Neuroscience & Medicine, 2010, 1, 43-49
doi:10.4236/nm.2010.12007 Published Online December 2010 (http://www.SciRP.org/journal/nm)
43
Serum AChE Activities Predict Exercise Heart
Rate Parameters of Asymptomatic Individuals
Jonathan Canaani1, Shani Shenhar-Tsarfaty1, Nir Weiskopf2, Reut Yakobi1, Einor Ben Assayag1,
Shlomo Berliner1, Hermona Soreq2‡
J. Canaani and S. Shenhar-Tsarfaty contributed equally to this work
1The Tel Aviv Sourasky Medical Center, Israel; 2The Life Sciences Institute, The Hebrew University, Jerusalem, Israel.
‡To whom correspondence should be addressed at the above address: Hermona Soreq, PhD, Biological Chemistry Department, The
Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
Received August 21st, 2010; revised September 15th, 2010; accepted September 17th, 2010
ABSTRACT
Background specific hea rt rate parameters notably associate with variab le risks of cardiovascular disease and mortal-
ity, however, to date there are no readily available blood tests associated with these parameters. Because of the estab-
lished parasympathetic contributions towards cardiac regulation, we challenged the working hypothesis that serum
acetylcholinesterase (AChE) activity is involved. Methods A total of 403 Healthy men and women were included in the
study and underwent treadmill exercise testing. Prior to exercise testing the subject’s serum AChE activity levels were
assessed by measurin g r ates o f acetylt hi oc ho li ne hydrolysis. Results In male subjects AChE activity was positively cor-
related to resting heart rate (r = 0.210, p = 0.001). Complementing this observation, AChE activity was negatively
correlated to the exercise-induced heart rate increase (r = –0.181, p = 0.005) and to heart rate recovery at 1, 2 and 5
minutes following cessation of exercise (r = –0.150, p = 0.022; r = –0.157, p = 0.016; r = –0.176, p = 0.008 respec-
tively). This indicated that lower than average AChE activities, which presumably reflect increased peripheral ACh
levels, might be correlated to favorable heart rate parameters. Similar observations were made in female subjects, ex-
cept for lack of correlation to their resting heart rate. Additionally, we observed that we were able to stratify subjects
into two groups of significan tly d ifferent AChE activity (p = 0.001 ) ba sed on a cut poin t of h eart ra te reco very belo w 20
beats one minute after cessation of exercise. Conclusion In asymptomatic individuals lower than average AChE activity
is associated with favorable indices of exercise-inducible heart rate increase as well as heart rate recovery. Future
studies will be needed to evaluate the added prognostic significance gained by implementing this marker into routine
practice.
Keywords: Exercise, Nervous System, Autonomic, Heart Rate
1. Introduction
A vast body of clinical and experimental evidence indi-
cates that cardiovascular functioning is tightly linked to
autonomous nervous system (ANS) activities. Prior
studies have shown that autonomic imbalance, being
either a decrease in vagal tone or an increase in sympa-
thetic activity is associated with increased mortality due
to cardiovascular pathologies including myocardial in-
farction [1,2] and cardiac arrhythmias [3]. Indirect meas-
ures of cardiac parasympathetic dysfunction obtained
during exercise testing such as elevated resting heart rate,
delayed heart rate recovery (HRR) from exercise and
attenuated heart rate increase (HRI) during exercise have
been shown to be independent predictors for adverse
cardiovascular outcome [4-6].
The principal neurotransmitter of the parasympathetic
branch of the ANS is acetylcholine (ACh), the levels of
which are regulated by the enzyme acetylcholinesterase
(AChE) and the closely related butyrylcholinesterase
(BChE), collectively determining the total cholinesterase
activity [7]. Based on previous studies demonstrating the
protective effect of ACh on ischemic myocardium [8,9]
and that administration of pyridostigmine, an inhibitor of
AChE, improved HRR and resting heart rate both in
healthy subjects [10] and in heart failure patients [11],
we sought to determine whether the peripheral serum
levels of AChE and BChE (i.e. the total cholinesterase
activity tested by aspecific assay [12]) can serve as bio-
markers for assessing the aforementioned parameters of

Serum AChE Activities Predict Exercise Heart Rate Parameters of Asymptomatic Individuals 44
autonomic activity.
