was excluded in 27 patients, these patients were not necessarily healthy, many having been referred because of signs or symptoms that led to a suspicion of pheochromocytoma.…”

Beyond postural tachycardia syndrome

“…While there is a theoretical possibility that an abnormality in the function of the NET itself might give similar findings in the four patients who failed to accumulate MIBG, the rarity of NET dysfunction encourages the view that they have identified the partial noradrenergic dysfunction which they propose. A different radiotracer, 6-[18F] fluorodopamine, has shown generally normal labelled noradrenergic innervation in POTS15 16 but there were gradations in the individual data and, given the heterogeneity of POTS, this current study is not inconsistent with these earlier findings.…”

“…Because these noradrenergic fibres have multiple roles in the heart, disease processes involving this autonomic innervation can impair cardiac function. Already, the ability of the 123 I-MIBG test to differentiate between innervated and denervated myocardium is proving useful to differentiate Parkinson's disease from multiple system atrophy early in the disease, as the former, but not the latter, often has loss of sympathetic neurons in the heart 15. This is so even though standard tests of cardiac autonomic function, for example, using heart rate variability analysis, fail to distinguish between Parkinson's disease and multiple system atrophy.…”

Takotsubo Cardiomyopathy

“…The heart stands out among organs of the body in terms of dependence on neuronal uptake for inactivating catecholamines in the extracellular fluid. 30 High circulating catecholamine levels such as in pheochromocytoma can interfere with the neuronal uptake process 31 and augment occupation of adrenoceptors on myocardial cells. These findings help to explain why emotional distress would induce mainly cardiac toxicity as a result of high plasma catecholamine levels despite being delivered to all organs via the arterial blood.…”