Carbon-11 hydroxyephedrine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans

Allman, Kevin C.; Wieland, Donald M.; Muzik, Otto; DeGrado, Timothy R.; Wolfe, Edwin R.; Schwaiger, Markus

doi:10.1016/0735-1097(93)90039-4

Cited by 131 publications

(70 citation statements)

References 15 publications

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“…HED is an inactive norepinephrine analogue and a highly specific tracer of the presynaptic sympathetic nerve terminals. 18 The patients' medications were reviewed before PET scanning for possible interaction with the neuronal uptake of HED. Dynamic images were acquired according to the following protocol: After positioning of the patient, a 15-minute transmission scan was obtained to correct emission data for tissue attenuation.…”

Section: Positron Emission Tomographymentioning

confidence: 99%

Cardiac Sympathetic Denervation After Transmyocardial Laser Revascularization

et al. 1999

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Background-Transmyocardial laser revascularization (TMR) has been shown to improve refractory angina not amenable to conventional coronary interventions. However, the mechanism of action remains controversial, because improved myocardial perfusion has not been consistently demonstrated. We hypothesized that TMR relieves angina by causing myocardial sympathetic denervation. Methods and Results-PET imaging of resting and stress myocardial perfusion with [13 N]ammonia (NH 3 ) and of sympathetic innervation with [11 C]hydroxyephedrine (HED) was performed before and after TMR in 8 patients with class IV angina ineligible for CABG or PTCA. A mean of 50Ϯ11 channels were created in the left ventricle (LV) with a holmium:YAG laser. A semiautomated program was used to determine NH 3 uptake and HED retention in the LV. Perfusion and innervation defects were defined as the percentage of LV with tracer uptake or retention Ͼ2 SD below normal mean values. All patients experienced improvement in their angina by 2.4Ϯ0.5 angina classes after surgery, Pϭ0.008. Sympathetic innervation defects exceeded resting perfusion defects in all patients before TMR (34.6Ϯ27.3% for HED versus 9.4Ϯ10.8% for NH 3 , Pϭ0.008). TMR did not significantly affect resting or stress myocardial perfusion but increased the extent of sympathetic denervation in 6 of 8 patients by 27.5Ϯ15.9%, Pϭ0.03. In the remaining 2 patients, both sympathetic denervation and stress perfusion defects decreased after surgery. Conclusions-TMR causes decreased myocardial HED uptake in most patients without significant change in resting or stress myocardial perfusion, suggesting that the improvement in angina may be at least in part due to sympathetic denervation. (Circulation. 1999;100:135-140.)

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Section: Positron Emission Tomographymentioning

confidence: 99%

Cardiac Sympathetic Denervation After Transmyocardial Laser Revascularization

et al. 1999

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“…Moreover, HED is resistant to the NE-metabolizing enzymes monoamine oxidase (MAO) and catechol-Omethyltransferase (9). Characterization studies of HED have demonstrated dependence of retention on the functionality and availability of NET (12,13), confirming specificity in myocardium, spleen, and adrenal glands (9,11,14). Pharmacokinetic studies performed in animal models and isolated organ systems (2,9,11,15) have implied a correlation between NE concentration and clearance rate of HED (2,15).…”

mentioning

confidence: 99%

“…Whereas cardiac retention of HED has been well documented and applied in several cardiovascular and autonomic disorders (10,13,14,17,18), uptake in other tissues with rich noradrenergic innervation remains equivocal. In this study, we analyzed the effect of treatments altering synaptic NE levels on specific retention of HED.…”