Specifically, we hypothesized that in apparently
healthy individuals, increased serum levels of AChE
and/or BChE, which presumably reflect lower peripheral
ACh levels would be correlated with an abnormal heart
rate profile including resting heart rate, heart rate in-
crease during exercise and heart rate recovery after exer-
cise.
2. Methods
2.1. Study Population
The study included 403 men and women who were re-
cruited to the Tel Aviv Medical Center Inflammation
Survey (TAMCIS) which comprises a population of ap-
parently healthy individuals attending the Tel Aviv Sourasky
Medical Center for routine health examinations [13,14].
Exclusion criteria included underlying inflammatory dis-
ease (arthritis, inflammatory bowel disease, etc.), as well
as any infections or other inflammatory conditions such
as myocardial infarction, surgery or angiography during
the 6 months preceding study enrollment. Cancer patients
were excluded as well. To minimize the effect of some
important confounders, we excluded an additional 44
subjects based on their medication usage, including alpha
and beta blockers and Amiodarone (owing to their chrono-
tropic effects). All individuals included in the present
study provided written consent according to the instruc-
tions of the Institutional Ethics Committee which ap-
proved this study (approval number 02-049).
2.2. Clinical Data
Prior to exercise testing, a review of each patient’s chart
and a structured interview were conducted to gather data
on symptoms, medications, coronary risk factors, previ-
ous cardiac events, and other diagnoses. Hypertension
was defined as a systolic blood pressure of ≥ 140 mm Hg
at rest, a diastolic blood pressure of ≥ 90 mm Hg at rest
in two separate measurements, or treatment with anti-
hypertensive medication. Dyslipidemia was defined as
low density lipoprotein (LDL) cholesterol concentration
or non-high density lipoprotein (HDL) cholesterol con-
centrations, for individuals with triglyceride concentra-
tions of > 200 mg/dl, above the recommended number
according to the risk profile defined by the updated ATP
III recommendations [15] or the use of lipid-lowering
medication.
2.3. Exercise Test Protocol
All subjects performed treadmill exercise testing using the
standardized Bruce protocol [16]. The Quinton Q STRESS
TM 55 (Quinton Instrument Company, Bothell, Washington)
hardware and software were used for recording and analyz-
ing stress test data. Heart rate was measured at rest, before
exercise, and every two minutes during exercise, at peak ex-
ercise, and at one, two and five minutes during recovery. The
heart-rate increase was defined as the difference between the
peak exercise rate and the resting rate, and heart-rate recovery
was defined as the reduction in rate from the peak exercise
level to the rate one, two and five minutes following cessa-
tion of exercise. Exercise capacity was measured in watts,
which were converted to maximum oxygen consumption
calculated as metabolic equivalents (MET) [17].
2.4. Enzyme Activity Measurements
Blood was drawn in the morning (7:15-10:30 am) after a
fasting period of at least 12 hours. Following centrifuga-
tion, serum samples were checked for lack of red blood
cells contaminants and were then stored at –80˚C until
cholinesterase activities were determined. AChE activity
levels were assessed in a microtiter plate assay by meas-
uring rates of acetylthiocholine (ATCh, Sigma, 1 mM)
hydrolysis following 20 min pre-incubation in the dark,
with 500 micromolar tetraisopropyl pyrophosphoramide
(iso-OMPA, Sigma), a specific BChE inhibitor [18]. The
non-enzymatic breakdown of substrate was subtracted
from the total rate of hydrolysis. Enzyme activities were
calculated using the e405 for 5-thio-2-nitrobenzoate, 13.600
M/cm [19]. The total cholinesterase activity (combined
activity of AChE and BChE) was determined by measur-
ing the rates of ATCh hydrolysis without a cholinesterase
inhibitor [12]. All laboratory methods were performed by
a blinded technician, each method by the same person for
all measures. Several samples were routinely thawed and
re-tested in subsequent days to evaluate between-days
variability of measurements, which were found to be lower
than 10%, excluding batch effects.
2.5. Statistical Analysis
Collected data was summarized and displayed as mean 
SD, Continuous values with non-Gaussian distributions
were compared by the Wilcoxon rank-sum or Mann-
Whitney U test. The 2 test was used to assess associa-
tions among categorical variables. Correlations between
the cholinesterase activities and exercise test parameters
were determined using the two-tailed Spearman rank
correlation. Significance was set at p < 0.05. Analyzing
data with the One-Sample Kolmogorov-Smirnov test yielded
a p-value of 0.001, indicating that AChE activity did not
distribute normally. SPSS/WIN (version 15.0, SPSS INC,
Chicago, IL, USA) software was used to carry out all
statistical analyses.
