Abstract
Parasympathetic activity influences long-term outcome in patients with cardiovascular disease, but the underlying mechanism(s) linking parasympathetic activity and the occurrence of major adverse cardiovascular events (MACEs) are incompletely understood. The aim of this pilot study was to evaluate the association between serum cholinesterase activities as parasympathetic biomarkers and the risk for the occurrence of MACEs. Cholinergic status was determined by measuring the cumulative capacity of serum acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) to hydrolyze the AChE substrate acetylthiocholine. Cholinergic status was evaluated in randomly selected patients undergoing cardiac catheterization. The patients were divided into two groups of 100 patients in each group, with or without occurrence of MACEs during a follow-up period of 40 months. Cox regression models adjusted for potential clinical, metabolic and inflammatory confounders served to evaluate association with clinical outcome. We found that patients with MACE presented lower cholinergic status and AChE values at catheterization (1,127 ± 422 and 359 ± 153 nmol substrate hydrolyzed per minute per milliliter, respectively) than no-MACE patients (1,760 ± 546 and 508 ± 183 nmol substrate hydrolyzed per minute per milliliter, p < 0.001 and p < 0.001, respectively), whose levels were comparable to those of matched healthy controls (1,622 ± 303 and 504 ± 126 nmol substrate hydrolyzed per minute per milliliter, respectively). In a multivariate analysis, patients with AChE or total cholinergic status values below median showed conspicuously elevated risk for MACE (hazard ratio 1.85 [95% confidence interval [CI] 1.09-3.15, p = 0.02] and 2.21 [95% CI 1.22-4.00, p = 0.009]) compared with those above median, even after adjusting for potential confounders. We conclude that parasympathetic dysfunction expressed as reduced serum AChE and AChE activities in patients compared to healthy controls can together reflect impaired parasympathetic activity. This impairment predicts the risk of MACE up to 40 months in such patients. Monitoring these parasympathetic parameters might help in the risk stratification of patients with cardiovascular disease.
Highlights
Imbalanced sympathetic-parasympathetic activity has been associated with poor cardiovascular outcome, calling for identifying readily measurable biomarkers of parasympathetic activity for predicting future risks
A total of 192 patients referred for coronary angiography at the Tel Aviv Med-Serum AChE, BChE and Cholinergic Status Values Show Inverse Associations with major adverse cardiovascular events (MACEs)
To enable in-depth interrogation of the cholinergic parameters, we analyzed the distributions of measured AChE and cholinergic status values and of calculated BChE in patients with and without MACEs compared with matched controls [19] without cardiac disease
Summary
Imbalanced sympathetic-parasympathetic activity has been associated with poor cardiovascular outcome, calling for identifying readily measurable biomarkers of parasympathetic activity for predicting future risks Supporting this notion, indirect measures of cardiac parasympathetic dysfunction such as elevated resting heart rate, delayed heart rate recovery after exercise and attenuated heart rate increase during exercise have all been shown to be independent predictors for adverse cardiovascular outcome [1,2,3]. Abnormalities in these parameters [4] have been shown in diverse study populations to be associated with sudden cardiac death [1,5] as well as all-cause mortality [2,3,6,7], but clinically validated biomarkers to assess the parasympathetic system are not yet available. A recent study demonstrated a strong inverse relation between serum BTCh hydrolyzing activity
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