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

Background-The frequent provocation of ventricular tachycardia by stress or catecholamines and the efficacy of antiarrhythmic drugs with antiadrenergi c properties suggest an involvement of the cardiac adrenergic system in arr hythmogenesis in patients with arrhythmogenic right ventricular cardiomyopa thy (ARVC). Previous studies demonstrated abnormalities of the presynaptic uptake-1 assessed by I-123-MIBG-single-photon emission computed tomography. Methods and Results-This study investigated neuronal reuptake of norepineph rine (uptake-1) and beta-adrenergic receptor density in 8 patients with ARV C and 39 age-matched control subjects. All subjects underwent positron emis sion tomography with the volume of distribution (V-d) of [C-11]hydroxyephed rine (C-11-HED) used to assess presynaptic norepinephrine reuptake, the max imum binding capacity (B-max) of [C-11]CGP-12177 (C-11-CGP-12177) to assess postsynaptic beta-adrenergic receptor density, and [O-15]H2O for quantific ation of myocardial blood now. Patients with ARVC demonstrated a highly sig nificant global reduction in postsynaptic beta-adrenergic receptor density compared with that in control subjects (B-max of C-11-CGP-12177: 5.9+/-1.3 vs 10.2+/-2.9 pmol/g tissue, P<0.0007), whereas the presynaptic uptake-1 te nded toward reduction only (V-d of C-11-HED: 59.1+/-25.2 vs 71.0+/-18.8 mL/ g tissue, NS). There were no differences in myocardial blood now between th e groups, and plasma norepinephrine was within normal limits in patients an d control subjects. Conclusions-The findings demonstrate a significant reduction of myocardial beta-adrenergic receptor density in patients with ARVC. This may result fro m a secondary downregulation after increased local synaptic norepinephrine levels caused by increased firing rates of the efferent neurons or as the r esult of impaired presynaptic catecholamine reuptake. These findings give n ew insights into the pathophysiology of arrhythmogenesis in ARVC, with pote ntial impact on diagnostic evaluation and therapeutic management.