3. Results
Baseline clinical characteristics of study subjects are
listed in Table 1. The study cohort consisted of 403 sub-

Serum AChE Activities Predict Exercise Heart Rate Parameters of Asymptomatic Individuals 45
jects, 65% of whom were male. Men tended to have
slightly higher systolic and diastolic blood pressure. There
was no significant gender difference in the rates of sub-
jects with Diabetes mellitus, Dyslipidemia and active
smoking. Parameters of the heart rate profile during exer-
cise are shown in Table 2 .A gender difference is noted
when examining most parameters. Women had higher
basal heart rate prior to exercise but lower heart rate at the
end of exercise compared to men. Women also showed
lower exercise capacity but better heart rate recovery val-
ues 1, 2 and 5 minutes following exercise. Both total
Table 1. Baseline characteristics of study participants ac-
cording to gender.
Men
(n = 262)
Women
(n = 141) P
Characteristic
Age (years) 45.1 (10.6) 46.7 (9.8) 0.123
BMI (Kg/m2) 27.0 (3.8) 26.2 (5.2) 0.101
Systolic blood pressure
(mm Hg) 123.0 (12.5) 116.0 (12.9) < 0.001
Diastolic blood pressure
(mm Hg) 76.6 (6.7) 73.5 (7.5) < 0.001
Hypertension, % 33.6 20.6 0.006
Diabetes mellitus, % 6.1 2.2 0.087
Dyslipidemia, % 18.6 15.2 0.397
Current smokers, % 17.8 20.4 0.527
BMI body mass index, Data are presented as mean ± standard deviation.
cholinesterase activities and AChE activities were con-
siderably lower in females compared to male subjects (p <
0.001 for both AChE alone and AChE and BChE), pre-
Table 2. Exercise test variables.
Variable Men
(n = 262)
Women
(n = 141) P
Basal heart rate (beat/min) 69.3 (11.4) 72.7 (11.3) 0.004
Heart rate peak, (beat/min) 163.5 (12.1) 161.3 (11.8)0.081
Heart rate 1 min after
end of exercise (beat/min) 134.9 (12.6) 130.6 (14.1)0.002
Heart rate 2 min after end
of exercise (beat/min) 110.2 (13.7) 101.8 (17.3)< 0.001
Heart rate 5 min after
end of exercise (beat/min) 93.1 (11.0) 87.3 (10.8) < 0.001
Heart rate recovery
1 min (beat/min) 28.8 (9.3) 30.8 (10.2) 0.046
Heart rate recovery
2 min (beat/min) 53.2 (13.2) 59.5 (17.2) < 0.001
Heart rate recovery
5 min (beat/min) 70.4 (13.3) 73.9 (12.1) 0.011
Exercise capacity (MET) 14.2 (3.3) 10.8 (2.5) < 0.001
MET metabolic equivalent, Data are presented as mean ± standard deviation.
gender
FemaleMale
Mean Cholinergic Status
2000
1500
1000
500
0
Error bars: +/- 2 SE
(a)
gender
FemaleMale
Mean AChE
600
500
400
300
200
100
0
Error bars: +/- 2 SE
(b)
Figure 1. Association between gender and total cholinesterase
activity (a) and AChE activity (b).
senting an obvious gender difference (Figure 1). Tables
3 and 4 show the Spearman rank correlation coefficient
between exercise test variables and serum activity levels
of AChE and BChE. In men favorable HRR parameters
and the rate of heart rate increase during exercise (re-
flected in heart rate peak) were both negatively corre-
lated to AChE but not BChE serum activity levels. Rest-
ing HR was correlated to AChE in men but not women
whereas peak HR was significantly correlated to AChE
in women but not in men. Further, the absolute values of
decrease in heart rate 1, 2 and 5 minutes following exer-
cise were associated with lower activity levels of AChE.
Both men and women showed strong correlations be-
tween AChE activities and HR recovery, which were
more pronounced in women.
All of the tested subjects were close in their age and
mean body mass (Table 1), suggesting that diversities in
their serum cholinesterase activity levels reflect physio-
logical, rather than demographic parameters [32,33].

Serum AChE Activities Predict Exercise Heart Rate Parameters of Asymptomatic Individuals 46
Table 3. Spearman rank correlation between exercise test
variables and total cholinesterase activity in men.