mentioning

confidence: 99%

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Thackeray¹,

Beanlands²,

DaSilva³

2007

Journal of Nuclear Medicine

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11 C-meta-Hydroxyephedrine (HED) is used in cardiac PET as an index of norepinephrine (NE) reuptake transporter (NET) density and synaptic NE levels. Whereas cardiac uptake is well documented, tracer retention in other tissues with rich noradrenergic innervation is unclear. Dysfunctional sympathetic nervous system (SNS) function in extracardiac metabolic storage tissues (i.e., adipose tissue and skeletal muscle) and endocrine organs contributes to several disorders. The aim of this study was to determine the potential of HED as an index of NE function in brown adipose tissue, lung, pancreas, skeletal muscle, and kidney by identifying NET-specific retention and determining the presence of radiolabeled metabolites. Methods: Male Sprague-Dawley rats were administered HED and sacrificed at 30 min after tracer injection. Tissues were rapidly excised and counted for radioactivity, and relative tracer retention was quantified. Pretreatment with NET inhibitors established specific HED accumulation. The effect of elevated NE was tested by subcutaneous minipump NE infusion or inhibition of monoamine oxidase. Column-switch high-performance liquid chromatography (HPLC) was used to analyze the presence of radiolabeled metabolites in heart, brown adipose tissue, pancreas, and plasma. Results: NET-specific retention was observed in heart, brown adipose tissue, lung, and pancreas but not in liver, skeletal muscle, or kidney. A dosedependent response of HED accumulation to treatments elevating NE levels was established in tissues exhibiting specific uptake. At 30 min after tracer administration, HPLC analysis revealed 93%-95% of total radioactivity signal derived from unchanged HED in heart, pancreas, and brown adipose tissue compared with 61% 6 8% unchanged HED in plasma. Conclusion: In addition to the heart, lung, pancreas, and brown adipose tissue exhibit specific and NE-responsive uptake of HED, supporting the potential for novel PET studies of SNS integrity in these tissues.Key Words: sympathetic nervous system function; norepinephrine transporter uptake-1; competition with norepinephrine; HPLC column-switch system The sympathetic nervous system (SNS) is a primary extrinsic control mechanism mediating cardiac function, metabolic processes, and adaptation to stress. In normal conditions, the neurotransmitter norepinephrine (NE) is released from the presynaptic bouton into the synapse, where it binds to and stimulates adrenoceptors on pre-and postsynaptic cells. Excess NE is recycled into the presynaptic neuron by active transport via the uptake-1 NE reuptake transporter (NET) (1,2).In myocardium, the SNS modulates heart rate, cardiac output, and stroke volume (2). In metabolic storage tissues, SNS activation stimulates 2 key processes: lipolysis-the breakdown of lipids primarily in white adipocytes-and thermogenesis-the uncoupling of mitochondrial energetics promoting heat release over energy storage, primarily in brown adipocytes and skeletal muscle (3). The SNS also partially controls pancreatic secretion of insulin and gl...

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“…Such neuronal dysfunction has also been shown in humans. 15 This represents one potential mechanism for adverse events in patients with viable myocardium. These swine have also been shown to experience sudden cardiac death preceded by a rise in LVEDP.…”

Section: Swine Model Of Myocardial Hibernation: Imaging Correlatesmentioning

confidence: 99%

“…134 Cardiac Sympathetic Neuronal Dysfunction in Patients with CAD Myocardial sympathetic innervation has been shown to be abnormal in viable myocardium. 15,170 This represents one potential cause for cardiac death in such subjects. The PAREPET trial 21 has shown (in a 630 Allman Journal of Nuclear Cardiology Noninvasive assessment myocardial viability July/August 2013 preliminary report) that extent of denervation determined by C-11 hydroxyephedrine PET is an independent predictor of cardiac arrest in patients with CAD and heart failure.…”

Section: Adequacy Of Revascularization In Relation To Viable Tissue Smentioning

confidence: 99%

Noninvasive assessment myocardial viability: Current status and future directions

Allman

2013

Journal of Nuclear Cardiology

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Observations of reversibility of cardiac contractile dysfunction in patients with coronary artery disease and ischemia were first made more than 40 years ago. Since that time a wealth of basic science and clinical data has been gathered exploring the mechanisms of this phenomenon of myocardial viability and relevance to clinical care of patients. Advances in cardiac imaging techniques have contributed greatly to knowledge in the area, first with thallium-201 imaging, then later with Tc-99m-based tracers for SPECT imaging and metabolic tracers used in conjunction with positron emission tomography (PET), most commonly F-18 FDG in conjunction with blood flow imaging with N-13 ammonia or Rb-82 Cl. In parallel, stress echocardiography has made great progress also. Over time observational studies in patients using these techniques accumulated and were later summarized in several meta-analyses. More recently, cardiac magnetic resonance imaging (CMR) has contributed further information in combination with either late gadolinium enhancement imaging or dobutamine stress. This review discusses the tracer and CMR imaging techniques, the pooled observational data, the results of clinical trials, and ongoing investigation in the field. It also examines some of the current challenges and issues for researchers and explores the emerging potential of combined PET/CMR imaging for myocardial viability.

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Carbon-11 hydroxyephedrine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans

Abstract: The results of abnormal regional sympathetic innervation in patients with infarction confirm previous experimental data and suggest persistent neuronal damage in infarct and peri-infarct territories, without evidence of reinnervation of reversibly injured myocardium.

Cited by 131 publications

References 15 publications

Cardiac Sympathetic Denervation After Transmyocardial Laser Revascularization

Cardiac Sympathetic Denervation After Transmyocardial Laser Revascularization

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Noninvasive assessment myocardial viability: Current status and future directions

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