Window on Cardiology

Imaging Neuronal Dysfunction in Heart Failure

"Educating students", (CWWJ©archives)

Pardise Moraghebi MD, Arnold Jacobson MD, PhD, Jagat Narula MD, PhD Division of Cardiology, University of California, Irvine School of Medicine

Correspondence: Jagat Narula MD, PhD, Professor of Medicine Chief, Division of Cardiology, Associate Dean, University of California, Irvine, School of Medicine, UCI Medical Center (E-mail and other contact info can be obtained from CWWJ's Editor-in-Chief).

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Norepinephrine (NE), a vital neurotransmitter in both the central and peripheral nervous systems, is produced in the cytoplasm of sympathetic neurons by dopamine beta-hydroxylase (DBH) mediated oxidation of dopamine and stored in vesicles via the action of vesicular monoamine transporter (VMAT). NE is released from its storage granules when the nerve is stimulated and enters the synaptic cleft to bind to alpha and beta receptors on the effector cells (Figure 1A). Chemical signaling is terminated by a rapid reuptake of neurotransmitter into presynaptic nerve terminals via NE transport systems, which belong to two large families; neuronal NE transporter (NET: uptake1) and non-neuronal NE transporter (uptake2). Unlike other tissue, neuronal uptake of NE is quantitatively more important for clearance of NE in human heart (1). In heart failure, both increased neuronal release of NE and decreased efficiency of NET contribute to decreased myocardial NE content which correlates directly with decreasing the left ventricular ejection fraction.

Neuronal Catecholamine Transporter

NET is a member of the Na+ and Cl- dependent family of neurotransmitter transporters and is highly homologous to other members of this family, such as the serotonin, dopamine and GABA transporters (2, 3, 4). NET function through the stoichiometric transport of NE+, Na+ and Cl- , with Na+ and Cl- moving down their electrochemical gradients to concentrate NE ( 5, 6, 7), referred to as Transporter Mode (T-mode) of conduction. The predicted stoichiometry of one NE+, one Na+ and one Cl- indicates the net transfer of one positive charge per transport cycle. Although T-mode is electrogenic, it generates negligible current. NET also has a novel Channel mode (C-mode) of conduction, wherein ion channels carry an arbitrary number of ions depending on the channel open time (5). It appears that C-mode carries virtually all of the transmitter-induced current, even though it occurs with low probability. This is because each C-mode opening transports hundreds of charges per event. Both T-mode and C-mode are gated by the same substrates and antagonized by the same blockers.

Figure 1. Click images to enlarge
Figure 2. Topological structure of NET. NET is a 617 amino acid protein that spans the membrane with 12 TMD. It has cytoplasmic amino and carboxy termini and a long hydrophilic loop between TMD 3 and 4. (Modified from ref. 7, with permission).

Topological Structure of NET

NET, a 617 amino acid protein, comprises 12 transmembrane domains (TMD) (8). TMD 9 and 10 have been defined as determinants for substrate affinity and stereoselectivity (9). NET has cytoplasmic amino and carboxy termini and a long hydrophilic loop between TMD 3 and 4 (Figure 2). The carboxy-terminal is critical for appropriate levels of NET expression (P Bauman, unpublished data). The human NET gene (SLC6A2) has been mapped to the long arm of chromosome 16 (16q12.2) (10) and is encoded by 14 exons spanning 45 kb in the human genome (11). The intron/exon organization of the gene is homologous to other known neurotransmitter transporter genes, except for the presence of an additional exon encoding the C terminus of the protein. Several human NET gene (SLC6A2) polymorphisms have been identified (12, 13, 14, 15, 16); one of these variants ( Gly478Ser; located in extracellular side of TMD 10) displays approximately a four-fold reduction in the affinity for NE (14). Another variant (Ala457Pro) in exon 9 results in more than 98% loss of the NET function and has been linked to familial orthostatic intolerance (17, 18).

In the human heart, 92% of the NE released by sympathetic nerves is recaptured by NET, 4% is removed by non-neuronal uptake and 4% escapes into the circulation (19, 20). More than 90% of the recaptured NE is sequestered back into storage vesicles by VMAT and the remainder is deaminated by monoamine oxidase (MAO) (19). Dihydroxyphenyglycol (DHPG), the deaminated metabolite of NE and epinephrine (EPI) is derived almost entirely from metabolism of catecholamines in neuronal compartments. Most antidepressants, sibutramine, and illicit drugs such as cocaine, inhibit NET.

