Abnormal Myocardial Presynaptic Norepinephrine Recycling in Patients With Brugada Syndrome

Kies, Peter; Wichter, Thomas; Schäfers, Michael; Paul, Matthias; Schäfers, Klaus P.; Eckardt, Lars; Stegger, Lars; Schulze‐Bahr, Eric; Rimoldi, Ornella; Breithardt, Günter; Schober, Otmar; Camici, Paolo G.

doi:10.1161/01.cir.0000146920.35020.44

Cited by 88 publications

(52 citation statements)

References 34 publications

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“…Clinical applications of HED PET have included cardiovascular disorders such as acute myocardial infarction (14), congestive heart failure (10,17), dilated cardiomyopathies (13), multivessel coronary artery disease (5), and Brugada syndrome ventricular fibrillation (18), as well as the systemic disorders pheochromocytoma (37), diabetes mellitus (8), and parkinsonian syndromes such as multisystem atrophy (38). Imaging of brown adipose tissue, lung, and pancreas present unique and formidable challenges because of problems in localization and signal identification for brown adipose tissue (3), low in vivo tissue density hindering acquisition of high-contrast images for lung (21), and nonpancreatic abdominal uptake causing poor signalto-noise ratios for pancreas (39).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

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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“…123 I-metaiodobenzylguanidine ( 123 I-MIBG) for use with SPECT [4], and 11 C-hydroxyephedrine ( 11 C-HED) [5][6][7] for use with PET [8]. Both have been used in patients and normal volunteers for a number of years, but so far due to the intrinsic limitations of each radiotracer (Table 1) they have not gained the confidence of practitioners as a guide for the treatment of their patients.…”

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confidence: 99%

“…A low uptake of the tracer in a definite region can have a binary interpretation: on the one hand it might indicate a lower density of neural terminals which have been damaged, and on the other hand sympathetic overactivity may increase the amount of endogenous mediator in the synaptic cleft which displaces the radiotracer. The latter phenomenon has been quantified using 11 C-HED and is distinctive of arrhythmogenic cardiomyopathies [6,7].…”

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confidence: 99%

Assessing the activity of cardiac sympathetic innervation with a novel PET tracer

Rimoldi

2012

Eur J Nucl Med Mol Imaging

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“…More recently, Kies and coworkers (Kies et al 2004) assessed autonomic nervous system function noninvasively in patients with the Brugada syndrome, quantifying myocardial presynaptic and postsynaptic sympathetic function by means of positron emission tomography with the norepinephrine analog 1lC-Hydroxyephedrine (11C-HED) and the nonselective β-blocker 11C-CGP 12177 ( 11C-CGP). Presynaptic sympathetic norepinephrine recycling, assessed by lIC-HED, was found to be globally increased in patients with Brugada syndrome compared with a group of age-matched healthy control subjects, whereas postsynaptic β-adrenoceptor density, assessed by 11C-CGP, was similar in patients and controls.…”

Section: Factors That Modulate Ecg and Arrhythmic Manifestations Of Tmentioning

confidence: 99%

Therapy for the Brugada Syndrome

Antzelevitch

Fish

Basis and Treatment of Cardiac Arrhythmias

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The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a distinct coved-type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and maybe revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, α-adrenergic agonists, β-adrenergic blockers, tricyclic ortetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF). KeywordsBrugada syndrome; Phase 2 reentry; ST segment elevation; I Na ; I to ; Implantable cardioverterdefibrillator (ICD); VT; SCN5A mutations; Sudden death; Bradycardia Clinical Characteristics and Diagnostic CriteriaThe Brugada syndrome typically manifests in the third or fourth decade of life (average age of 41±15 years), although patients have been diagnosed with the syndrome at an age as young as 2 days and as old as 84 years. The prevalence of the disease is estimated to be at least 5 per 10,000 inhabitants in Southeast Asia, where the syndrome is endemic (Nademanee et al. 1997). In Japan, a Brugada syndrome ECG (type 1) is observed in 12 per 10,000 inhabitants; type 2 and type 3 ECGs, which are not diagnostic of Brugada syndrome, are much more prevalent, appearing in 58 per 10,000 inhabitants (Miyasaka et al. 2001). The true prevalence of the disease in the general population is difficult to estimate because the ECG pattern is often concealed (Brugada et al. 2003). Sudden unexplained nocturnal death syndrome (SUNDS also known as SUDS) and Brugada syndrome have been shown to be phenotypically, genetically, and functionally the same disorder (Vatta et al. 2002).Although syncope and sudden death are a consequence of ventricular tachycardia/fibrillation (VT/VF), approximately 20% of Brugada syndrome patients also develop supraventricular arrhythmias (Morita et al. 2002). Atrial fibrillation (AF) is reported in approximately 10%-20% of cases. Atrio-ventricular (AV) nodal reentrant tachycardia (AVNRT) and Wolf-ParkinsonWhite (WPW) syndrome have been described as well (Eckardt et al. 2001 et al. 2004)...

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Abnormal Myocardial Presynaptic Norepinephrine Recycling in Patients With Brugada Syndrome

Cited by 88 publications

References 34 publications

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

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

Assessing the activity of cardiac sympathetic innervation with a novel PET tracer

Therapy for the Brugada Syndrome

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