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Myocardial presynaptic and postsynaptic autonomic dysfunction in hypertrophic cardiomyopathy
M Schäfers1, D Dutka, C G Rhodes
1Department of Nuclear Medicine, University of Münster, Germany.
Insights
Hypertrophic cardiomyopathy (HCM) patients show reduced beta-adrenoceptor (betaAR) density and impaired catecholamine reuptake in the heart. This suggests higher local norepinephrine levels contribute to HCM progression.
Area of Science:
- Cardiology
- Nuclear Medicine
- Pharmacology
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart condition influenced by factors like autonomic dysfunction.
- Previous studies indicated reduced beta-adrenoceptor (betaAR) density in HCM, correlating with disease progression.
- The role of catecholamine reuptake in HCM's phenotypic expression requires further investigation.
Purpose of the Study:
- To test the hypothesis that reduced betaAR density in HCM is linked to impaired catecholamine reuptake (uptake 1) by sympathetic nerve terminals.
- To investigate if impaired uptake 1 leads to increased local norepinephrine concentration in HCM patients.
- To correlate myocardial betaAR density and catecholamine reuptake function in HCM.
Main Methods:
- Utilized positron emission tomography (PET) with [11C]hydroxyephedrine ([11C]HED) to assess myocardial presynaptic catecholamine reuptake (volume of distribution, Vd) in 9 HCM patients.
- Employed PET with [11C]CGP 12177 ([11C]CGP) to measure beta-adrenoceptor (betaAR) density (Bmax) in 13 HCM patients.
- Compared PET imaging results from HCM patients with those from healthy control subjects for both ligands.
Main Results:
- HCM patients exhibited significantly reduced myocardial Vd of [11C]HED (33.4+/-4.3 mL/g) compared to controls (71.0+/-18.8 mL/g, P<.001).
- Myocardial betaAR density was also significantly lower in HCM patients (7.3+/-2.6 pmol/g) than in controls (10.2+/-2.9 pmol/g, P=.008).
- Six patients studied with both tracers showed consistent reductions.
Conclusions:
- The findings support the hypothesis that myocardial betaAR downregulation in HCM is associated with impaired catecholamine reuptake (uptake 1).
- This impaired uptake mechanism likely results in elevated local norepinephrine levels within the myocardium of HCM patients.
- These alterations in sympathetic nerve terminal function may contribute to the progression and phenotypic expression of HCM.
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 beta-adrenoceptor (betaAR) 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 betaAR density was measured in 13 unrelated HCM patients aged 40+/-12 years using the nonselective beta 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 betaAR 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 betaAR downregulation in HCM is associated with an impaired uptake-1 mechanism and hence increased local catecholamine levels.