Non-neuronal Catecholamine Transporters

Multiple non-neuronal catecholamine transporter systems, different from the NET in monoaminergic neurons (21, 22, 23) include organic cationic transporters (OCT1, OCT2) and extraneuronal monoamine transporter (EMT: uptake2) (24, 25) are identified and may be relatively more important in extracardiac tissue. Unlike NET which mainly functions to selectively remove catecholamines, the non-neuronal catecholamine transporters handle a much wider range of endogenous and exogenous substrates in a Na+ and Cl- independent manner (26). The genes of all three human non-neuronal catecholamine transporters are located within a cluster on the long arm of chromosome 6 (6q26-27) (27). EMT like NET has 12 putative TMD, but demonstrates a different primary structure compatible with amphiphilic solute facilitators. Unlike NET, EMT favors epinephrine over NE and exhibits lower affinity but higher maximum rate for catecholamine uptake. Non-neuronal NE metabolism involves both MAO and catechol-O-methyltransferase (COMT). Normetanephrine (NMN) and metanephrine (MN), the O-methylated metabolites of NE are derived exclusively in non-neuronal cells (28).

Reduced Efficiency of NE Transporter in Heart Failure

The neuronal NE uptake is significantly reduced in heart failure (HF), which was first shown in experimental animal models (29, 30) and proven subsequently in human HF (31, 32, 33). The reduced NE uptake in HF is associated with reduced NET carrier binding sites (34, 35, 36, 37) and NET dysfunction (38) in the failing ventricle; the uninvolved ventricle may be relatively unaffected (39, 40, 41).

Reduced and heterogeneous NET activity in the failing heart has been documented in vivo through scintigraphic imaging with MIBG, a NE analog (42, 43). Low myocardial MIBG uptake is demonstrate to be an independent predictor of adverse long-term outcome in HF (44, 45, 46) and useful in monitoring the therapeutic efficacy of pharmacological interventions (47, 48, 49). Similarly to MIBG, c-11-HED, a PET-based NE analog, has demonstrated marked regional variations in density of NET and tissue NE stores in dilated cardiomyopathy (50). Regional variation of NET could form the basis of ventricular tachyarrhythmias; in fact increased refractory periods are observed in areas of reduced HED retention (51) and promote reentry arrhythmias.(52) Reductions in cardiac HED uptake also been related to differences in blood pressure variation, a functional marker for the autonomic innervation of the heart (53).

Impaired transporter function is shown in cardiac failure or hypertrophy with different etiologies, including idiopathic hypertrophic cardiomyopathy (54), ischemic heart disease, hypertension, and valvular heart disease (19, 49). The abnormality could be reversed by correcting the underlying cause (16) or by pharmacological interventions that improve cardiac function (55, 56). Impaired NE uptake is unlikely to be of primary etiologic significance, but more likely, reflects a general consequence of heart failure or cardiac hypertrophy (24). This conjecture is supported by the finding that one of the mutations of NET (Ala457Pro) that results in more than 98% loss of NET function is not linked to HF (17, 18).

Decreased NET efficiency in association with increased cardiac sympathetic stimulation in heart failure results in increased interstitial NE concentration which predisposes the failing ventricle to beta-receptors down regulation (57, 58, 39) (Figure 1, B-C), which may contribute to progress of HF.

Mechanisms Underlying Reduced NET Efficiency in HF

Significant decrease in NE uptake activity and NET carrier density has been observed in the right ventricles (RV) of dogs with induced right heart failure (RHF) (35), which correlated significantly with beta-receptor density. NE uptake activity and beta-receptor density in the left ventricle (LV) was not affected by RHF, suggesting that the failing myocardium is associated with an organ- and chamber-specific subnormal neuronal NE uptake. In a model of rapid pacing induced LVF (39), LV function normalized quickly, after cessation of cardiac pacing, followed by resolution of tyrosine hydroxyls and NE profiles in 1 week and NE uptake activity in 2 weeks. These results suggested that there were no permanent structural neuronal damage in cardiomyopathy.

Elevated NE levels may play a role in the development of sympathetic nerve dysfunction in HF. This hypothesis is supported by decrease of NET binding sites and NE uptake activity following infusion of NE in intact animals (57, 58), in PC12 cells (59, 60, 38) and in 293-hNET cells (61, 62). It has been shown that ventricular hypertrophy per se is not sufficient to cause the characteristic alterations in the NET (binding sites and activity) often seen in HF; only if ventricular hypertrophy was associated with neurohumoral activation, ß-adrenoceptors were down regulated and NET efficiency decreased (63). The exact mechanism by which NE reduces NET efficiency is not known. Although high doses of NE (>100 mcg in PC12 cells) could result in cellular necrosis, NE level observed typically in HF does not produce myocardial necrosis (64). Studies have shown that the reduction of NET protein produced by NE is a posttranscriptional event (38, 62, 65) and may result from decreasing the total number of NET binding sites, NET surface expression and NET function (Figure 3). NE produces a partially reversible reduction of neuronal NE uptake activity and NET binding sites in a dose-dependent manner in PC12 cells (38). The degree of NE uptake inhibition produced by NE is often greater than the reduction of NET protein which is suggestive of functional modification of NET. The effect of NE on NE uptake activity is associated with an increase in oxidative stress; free-radical scavenger (mannitol) and antioxidant enzymes (superoxide dismutase and catalase) reduce oxidative stress and restore NE uptake activity and NET binding site density (38). NE infusion in vivo induces an increase in cardiac tissue oxidized glutathione (GSSG) and decrease of reduced glutathione (GSH) consistent with oxidative stress (40).

