Myocardial Presynaptic and Postsynaptic Autonomic Dysfunction in Hypertrophic Cardiomyopathy

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Abstract
—Although hypertrophic cardiomyopathy (HCM) is genetically determined, several other factors, including autonomic dysfunction, may play a role in the phenotypic expression. A recent study using positron emission tomography with [11C]CGP 12177 ([11C]CGP) demonstrated that β-adrenoceptor (βAR) density is reduced in HCM and is correlated with disease progression. This present study tested the hypothesis that this downregulation is associated with reduced catecholamine reuptake (uptake 1) by myocardial sympathetic nerve terminals leading to increased local norepinephrine concentration. Myocardial presynaptic catecholamine reuptake was assessed by measuring the volume of distribution (Vd) of the catecholamine analogue [11C]hydroxyephedrine ([11C]HED) in 9 unrelated HCM patients aged 45±15 years. The maximum number of binding sites (Bmax) for myocardial βAR density was measured in 13 unrelated HCM patients aged 40±12 years using the nonselective β blocker [11C]CGP. Six patients were studied with both [11C]HED and [11C]CGP. Comparison was made with two groups of healthy control subjects for each ligand ([11C]HED, n=10, aged 35±8 years; [11C]CGP, n=19, aged 44±16 years). Myocardial Vd of [11C]HED (33.4±4.3 mL/g tissue) and βAR density (7.3±2.6 pmol/g tissue) were significantly reduced in HCM patients compared with control subjects (71.0±18.8 mL/g tissue, P<.001, and 10.2±2.9 pmol/g tissue, P=.008, respectively). These results are consistent with our hypothesis that myocardial βAR downregulation in HCM is associated with an impaired uptake-1 mechanism and hence increased local catecholamine levels.