Imaging Targets of the Sympathetic Nervous System of the Heart: Translational Considerations

Bengel, Frank M.

doi:10.2967/jnumed.110.084228

Cited by 36 publications

(30 citation statements)

References 18 publications

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“…Desipramine (DMI) chase enhanced 11 C-hydroxyephedrine ( 11 C-HED) washout from heart, whereas 18 F-LMI1195 washout did not change. Although all available presynaptic sympathetic nerve norepinephrine analog tracers are designed to be initially transported into nerve terminals to visualize the nervous system, significant differences in intraneural kinetics have been reported among these tracers (22,23). Understanding this subcellular tracer handling is essential for fundamental interpretation of the imaging results.…”

Section: Discussionmentioning

confidence: 99%

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

et al. 2015

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]-guanidine (18 F-LMI1195) is a new PET tracer designed for noninvasive assessment of sympathetic innervation of the heart. The 18 F label facilitates the imaging advantages of PET over SPECT technology while allowing centralized manufacturing. Highly specific neural uptake of 18 F-LMI1195 has previously been established, but the retention kinetics are not yet fully understood. Methods: Healthy New Zealand White rabbits were studied with 18 F-LMI1195 using a small-animal PET system. Dynamic 40-min chest scans were started just before intravenous bolus injection of 18 F-LMI1195. Imaging was performed under norepineph-rine transport inhibition with desipramine pretreatment, a 1.5 mg/kg desipramine chase administered 10 min after tracer injection, and saline treatment of controls. As a reference, cardiac uptake of 11 C-hydroxyephedrine and 123 I-metaiodobenzylguanidine (123 I-MIBG) was examined by PET and planar scintigraphy, respectively. Results: Cardiac uptake of all 3 tracers was inhibited by pretreatment with desipramine. Stable cardiac tracer retention was delineated by dynamic PET in control rabbits for 11 C-hydroxyephedrine (washout rate, 0.42% ± 0.57%/min) and 18 F-LMI1195 (washout rate, 0.058% ± 0.28%/min). A desipramine chase increased 11 C-hydroxyephedrine washout from the heart (2.43% ± 0.15%/min, P , 0.001), whereas 18 F-LMI1195 washout was not influenced (0.059% ± 0.11%/min, not statistically significant). Additionally, a desipramine chase did not change the cardiac 123 I-MIBG uptake (delayed heart-to-mediastinum ratio, 1.99 ± 0.12 (desipramine chase) vs. 2.05 ± 0.16 (controls), not statistically significant). Conclusion: In vivo norepinephrine transporter (NET) blockade with desipramine confirmed specific neural uptake of 18 F-LMI1195, 11 C-hydroxyephedrine, and 123 I-MIBG in rabbit hearts. 11 C-hydroxyephedrine cardiac retention was sensitive to a NET inhibitor chase, indicating a cycle of continuous NET uptake and release at the nerve terminals. In contrast, 18 F-LMI1195 and 123 I-MIBG demonstrated stable storage at the nerve terminal with resistance to a NET inhibitor chase, mimicking physiologic norepinephrine turnover.

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Section: Discussionmentioning

confidence: 99%

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

et al. 2015

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“…In the synaptic cleft, most norepinephrine undergoes reuptake into nerve terminals by the presynaptic norepinephrine transporter and recycles into vesicles or is metabolized in the cytosol by monoamine oxidase. 4 A small fraction of ≈20% diffuses into the vascular space, where it can be measured in coronary sinus blood. 5 Norepinehprine spillover can also be measured in the blood and used to infer sympathetic outflow to the heart.…”