NE generates reactive oxygen species (ROS) by activation of several enzymatic and nonenzymatic pathways, which deamination of catecholamine by Monoamine oxidase (MAO) contributes to the formation of cytotoxic free radicals in the presence of transition metals such as iron, copper and manganese (66, 67, 68, 69). Although free radical reactions are a part of normal metabolism, the overproduction of ROS such as superoxide anion (O2-), H2O2 and hydroxyl free radical (.OH) may contribute to cellular injury (38,70) especially in a failing myocardium which has a reduced antioxidant capacity (71).

Exposure to such oxidants lead to amino acid modifications and subsequent changes in protein structure and function, particularly involving cysteine residues.(72 ). Nitric oxide also plays a key role in modulating NE uptake via S-nitrosylation of a key cysteine residue in TMD 7 of the NET (73).On the other hand, second messengers, in particular c-AMP, may decrease NE uptake activity after short term exposure (74, 75) and NET protein expression after long-term exposure in PC12 cells (75). Oxidative stress may also lead tois often associated with activation of tissue inflammatory mediators, such as tissue necrosis factor and interleukins ( which are known to exist in HF) and contribute to sympathetic nerve terminal dysfunction (38). It has been observed that protein kinase C (PKC) activation leads to a reduction in amine transport capacity apparently due to rapid internalization of cell surface transporter protein (76, 77, 78) (Figure 3).

Figure 3. Possible subcellular mechanism underlying reduction in NET efficiency. Increased amount of NE in heart failure (HF) reduces NET uptake activity and total NET binding site density via production of reactive oxygen radicals (ROS), and decreases NET surface expression via activation of protein kinase (PKC).

MIBG Imaging and Stress MIBG in HF

As discussed above MIBG is an analogue of NE that share the same reuptake and storage mechanisms with NE, but is neither metabolized nor does it interact with postsynapthic receptors (79). Its uptake reflects the extent of sympathetic innervation in tissues including the myocardium. MIBG Imaging studies involve a two-step protocol, with early imaging after MIBG injection followed by delayed imaging in 4 or more hours. The late images are specific for the relative distribution of sympathetic nerve terminals while the washout rate represents the neuronal function. Multiple studies have demonstrated that impaired cardiac sympathetic innervation, assessed by MIBG uptake, has valuable potential for predicting adverse clinical outcome; including ventricular arrhythmia and mortality in HF patients (43, 44, 45, 80, 81) (Figure 4). It is been shown that MIBG uptake improves in response to effective treatment of HF (47, 48, 49).

Figure 4. Conventional I-123 planar MIBG imaging. Comparison of MIBG uptake in normal myocardium (A) with failing (B) myocardium. There is a marked reduction in MIBG uptake in pre-cordial region in the failing heart (B). The uptake shows significant association with the clinical outcomes including mortality (C).

Future Perspectives

Although valuable information is obtained by standared MIBG imaging, it is suggested that pharmacological blocking of the NET activity, would exaggerate the relative difference of MIBG uptake, particularly in regions with already reduced NET efficiency and can help to unmask subclinical neuronal dysfunction. This may have similar pathophysiologyical implications as pharmachological stress for myocardial perfusion imaging (82). In a recent study of patients with movement disorders and a normal cardiac MIBG scan, a single, low dose amitriptyline (which inhibits NET) induced a significant regional decrease (lateral , apical and inferior regions) in cardiac MIBG uptake (82) (Figure 5). It is expected that amitriptyline stress in very low dose may help to detect the early sympathetic neuronal dysfunction in asymptomatic patients predisposed to HF. This may empower an important step in our quest towards early detection and prevention of HF.

Figure 5a: Proposing stress MIBG imaging for uncovering covert neuronal dysfunction. MIBG polar maps at rest (left) and after administration of amitriptyline (right) show induction of severe regional decrease in tracer uptake in lateral, inferior, septal and apical wall after pharmacologic stress.

Figure 5b: Individual regional distribution of cardiac MIBG uptake based on a polar map (20-segment model) in 6 patients demonstrates segments with a decrease in MIBG uptake of 5NE, Norepinephrine; DOPA, dihydroxyphalanine; DA, dopamine; RUT-1, reuptake-1; AC, adenyl cyclase; cAMP, cyclic adenosine monophosphate; NMN, normetanephrine; MAO, monoamineoxidase; COMT, catechol-o-methyltransferase; DHPG, dihydroxyphenylglycol.
Decrease of < 10% after amitriptyline administration are represented in grey, and segments with a decrease of >10% in black. (Modified from ref. 82, with permisson).


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