AChE+BChE AChE
Correlation
coefficient
P Correlation
coefficient
P
Resting heart
rate, (beat/min) 0.102 0.100 0.210 0.0
01
Heart rate peak,
(beat/min) –0.113 0.069 –0.06 0.3
51
Increase in
heart rate –0.152 0.014 –0.181 0.0 05
Heart rate
recovery 1 min
(beat/min)
–0.073 0.243 –0.150 0.0
22
Heart rate
recovery 2 min
(beat/min)
–0.081 0.197 –0.157 0.0
16
Heart rate
recovery 5 min
(beat/min)
–0.141 0.026 –0.176 0.0
08
AChE acetylcholinesterase, BChE butyrylcholinesterase.
Stratification of subjects according to their measured
levels of AChE and total cholinesterase activities into
those having above and below mean serum activity levels
(Table 5) indicated significant differences. Thus, men
who had lower than mean enzyme levels also showed
better rates of increase in heart rate as compared with
those men who had higher than mean enzyme levels (p =
0.017). This cutoff also extended to HR recovery at 2 and
5 minutes. Women showed a similar dichotomy with re
gards to increase in heart rate, but their HR recovery
Table 4. Spearman rank correlation between exercise test
variables and total cholinesterase activity in women.
AChE+BChE AChE
Correlation
coefficient P Correlation coefficient P
Resting heart
rate, (beat/min) 0.065 0.447 0.07 0.431
Heart rate
peak,
(beat/min)
–0.191 0.024 –0.219 0.012
Increase in
heart rate –0.183 0.03 –0.254 0.004
Heart rate
recovery 1 min
(beat/min)
0.072 0.402 –0.246 0.005
Heart rate
recovery 2 min
(beat/min)
–0.089 0.298 –0.251 0.004
Heart rate
recovery 5 min
(beat/min)
–0.165 0.055 –0.264 0.003
AChE acetylcholinesterase, BChE butyrylcholinesterase.
Table 5. Comparison of subjects according to total choli-
nesterase activity above and below mean serum activity
level.
5a. Men
AChE and BChE
Below mean
AChE and
BChE Above
mean
P
(t-test)
Increase in
heart rate 97.6 (15.6) 93.2 (16.6) 0.017
Heart rate recov-
ery 1 min
(beat/min)
29.7(9.8) 27.8 (8.5) 0.105
Heart rate recov-
ery 2 min
(beat/min)
54.8 (13.1) 51.4 (13.1) 0.039
Heart rate recov-
ery 5 min
(beat/min)
72.8 (12.4) 67.7 (13.8) 0.002
5b. Women
Increase in
heart rate 91.5 (14.2) 86.7 (14.3) 0.047
Heart rate recov-
ery 1 min
(beat/min)
31.0 (9.2) 30.7 (11.2) 0.857
Heart rate recov-
ery 2 min
(beat/min)
61.2 (19.6) 57.7 (14.1) 0.238
Heart rate recov-
ery 5 min
(beat/min)
75.5 (11.5) 72.2 (12.6) 0.124
AChE acetylcholinesterase, BChE butyrylcholinesterase, Data are presented
as mean ± standard deviation.
values showed no significant correlation to cholinesterase
activities. In addition, subjects with heart rate recovery
below 20 beats/min had significantly higher AChE +
BChE activity levels (p = 0.004) and AChE activity level
(p = 0.001) compared to subjects with normal heart rate
recovery.
4. Discussion
Our findings, obtained in a cohort of apparently healthy
subjects, suggest that increased total cholinesterase ac-
tivities as measured in the peripheral blood correlate with
increased resting heart rate, attenuated heart rate increase
during exercise testing, and delayed heart rate recovery.
To the best of our knowledge, the present study is the
first to report a readily measurable serum marker for au-
tonomic cardiovascular imbalance.
The link between the autonomic nervous system and
cardiovascular mortality has been investigated thoroughly
in the last decade, with a multitude of studies indicating a
tight association between exercise testing parameters
among them resting heart rate, heart rate variability, heart
rate recovery after exercise, heart rate increase during
exercise and adverse cardiovascular outcome. Abnor-
malities in these parameters, which are believed to reflect
autonomic activity [20], have been shown in diverse

Serum AChE Activities Predict Exercise Heart Rate Parameters of Asymptomatic Individuals 47
study populations to be associated with sudden cardiac
death in asymptomatic men (resting heart rate and heart
rate recovery) [4,21], all cause mortality in cardiac pa-
tients (heart rate recovery) [5,22], and all cause mortality
and cardiovascular mortality correlated with attenuated
heart rate increase [6,23].
These exercise test parameters are postulated to reflect
ANS activity consisting mainly of parasympathetic con-
trol and to a lesser degree of sympathetic components
[20].Specifically, heart rate recovery and heart rate in-
crease during exercise are presumed to be mainly con-
trolled by the parasympathetic branch of the ANS [6]
whereas resting heart rate is determined by both sympa-
thetic and parasympathetic activities [24]. Considering
that parasympathetic activity is mediated via ACh release
from efferent vagal nerve discharge, we searched for
possible associations between the peripheral activity of
serum cholinesterases, AChE and BChE and exercise test
parameters. Our results clearly demonstrate for both
genders that decreased activity of AChE, most likely
reflecting increased peripheral ACh levels, was corre-
lated to faster heart rate recovery 1,2 and 5 minutes fol-
lowing cessation of exercise. Additionally, we found that
decreased AChE activity was correlated with a rapid
heart rate increase in both genders and more profoundly
so in women. Two findings which showed genders speci-
fity were that higher than average heart rate peak was
correlated to decreased AChE activity in women only
and that higher than average resting heart rate was asso-
ciated with increased AChE activity in men only. An-
other interesting observation was that using a cut point of
20 beats per minute we were able to stratify subjects into
two groups of significantly different AChE activity.
These results are in accordance with previous studies.
First, Kakinuma et al. [8] have shown that in a model of
acute myocardial ischemia, increasing local ACh secre-
tion in rat cardiomyocytes by electrical stimulation of the
vagal efferent nerve decreased infarct size via the PI3K/
Akt/HIF-1alpha pathway. Complementing this study, Ando
et al. [9] demonstrated, also in a rat model of myocardial
ischemia, that vagal nerve stimulation which elevates
release of ACh exerted antiarrhythmogenic effects ac-
companied by prevention of the loss of phosphorylated
Cx43 during acute myocardial infarction. In line with
these data, atria from elderly and diabetic patients were
shown to have locally reduced ACh secretion, thus re-
flecting impaired local parasympathetic activity [25].
Second, previous studies by Katz and coworkers have
characterized the systemic effect of AChE inhibition with
Pyridostigmine, a short-acting, brain-impenetrable re-
versible AChE inhibitor which only affects peripheral
cholinergic activity. The first study, in chronic heart fail-
ure (CHF) patients, showed marked improvement in
heart rate recovery [11] and a more recent work showed
that Pyridostigmine improved heart rate recovery and
resting heart rate in sedentary adults [10].
Strengths of our study include the exclusion of sub-
jects using beta blockers, since the issue of the potential
effects of beta blockers on heart rate recovery is still un-
resolved [29]. Previous studies used statistical adjustment
as a means of rectifying this effect, but we chose to re-
move this possible confounding factor altogether. Addi-
tionally, our study population consisted of relatively
young subjects without any overt cardiovascular disease
thus enabling us to characterize their total cholinesterase
activities with less possible confounding factors as would
be expected in patients with known cardiovascular dis-
ease. Finally, heart rate recovery is a modifiable factor as
was previously shown in exercise training of cardiovas-
cular patients [30,31] and with pharmacological therapy
with AChE inhibition as noted above.
The limitations of our study involve our ignoring of
psychological and/or inflammatory confounding factors;
thus, higher than average serum AChE activity may be
due to a transient anxiety state [32] or reflect the out-
come of infection [12], in which case it would not nec-
essarily predict cardiovascular risk. Additionally, inher-
ited and/or experience-derived changes in the total cho-
linesterase activities may be caused by polymorphisms in
these and/or other genes, e.g. paraoxonase [33] or by
altered micro-RNA levels under stress [34,35]. The ap-
parent associations between serum cholinesterase activi-
ties and cardiovascular parameters thus merit further
in-depth studies.
5. Conclusions
Our study links heart rate parameters during exercise
testing to a simple, measurable serum marker. We be-
lieve that our findings provide important additional in-
sights into the pathophysiology of ANS dysfunction in
cardiovascular disease. In view of previous research our
findings suggest a possible future avenue for novel ther-
apy modalities of autonomic imbalance. Future studies
will be needed to evaluate the added prognostic signifi-
cance gained by implementing this marker into routine
practice.
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