title: Abnormalities of cardiac sympathetic innervation in arrhythmogenic right ventricular cardiomyopathy : quantitative assessment of presynaptic norepinephrine reuptake and postsynaptic beta-adrenergic receptor density with positron emission tomography.
abstract: BACKGROUND
  The frequent provocation of ventricular tachycardia by stress or catecholamines and the efficacy of antiarrhythmic drugs with antiadrenergic properties suggest an involvement of the cardiac adrenergic system in arrhythmogenesis in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Previous studies demonstrated abnormalities of the presynaptic uptake-1 assessed by (123)I-MIBG-single-photon emission computed tomography.
  
  
  RESULTS
  This study investigated neuronal reuptake of norepinephrine (uptake-1) and beta-adrenergic receptor density in 8 patients with ARVC and 29 age-matched control subjects. All subjects underwent positron emission tomography with the volume of distribution (V(d)) of [(11)C]hydroxyephedrine ((11)C-HED) used to assess presynaptic norepinephrine reuptake, the maximum binding capacity (B(max)) of [(11)C]CGP-12177 ((11)C-CGP-12177) to assess postsynaptic beta-adrenergic receptor density, and [(15)O]H(2)O for quantification of myocardial blood flow. Patients with ARVC demonstrated a highly significant global reduction in postsynaptic beta-adrenergic receptor density compared with that in control subjects (B(max) of (11)C-CGP-12177: 5.9+/-1.3 vs 10.2+/-2.9 pmol/g tissue, P<0.0007), whereas the presynaptic uptake-1 tended toward reduction only (V(d) of (11)C-HED: 59.1+/-25.2 vs 71.0+/-18.8 mL/g tissue, NS). There were no differences in myocardial blood flow between the groups, and plasma norepinephrine was within normal limits in patients and control subjects.
  
  
  CONCLUSIONS
  The findings demonstrate a significant reduction of myocardial beta-adrenergic receptor density in patients with ARVC. This may result from a secondary downregulation after increased local synaptic norepinephrine levels caused by increased firing rates of the efferent neurons or as the result of impaired presynaptic catecholamine reuptake. These findings give new insights into the pathophysiology of arrhythmogenesis in ARVC, with potential impact on diagnostic evaluation and therapeutic management.
authors.affiliation: Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Münster, Germany. wichtet@uni-muenster.de
authors.forename: T
authors.initials: T
authors.lastname: Wichter
authors.forename: M
authors.initials: M
authors.lastname: Schäfers
authors.forename: C G
authors.initials: CG
authors.lastname: Rhodes
authors.forename: M
authors.initials: M
authors.lastname: Borggrefe
authors.forename: H
authors.initials: H
authors.lastname: Lerch
authors.forename: A A
authors.initials: AA
authors.lastname: Lammertsma
authors.forename: F
authors.initials: F
authors.lastname: Hermansen
authors.forename: O
authors.initials: O
authors.lastname: Schober
authors.forename: G
authors.initials: G
authors.lastname: Breithardt
authors.forename: P G
authors.initials: PG
authors.lastname: Camici
mesh_terms: D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology*; D003326:Coronary Circulation; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006439:Hemodynamics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D013569:Synapses / Q000378:metabolism; D014055:Tomography, Emission-Computed
chemical_list: D011943:Receptors, Adrenergic, beta; D009638:Norepinephrine