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confidence: 99%

The Autonomic Nervous System and Heart Failure

Florea

Cohn

2014

Circulation Research

439

366

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Abstract:The pathophysiology of heart failure (HF) is characterized by hemodynamic abnormalities that result in neurohormonal activation and autonomic imbalance with increase in sympathetic activity and withdrawal of vagal activity. Alterations in receptor activation from this autonomic imbalance may have profound effects on cardiac function and structure. Inhibition of the sympathetic drive to the heart through β-receptor blockade has become a standard component of therapy for HF with a dilated left ventricle because of its effectiveness in inhibiting the ventricular structural remodeling process and in prolonging life. Several devices for selective modulation of sympathetic and vagal activity have recently been developed in an attempt to alter the natural history of HF. The optimal counteraction of the excessive sympathetic activity is still unclear. A profound decrease in adrenergic support with excessive blockade of the sympathetic nervous system may result in adverse outcomes in clinical HF. In this review, we analyze the data supporting a contributory role of the autonomic functional alterations on the course of HF, the techniques used to assess autonomic nervous system activity, the evidence for clinical effectiveness of pharmacological and device interventions, and the potential future role of autonomic nervous system modifiers in the management of this syndrome. (Circ Res. 2014;114:1815-1826.) Key Words: autonomic nervous system ■ heart failure ■ norepinephrine ■ receptors, adrenergicThe Autonomic Nervous System and Heart Failure Viorel G. Florea, Jay N. Cohn This Review is in a thematic series on The Autonomic Nervous System and the Cardiovascular System, which includes the following articles: Role of the Autonomic Nervous System in Modulating Cardiac Arrhythmias [Circ Res. 2014;114:1004-1021 The Autonomic Nervous System and Hypertension [Circ Res. 2014;114:1804-1814 The Autonomic Nervous System and Heart Failure Renal Denervation for the Treatment of Cardiovascular High Risk-Hypertension or Beyond? Original received February 10, 2014; revision received April 29, 2014; accepted April 29, 2014. In March 2014, the average time from submission to first decision for all original research papers submitted to Circulation Research was 12.63 days.From the Minneapolis VA Health Care System, Section of Cardiology (V.G.F.) and Rasmussen Center for Cardiovascular Disease Prevention, Department of Medicine (J.N.C.), University of Minnesota Medical School.Correspondence to Jay N. endocardium. Parasympathetic effects are carried by the right and left vagus nerves, originating in the medulla. The vagus nerve further divides into the superior and inferior cardiac nerves, finally merging with the postganglionic sympathetic neurons to form a plexus of nerves at the base of the heart, known as the cardiac plexus. 1The 2 mediators of the SNS, norepinephrine and epinephrine, derive from 2 major sources in the body: the sympathetic nerve endings, which release norepinephrine directly into the synaptic cleft, and the adren...

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“…Reduced tracer uptake may be due to the absence of nerve terminals or due to impaired function (8). These 2 conditions may not be equal with regards to disease progression or regeneration.…”

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confidence: 99%

Multiparametric Molecular Imaging Provides Mechanistic Insights into Sympathetic Innervation Impairment in the Viable Infarct Border Zone

et al. 2015

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Impaired catecholamine handling in the viable infarct border zone may play an important role in ventricular remodeling and lethal arrhythmia. We sought to get further biologic insights into cardiac sympathetic neuronal pathology after myocardial infarction, using multiple tomographic imaging techniques. Methods: In a porcine model of myocardial infarction (n 5 13), PET and MR imaging were performed after 4-6 wk and integrated with electrophysiologic testing and postmortem histology. Results: PET with the physiologic neurotransmitter 11 C-epinephrine, which is sensitive to metabolic degradation unless it is stored and protected in neuronal vesicles, identified a defect exceeding the perfusion defect (defined by 13 Nammonia; defect size in all animals, 42 ± 12 vs. 35% ± 12% of left ventricle, P , 0.001). In a subgroup of 7 animals, defect of the metabolically resistant catecholamine 11 C-hydroxyephedrine was smaller than epinephrine (41 ± 8 vs. 47% ± 6% of left ventricle, P 5 0.004), whereas defect of a third catecholamine, 11 C-phenylephrine, which is sensitive to metabolic degradation, was similar to epinephrine (48 ± 6 vs. 47% ± 6%, P 5 0.011 vs. perfusion defect). Histology confirmed the presence of nerve fibers in the infarct border zone. Tagged MR imaging identified impaired peak circumferential wall strain and wall thickening in myocardial segments with epinephrine/perfusion mismatch (n 5 6). Confirmatory of prior work, inducible ventricular tachycardia was associated with a larger epinephrine/perfusion mismatch (n 5 11). Conclusion: In the viable infarct border zone, neuronal vesicular catecholamine storage and protection from metabolic degradation are more severely altered than catecholamine uptake. This alteration may reflect an intermediate state between normal innervation and complete denervation in advanced disease.

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Imaging Targets of the Sympathetic Nervous System of the Heart: Translational Considerations

Cited by 36 publications

References 18 publications

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

The Autonomic Nervous System and Heart Failure

Multiparametric Molecular Imaging Provides Mechanistic Insights into Sympathetic Innervation Impairment in the Viable Infarct Border Zone

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Imaging Targets of the Sympathetic Nervous System of the Heart: Translational Considerations

Cited by 36 publications

References 18 publications

Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG

Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG

The Autonomic Nervous System and Heart Failure

Multiparametric Molecular Imaging Provides Mechanistic Insights into Sympathetic Innervation Impairment in the Viable Infarct Border Zone

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Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG