ORIGINAL RESEARCH ARTICLE
published: 05 September 2011
Heart rate dynamics after exercise in cardiac patients with
and without type 2 diabetes
Victor R. Neves1,2,Antti M. Kiviniemi1,Arto J. Hautala1, Jaana Karjalainen3, Olli-Pekka Piira3,Aparecida
M. Catai2,Timo H. Mäkikallio3, HeikkiVeli Huikuri3and Mikko P .Tulppo1,3*
1Department of Exercise and Medical Physiology, Verve, Oulu, Finland
2Department of Physiotherapy, Federal University of São Carlos, São Carlos, Brazil
3Department of Internal Medicine, Institute of Clinical Medicine, University of Oulu, Oulu, Finland
Jaakko Hartiala,Turku University
Antti Saraste, University ofTurku,
Petri Haapalahti, HUSLAB, Finland
Tomi Laitinen, University of Eastern
Finland and Kuopio University
Mikko P .Tulppo, Department of
Exercise and Medical Physiology,
Verve, P .O. Box 404, FI-90101 Oulu,
Purpose: The incidence of cardiovascular events is higher in coronary artery disease
patients with type 2 diabetes (CAD+T2D) than in CAD patients without T2D. There is
increasing evidence that the recovery phase after exercise is a vulnerable phase for var-
ious cardiovascular events. We hypothesized that autonomic regulation differs in CAD
patients with and without T2D during post-exercise condition. Methods: A symptom-
limited maximal exercise test on a bicycle ergometer was performed for 68 CAD+T2D
patients (age 61±5years, 78% males, ejection fraction (EF) 67±8, 100% on β-blockade),
and 64 CAD patients (age 62±5years, 80% males, EF 64±8, 100% on β-blockade). Heart
rate (HR) recovery after exercise was calculated as the slope of HR during the first 60s
after cessation of exercise (HRRslope). R–R intervals were measured before (5min) and
after exercise from 3 to 8min, both in a supine position. R–R intervals were analyzed using
time and frequency methods and a detrended fluctuation method (α1). Results: BMI was
30±4 vs. 27±3kgm2(p <0.001); maximal exercise capacity, 6.5±1.7 vs. 7 .7±1.9 METs
(p <0.001); maximal HR, 128±19 vs. 132±18bpm (p =ns); and HRRslope, −0.53±0.17
vs. −0.62±0.15beats/s (p =0.004), for CAD patients with and withoutT2D, respectively.
There was no differences between the groups in HRRslopeafter adjustment for METs, BMI,
and medication (ANCOVA, p =0.228 for T2D and, e.g., p =0.030 for METs). CAD+T2D
patients had a higher HR at rest than non-diabetic patients (57±10 vs. 54±6bpm,
p =0.030), but no other differences were observed in HR dynamics at rest or in post-
exercise condition. Conclusion:HR recovery is delayed in CAD+T2D patients, suggesting
impairment of vagal activity and/or augmented sympathetic activity after exercise. Blunted
closely related to low exercise capacity and obesity than toT2D itself.
Keywords: heart rate recovery, type 2 diabetes, autonomic regulation
disease patients (CAD) with type 2 diabetes (T2D) than in CAD
differences are not well known. Altered autonomic regulation is
one potential mechanism resulting in the increased number of
cardiovascular events in CAD+T2D patients (Okada et al.,2010;
Pop-Busui et al., 2010; Lanza et al., 2011). Autonomic regulation
can be studied using various methods at the laboratory,or ambu-
latory condition tests such as passive head-up tilt and handgrip
tests (Montano et al., 1994; Tulppo et al., 2001, 2005; Fu et al.,
2002), or ambulatory heart rate (HR) variability and blood pres-
sure measurements (Pagani et al., 1985; Kleiger et al., 1987; Piira
et al., 2011). Analysis of autonomic regulation during and after
exercise has also been used in various physiological (Yamamoto
et al., 1991; Gregoire et al., 1996; Tulppo et al., 1996, 1998b) and
clinical settings (Cole et al., 1999, 2000; Jouven and Ducimetiere,
2000; Jouven et al., 2005; Kiviniemi et al., 2011).
There is increasing evidence that the recovery phase after exer-
cise is a vulnerable phase for various cardiovascular events. Case-
crossover studies have shown that exercise as a trigger of acute
myocardial infarction is not limited to the time of exercise, but
extends for a certain time period after cessation of physical activ-
ity (Siscovick et al., 1982, 1984; Albert et al., 2000; von Klot et al.,
2008). Similarly, the risk of sudden cardiac death is transiently
increased in the 30-min after vigorous exercise, and atrial fibril-
lation episodes occur more commonly after rather than before
exercise (Siscovick et al., 1982, 1984; Coumel, 1994; Albert et al.,
2000; Huikuri,2008). Measurement of autonomic function in the
very early phase of recovery after exercise has also provided prog-
nostic information. For example, delayed HR recovery 1–2min
after exercise has been shown to predict cardiovascular events in
the general population and in various patient groups and animal
studies (Cole et al., 1999; Lauer and Froelicher, 2002; Nissinen
et al., 2003; Jouven et al., 2005; Smith et al., 2005). Recently, we
during the recovery phase of exercise (Tulppo et al., 2011), which
September 2011 | Volume 2 | Article 57 | 1
Neves et al. Heart rate recovery after exercise
may partly explain the clustering of various cardiovascular events
in the recovery phase of exercise.
The present research was designed to study the behavior of
HR dynamics during exercise and in the recovery phase of exer-
cise in CAD patients with and without T2D, matched for age,
ejection fraction (EF), and sex. We hypothesized that autonomic
MATERIALS AND METHODS
SUBJECTS AND STUDY PROTOCOL
The present study was conducted in the Department of Exercise
and Medical Physiology at Verve (Oulu, Finland) and Oulu Uni-
ARTEMIS (Innovation to Reduce Cardiovascular Complications
of Diabetes at the Intersection) study database who had stable
CAD without (n =64) and with T2D (n =68). The exclusion cri-
teria were inability to perform the exercise stress test, unstable
angina at the time of recruitment, advanced age (>75years), a
recent (<6months) myocardial infarction, severe nephropathy,
heart failure, scheduled cardiac revascularization therapy, T2D
autonomic neuropathy, dementia, alcoholism, drug abuse, or any
consent. CAD was documented by coronary angiography and
T2D was verified by oral glucose tolerance test according to cur-
rent recommendations (WHO, 1999). The study was performed
according to the Declaration of Helsinki, the local committees of
research ethics in the Northern Ostrobothnia Hospital District
(Oulu, Finland) approved the protocol, and all the subjects gave
written informed consent.
The laboratory measurements were performed in the Depart-
The patients were not allowed to eat or consume caffeine for 3h
before the tests. Physical exercise and use of alcohol were prohib-
ited for 24h before testing. Electrocardiography (ECG) and R–R
intervals were collected for 10min at supine rest, during exercise,
and 10min after exercise in supine position. Breathing was spon-
taneous in all phases. A capillary blood sample was obtained for
analysis of HbA1c concentration before testing (Afinion™AS100,
Axis-Shield PoC AS, Oslo, Norway).
EXERCISE STRESS TEST
The patients performed an incremental maximal test on a bicy-
cle ergometer (Monark Ergomedic 839 E; Monark Exercise AB,
Vansbro, Sweden), starting at 30W with the work rate increasing
at a rate of 10 and 15W every 1min until exhaustion for females
and males, respectively. The patients moved to the supine posi-
tion within 30s after cessation of exercise. The patients were not
allowed to move or talk during the recovery phase.
Ventilation (VE) and gas exchange (M909 Ergospirometer,
Medikro, Kuopio, Finland) were measured and reported as the
mean value for every minute. The highest 1-min mean value
of oxygen consumption was expressed as the peak oxygen con-
sumption (VO2peak). Maximal workload (W) and maximal METs
were calculated as average workload and METs during the last
1min of the test. ECG was monitored and recorded using a
standard 12-lead ECG (GE Healthcare, Cam-14, Waukesha, WI,
USA) and at the same time R–R intervals were recorded with
a Polar R–R recorder with a sampling frequency of 1,000Hz
(Polar Electro, Kempele, Finland). Blood pressure was mea-
sured with an electronic sphygmomanometer (Tango, Sun-Tech,
Raleigh, NC, USA) at rest and during exercise testing. The
patients were encouraged to reach a symptom-limited maxi-
mal workload, and exercise was stopped if ST depression was
The maximal HR was calculated as a mean value of 5 R–R
intervals before cessation of exercise from Polar R–R interval data
and converted to maximal HR in beats/min with the following
equation: maximal HR (beats/min)=60·(mean R–R interval in
by chronotropic response index (CRI) with the following equa-
HR)−1(Kiviniemi et al., 2011), and HR reserve as maximal
HR−resting HR. HR recovery values were calculated as mean
values of 5 R–R intervals around the time points of 15 (HRR15),
30 (HRR30), 60 (HRR60), and 120 (HRR120)s after cessation of
exercise from Polar data. Thereafter,HR recovery (beats/min) was
calculated as the change in HR from maximal HR to recovery
HR at the time points of 15, 30, 60, and 120s after cessation
of exercise. The slope of HR during the 60-s after cessation of
exercise (HRRslope) was calculated by linear model using above
described HR values at the maximum and 15, 30, and 60s time
points (Figure 1).
HEART RATE VARIABILITY
R–R intervals were analyzed from the last 5-min period at rest,
at every load during exercise (1-min periods), and from 3 to
8min (5-min) after exercise. Before HR variability analysis (using
FIGURE 1 | Example of heart rate recovery as the slope of heart rate
during the first 60s after cessation of exercise for two patients (with
and without type 2 diabetes) with similar age and maximal heart rate.
The slope was calculated by linear model using mean values of 5 R–R
intervals [converted to the HR values in beats/min as 60·(mean R–R interval
in ms/100)−1] at maximum and around the time points of 15, 30, and 60s
after cessation of exercise.
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September 2011 | Volume 2 | Article 57 | 2
Neves et al.Heart rate recovery after exercise
Polar R–R data), all of the R–R intervals were edited manually
to exclude all premature beats and noise, which accounted for
<8% in every subject. ECG data was used during the editing to
confirm sinus origin of the beats. An autoregressive model was
used to estimate the power spectrum densities of HR variability
after period level detrending (Huikuri et al., 1996; Tulppo et al.,
1996). The power spectra were quantified by measuring the area
under two frequency bands: LF power (0.04–0.15Hz) and HF
power (0.15–0.4Hz). Details of the spectrum analyses have been
described previously elsewhere (Task Force of the European Soci-
ety of Cardiology and the North American Society of Pacing and
Electrophysiology, 1996). Detrended fluctuation analysis (DFA)
method was used to calculate fractal-like correlation properties
of the R–R interval data (Peng et al., 1995; Iyengar et al., 1996).
In this study the short-term (4–11beats) scaling exponent (α-1)
was calculated based on previous experiments (Mäkikallio et al.,
The data were presented as mean±SD. The normal Gaussian dis-
tribution of the data was verified with the Kolmogorov–Smirnov
goodness-of-fit test (z value>1.0). For repeated measurements
of post-exercise HR recovery (HRR15, HRR30, HRR60, HRR120),
followed by post hoc comparison (unpaired t-test). Significant
post hoc differences in HR recovery between the groups were
adjusted for maximal METs, BMI, and medications (calcium
antagonists and nitrates) using ANCOVA. For other variables,the
CAD and CAD+T2D groups in normally distributed data. The
Mann–Whitney U-test was used to assess the difference in HR
variability indices between groups. The Chi-square test was used
for categorical variables. The data were analyzed using SPSS soft-
ware (SPSS 19.0, SPSS Inc., Chicago, USA). A p-value<0.05 was
considered statistically significant.
The characteristics of the study population, including compar-
isons between diabetic and non-diabetic patients, are given in
Table 1. The diabetic patients’ body composition, e.g., weight
(p <0.001), waist circumference (p <0.001), BMI (p <0.001),
and HbA1c (p <0.001) differed from that of the non-diabetic
patients. However, blood pressure, EF, history of infarction, and
revascularization or smoking did not differ between the diabetic
and non-diabetic patients (Table 1). Medication did not differ
between the groups,except that calcium antagonists,nitrates,and
antidiabetics were more common among the diabetic than the
non-diabetic patients (Table 1).
HR RESPONSE TO MAXIMAL EXERCISE
The results of the maximal exercise test, including comparisons
between diabetic and non-diabetic patients, are given in Table 2.
Maximal exercise capacity was lower (p <0.001) in the diabetes
patients, but maximal HR (p =0.178) was at the same level com-
pared with the non-diabetic patients (Table 2). HR reserve was
smaller (p =0.027) and CRI tended to be smaller (p =0.057) in
Table 1 | Characteristics of patients.
CAD+T2D (n =68)CAD (n =64)p-Level
Values are mean±SD. BMI, body mass index; HbA1c, Glycosylated hemoglo-
bin; SBP , systolic blood pressure; DBP , diastolic blood pressure; HR, heart rate;
AMI, acute myocardial infarction; NSTEMI, no-ST segment elevation myocardial
infarction; STEMI, ST segment elevation myocardial infarction; revascularized, the
patients who had at least one of the procedures (CABG, coronary artery by-pass
grafting or PCI, Percutaneus coronary intervention); LVEF , left ventricular ejec-
tion fraction; ACEI, angiotensin conversion enzyme inhibitor; AT2, angiotensin II
disease with type 2 diabetes.
the diabetic patients than in the non-diabetic patients. However,
or CRI after adjustment for maximal METs, BMI, and medica-
tion,e.g.,forHRreserveANCOVAp =0.686,p <0.001,p =0.126,
and p =0.169 for diabetes, Mets, BMI, and calcium antagonists,
respectively. There was no difference between the groups in the
Type 2 diabetes modified post-exercise HR recovery (main effect
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Neves et al.Heart rate recovery after exercise
Table 2 | Maximal exercise capacity and heart rate recovery.
CAD+T2D (n =68) CAD (n =64)p-Level
Max load (W)
Max HR (bpm)
HR reserve (bpm)
Slope 60 (beats/s)
Values are mean±SD. METs, metabolic equivalents; VO2peak, peak uptake
oxygen; HR, heart rate; CRI, maximal chronotropic response index.
delayed HRR60 (p =0.006), HRR120 (p =0.037), and HRRslope
(p =0.004) compared with the non-diabetic patients (Table 2).
However, there were not significant differences between groups
in HRR60, HRR120, or HRRslopeafter adjustment for maximal
METs,BMI,and medication,e.g.,for HRR60ANCOVA p =0.223,
p =0.061, p =0.387, and p =0.094 for diabetes, Mets, BMI, and
calcium antagonists, respectively. The corresponding p values for
HRR120were p =0.980, p =0.001, p =0.451, and p =0.006 and
for HRRslopep =0.228, p =0.030, p =0.404, and p =0.079 for
did not modify HR behavior between groups at any condition.
Examples of HRRslopefor non-diabetic and diabetic subjects are
shown in Figure 1.
HR AND HR VARIABILITY AT REST, DURING SUBMAXIMAL EXERCISE
AND AFTER EXERCISE
Heart rate and HR variability before and after exercise, includ-
ing comparisons between diabetic and non-diabetic patients, are
given in Table 3. Five diabetic patients were excluded from the
analysis due to the significant number of extra systoles or techni-
excluded due to the extra systoles in both pre- and post-exercise
conditions and one in post-exercise condition due to the same
The diabetic patients had a higher HR in resting condition
than the non-diabetic patients (p =0.030), but no other differ-
maximalexerciseatthelevelsof 40,60,or80%of maximaloxygen
uptake, e.g., HR was 92±12 vs. 95±14bpm (p =0.099) and α1
1.02±0.37 vs. 1.02±0.32 (p =0.93) at the level of 61±5% and
61±5% of maximal oxygen uptake for diabetic and non-diabetic
Table 3 |Average values of linear and non-linear heart rate variability
before exercise (5min) and in post-exercise condition from 3 to 8min
after exercise, both in supine position.
HF power (ms2)
LF power (ms2)
HF power (ms2)
LF power (ms2)
Values are mean±SD. HR, heart rate; SDNN, SD of normal-to-normal R–R inter-
vals; HF , high frequency power of R–R intervals; LF , low frequency power of R–R
intervals; α-1, fractal scaling exponent of R–R intervals.
The present study showed that post-exercise HR recovery was
impairment of vagal modulation and/or augmented sympathetic
activity initially after exercise for diabetic patients. The impaired
HR recovery in diabetic patients was the most obvious 1min after
exercise, documented by HRR60and HRRslopeindices. However,
blunted HR recovery initially after exercise in diabetic patients
compared with non-diabetic patients was more closely related to
these findings suggest that delayed HR recovery after exercise in
including, e.g., regular exercise and weight management.
POST-EXERCISE HR DYNAMICS
The interplay between sympathetic and vagal regulation of HR
during exercise is organized in a reciprocal fashion, i.e., increased
sympathetic activity is accompanied by decreased vagal activity in
the heart during dynamic exercise (Robinson et al., 1966; Maciel
et al., 1986; Orizio et al., 1988; Yamamoto and Hughson, 1991;
Tulppo et al., 1996, 1998b). However, this reciprocal behavior
is altered in the recovery phase after exercise due to temporal
differences in the recovery pattern of the autonomic arms in post-
exercise condition (Tulppo et al., 2011). A rapid restoration of
vagal activity occurs after cessation of exercise (Imai et al., 1994;
Goldberger et al., 2006; Martinmaki and Rusko, 2008; Tulppo
et al., 2011). On the contrary, the sympathetic nervous system
seems to have a longer latency to return to the baseline after
pathetic activity (Ray, 1993; Tulppo et al., 2011). Taken together,
these changes in autonomic regulation may result in dual activa-
tion of the sympathetic and vagal arms in post-exercise condition
Frontiers in Physiology | Clinical andTranslational Physiology
September 2011 | Volume 2 | Article 57 | 4
Neves et al.Heart rate recovery after exercise
exercise condition may partly explain the clinical findings, since
particularly the recovery phase of exercise has been shown to be a
1982, 1984; Albert et al., 2000; von Klot et al., 2008).
It is well known that CAD+T2D patients are at a higher risk
for cardiac events than CAD patients without diabetes. Altered
autonomic regulation in post-exercise condition is one poten-
tial mechanism, since slow HR recovery after exercise has also
been associated with cardiovascular events in various clinical and
subclinical populations (Cole et al., 1999; Lauer and Froelicher,
2002; Nissinen et al., 2003; Jouven et al., 2005). In the present
study, HR recovery from 1 to 2min after exercise was the only
cardiac patients matched with age, sex, and EF all in optimal
medications, including β-blockade. Since a complex interaction
of autonomic regulation occurs in the initial phase after exercise,
it is difficult to detect the difference in HR recovery between dia-
betic and non-diabetic patients due to impaired vagal activation
echolamines have an important contribution for the sympathetic
were no differences between patients groups in HR recovery after
exercise training and weight management as potential treatments
to improve post-exercise HR recovery in CAD+T2D patients.
Importantly, also calcium antagonists modified HR recovery par-
ticularly 2min after exercise. Patients with calcium antagonists
usually have more severe hypertension which is associated with
delayed HR recovery (Carnethon et al., 2011).
HR RESPONSE TO MAXIMAL EXERCISE
Measurement of the chronotropic response of HR to exercise
has been used to assess particularly sympathetic influence on the
heart and it has been shown to be a powerful predictor of car-
diac mortality in both asymptomatic populations (Azarbal et al.,
2004; Gulati et al., 2005; Jouven et al., 2005; Savonen et al., 2006;
(Myers et al., 2007; Savonen et al., 2008; Kiviniemi et al., 2011).
In the present study HR reserve was lower and the maximal
chronotropic response adjusted for age (CRI) tended to be lower
in CAD+T2D patients than in CAD patients without diabetes.
However, there were no differences between patients groups in
these indices after adjustment for fitness and BMI.
Type 2 diabetes has been shown to decrease HR variability and
baroreflex sensitivity in T2D patients without CAD (Masaoka
et al.,1985; Frattola et al.,1997). There are previous studies where
T2D has shown no additional decrease in baroreflex sensitivity
among patients with CAD (Wykretowicz et al., 2005) or in HR
and Aronson, 2001; Kiviniemi et al., 2010). Also in the present
study the short-term HR variability indices measured at resting
or post-exercise condition were not able to separate CAD patients
with and without T2D. There are several potential explanations
for these findings. First, the populations are carefully matched
according to age, sex, EF, and β-blockade which all are known
to effect on HR variability and may partly explain the present
findings. Secondly, short-term HR variability measures at labora-
tory condition are not so well reproducible than 24-h recordings
(Huikuri et al., 1990; Tulppo et al., 1998b) and may be influ-
enced by“white coat”effects in some subjects (Grassi et al.,1999).
Thirdly, high level of circulating norepinephrine particularly in
post-exercise condition may results in abrupt changes in beat-to-
beat R–R interval dynamics which are not detected by used HR
variability methods (Tulppo et al., 1998a). On the contrary to
HR variability measurements at rest or few minutes after exer-
cise, rapid and marked changes occurs in both autonomic arms
in tens of seconds from sympathetic dominance to restoration
of vagal activity resulting decreased HR after exercise (Tulppo
after maximal exercise is the major candidate to explain differ-
ences in HR recovery between diabetic and non-diabetic patient
The measurements of the present study were performed under
continued prescribed medication because of ethical reasons
and the well known withdrawal effect of beta-block cessation.
However,the present results will have more practical implications
when the analyses are performed at a time when the patients are
on their normal medication.
Based on the present study, it is important to emphasize the role
of physical exercise in maintaining good cardiovascular function,
improving physical performance, and losing weight. Although all
the patients were on optimized medication, it is important to
be given priority similar to other preventive medications (Chow
et al., 2010).
separating CAD patients with and without T2D in the modern
rest, during exercise, or in post-exercise condition. HR recovery
is delayed in CAD+T2D patients compared with CAD patients
without T2D,suggesting impairment of vagal activity and/or aug-
mented sympathetic activity after exercise. However, blunted HR
recovery initially after exercise in diabetic patients compared with
non-diabetic patients is more closely related to exercise capacity
and obesity than to T2D itself.
This work was supported by grants from the Finnish Technology
Development Centre (TEKES. Helsinki. Finland), Paavo Nurmi
Foundation, Turku, Finland, Polar Electro Oy, Kempele, Finland
and Hur Oy, Kokkola, Finland, and the National Council for Sci-
entific and Technological Development, Brasília, Brazil. (proc.
September 2011 | Volume 2 | Article 57 | 5
Neves et al. Heart rate recovery after exercise
Albert, C. M., Mittleman, M. A., Chae,
C. U., Lee, I. M., Hennekens, C. H.,
and Manson,J. E. (2000). Triggering
of sudden death from cardiac causes
Azarbal, B., Hayes, S. W., Lewin, H. C.,
Hachamovitch, R., Cohen, I., and
Berman, D. S. (2004). The incre-
mental prognostic value of percent-
age of heart rate reserve achieved
over myocardial perfusion single-
photon emission computed tomog-
raphy in the prediction of cardiac
death and all-cause mortality: supe-
riority over 85% of maximal age-
predicted heart rate. J. Am. Coll.
Cardiol. 44, 423–430.
Burger, A. J., and Aronson, D. (2001).
Effect of diabetes mellitus on heart
rate variability in patients with con-
gestive heart failure. Pacing Clin.
Electrophysiol. 24, 53–59.
Carnethon, M. R., Sternfeld, B., Liu,
K., Jacobs, D. R. Jr., Schreiner,
P. J., Williams, O. D., Lewis, C.
E., and Sidney, S. (2011). Corre-
lates of heart rate recovery over
20 years in a healthy population
sample. Med. Sci. Sports Exerc. doi:
[Epub ahead of print].
Chow, C. K., Jolly, S., Rao-Melacini, P.,
(2010). Association of diet, exercise,
and smoking modification with risk
of early cardiovascular events after
acute coronary syndromes. Circula-
tion 121, 750–758.
Cole, C. R., Blackstone, E. H., Pashkow,
F. J., Snader, C. E., and Lauer, M. S.
(1999). Heart-rate recovery imme-
diately after exercise as a predictor
of mortality. N. Engl. J. Med. 341,
Cole, C. R., Foody, J. M., Blackstone,
E. H., and Lauer, M. S. (2000).
Heart rate recovery after submaxi-
mal exercise testing as a predictor
of mortality in a cardiovascularly
healthy cohort. Ann. Intern. Med.
Coumel, P. (1994). Paroxysmal atrial
fibrillation: a disorder of autonomic
tone? Eur. Heart J. 15(Suppl. A),
Frattola, A., Parati, G., Gamba, P.,
Paleari, F., Mauri, G., Di Rienzo,
M., Castiglioni, P., and Mancia, G.
(1997). Time and frequency domain
estimates of spontaneous barore-
flex sensitivity provide early detec-
tion of autonomic dysfunction in
diabetes mellitus. Diabetologia 40,
Fu, Q., Levine, B. D., Pawelczyk, J. A.,
Ertl, A. C., Diedrich, A., Cox, J. F.,
Zuckerman, J. H., Ray, C. A., Smith,
Y., Mano, T., Zhang, R., Iwasaki, K.,
Lane, L. D., Buckey, J. C. Jr., Cooke,
W. H., Robertson, R. M., Baisch,
F. J., Blomqvist, C. G., Eckberg, D.
L., Robertson, D., and Biaggioni, I.
(2002). Cardiovascular and sympa-
thetic neural responses to handgrip
and cold pressor stimuli in humans
before, during and after spaceflight.
J. Physiol. (Lond.) 544, 653–664.
Goldberger, J. J., Le, F. K., Lahiri,
M., Kannankeril, P. J., Ng, J., and
Kadish, A. H. (2006). Assessment of
parasympathetic reactivation after
exercise. Am. J. Physiol. Heart Circ.
Physiol. 290, H2446–H2452.
Grassi, G., Turri, C.,Vailati, S., Dell’oro,
R., and Mancia, G. (1999). Mus-
cle and skin sympathetic nerve traf-
fic during the “white-coat” effect.
Circulation 100, 222–225.
Hughson, R. L. (1996). Heart rate
variability at rest and exercise: influ-
ence of age, gender, and physical
training. Can. J. Appl. Physiol. 21,
Gulati, M., Black, H. R., Shaw, L. J.,
Arnsdorf, M. F., Merz, C. N., Lauer,
M. S., Marwick, T. H., Pandey, D.
K., Wicklund, R. H., and Thisted,
R. A. (2005). The prognostic value
of a nomogram for exercise capac-
ity in women. N. Engl. J. Med. 353,
Haffner, S. M., Lehto, S., Rönnemaa, T.,
Pyorälä, K., and Laakso, M. (1998).
Mortality from coronary heart dis-
ease in subjects with type 2 dia-
betes and in nondiabetic subjects
with and without prior myocardial
infarction. N. Engl. J. Med. 339,
Huikuri, H. V. (2008). Heart rate
dynamics as a marker of vulnerabil-
Electrophysiol. 19, 913–914.
Huikuri, H. V., Kessler, K. M., Terracall,
E., Castellanos, A., Linnaluoto, M.
K., and Myerburg, R. J. (1990).
rhythm of heart rate variability in
healthy subjects. Am. J. Cardiol. 65,
Huikuri, H. V., Seppanen, T., Koisti-
nen, M. J., Airaksinen, J., Ikaheimo,
M. J., Castellanos, A., and Myer-
burg, R. J. (1996). Abnormalities
in beat-to-beat dynamics of heart
rate before the spontaneous onset
of life-threatening ventricular tach-
yarrhythmias in patients with prior
myocardial infarction. Circulation
Inoue, M., and Kamada, T. (1994).
Vagally mediated heart rate recov-
ery after exercise is accelerated in
athletes but blunted in patients with
chronic heart failure. J. Am. Coll.
Cardiol. 24, 1529–1535.
Iyengar, N., Peng, C. K., Morin, R.,
Goldberger, A. L., and Lipsitz, L. A.
fractal scaling of cardiac interbeat
interval dynamics. Am. J. Physiol.
Jouven, X., and Ducimetiere, P. (2000).
Recovery of heart rate after exercise.
N. Engl. J. Med. 342, 662–663.
Jouven, X., Empana, J. P., Schwartz, P.
J., Desnos, M., Courbon, D., and
Ducimetiere, P. (2005). Heart-rate
profile during exercise as a predic-
tor of sudden death. N. Engl. J. Med.
Junttila, M. J., Barthel, P., Myerburg,
R. J., Makikallio, T. H., Bauer, A.,
Ulm, K., Kiviniemi, A., Tulppo,
M., Perkiomaki, J. S., Schmidt, G.,
and Huikuri, H. V. (2010). Sud-
den cardiac death after myocar-
dial infarction in patients with
type 2 diabetes. Heart Rhythm 7,
Kiviniemi,A. M., Tiinanen, S., Hautala,
A. J., Seppanen, T., Norton, K. N.,
Frances,M. F.,Nolan,R. P.,Huikuri,
H.V.,Tulppo,M. P.,and Shoemaker,
J. K. (2010). Low-frequency oscilla-
vascular risk. Auton. Neurosci. 158,
A. J., Makikallio, T. H., Perkiomaki,
J. S., Seppanen, T., and Huikuri, H.
V. (2011). Long-term outcome of
patients with chronotropic incom-
petence after an acute myocar-
Kleiger, R. E., Miller, J. P., Bigger, J. T.
heart rate variability and its associ-
ation with increased mortality after
acute myocardial infarction. Am. J.
Cardiol. 59, 256–262.
Krock,L. P.,and Hartung,G. H. (1992).
plasma catecholamines, blood pres-
sure and heart rate in normal sub-
jects. Clin. Auton. Res. 2, 89–97.
Lanza, G. A., Barone, L., Scalone,
G., Pitocco, D., Sgueglia, G. A.,
Mollo, R., Nerla, R., Zaccardi, F.,
Ghirlanda, G., and Crea, F. (2011).
adjuvant influenza A vaccination on
platelet activation and cardiac auto-
nomic function. J. Intern. Med. 269,
Lauer, M. S., and Froelicher, V. (2002).
Abnormal heart-rate recovery after
exercise. Lancet 360, 1176–1177.
A.,Lima Filho,E. C.,and Martins,L.
E. (1986). Autonomic nervous con-
Ann. Med. 43,
Niemelä, M., Airaksinen, K. E.,
Tulppo, M., and Huikuri, H. V.
to beat complexity of heart rate
myocardial infarction. J. Am. Coll.
Cardiol. 28, 1005–1011.
Martinmaki, K., and Rusko, H. (2008).
Time-frequency analysis of heart
rate variability during immediate
exercise. Eur. J. Appl. Physiol. 102,
Masaoka, S., Lev-Ran, A., Hill, L. R.,
Vakil, G., and Hon, E. H. (1985).
Heart rate variability in diabetes:
relationship to age and duration
of the disease. Diabetes Care 8,
Montano, N., Ruscone, T. G., Porta,
A., Lombardi, F., Pagani, M., and
Malliani,A. (1994). Power spectrum
analysis of heart rate variability to
assess the changes in sympathovagal
balance during graded orthostatic
tilt. Circulation 90, 1826–1831.
Myers, J., Tan, S. Y., Abella, J., Aleti, V.,
ison of the chronotropic response to
exercise and heart rate recovery in
predicting cardiovascular mortality.
Eur. J. Cardiovasc. Prev. Rehabil. 14,
Nissinen, S. I., Makikallio, T. H., Sep-
panen, T., Tapanainen, J. M., Salo,
M., Tulppo, M. P., and Huikuri, H.
V. (2003). Heart rate recovery after
exercise as a predictor of mortality
among survivors of acute myocar-
dial infarction. Am. J. Cardiol. 91,
Okada, N., Takahashi, N., Yufu, K.,
Murozono, Y., Wakisaka, O., Shi-
nohara, T., Anan, F., Nakagawa,
M., Hara, M., Saikawa, T., and
Yoshimatsu, H. (2010). Baroreflex
sensitivity predicts cardiovascular
events in patients with type 2
diabetes mellitus without struc-
tural heart disease. Circ. J. 74,
Orizio, C., Perini, R., Comande, A.,
steinas, A. (1988). Plasma cate-
cholamines and heart rate at the
beginning of muscular exercise in
man. Eur. J. Appl. Physiol. Occup.
Physiol. 57, 644–651.
Pagani, M., Furlan, R., Lombardi, F.,
Pizzinelli, P., Lanzi, G., Castelli,
P., Cerutti, S., Santoli, C., and
Malliani, A. (1985). Technique for
24 hour recording of continuous
high fidelity arterial pressure and
electrocardiogram in ambulatory
patients. Clin. Exp. Hypertens. A 7,
Frontiers in Physiology | Clinical andTranslational Physiology
September 2011 | Volume 2 | Article 57 | 6
Neves et al. Heart rate recovery after exercise Download full-text
Peng, C. K., Havlin, S., Stanley, H. E.,
and Goldberger,A. L. (1995). Quan-
tification of scaling exponents and
crossover phenomena in nonsta-
tionary heartbeat time series. Chaos
Piira, O. P., Huikuri, H. V., and Tulppo,
M. P. (2011). Effects of emotional
excitement on heart rate and blood
pressure dynamics in patients with
coronary artery disease.Auton. Neu-
rosci. 160, 107–114.
Pop-Busui, R., Evans, G. W., Gerstein,
H. C., Fonseca, V., Fleg, J. L., Hoog-
werf, B. J., Genuth, S., Grimm, R.
H., Corson, M. A., and Prineas, R.
dysfunction on mortality risk in the
action to control cardiovascular risk
in diabetes (ACCORD) trial. Dia-
betes Care 33, 1578–1584.
Ray, C. A. (1993). Muscle sympathetic
nerve responses to prolonged one-
legged exercise. J. Appl. Physiol. 74,
Robinson,B. F.,Epstein,S. E.,Beiser,G.
D., and Braunwald, E. (1966). Con-
trol of heart rate by the autonomic
nervous system. Studies in man on
tor mechanisms and exercise. Circ.
Res. 19, 400–411.
Savonen, K. P., Kiviniemi, V., Laukka-
nen, J. A., Lakka, T. A., Rauramaa,
T. H., Salonen, J. T., and Rauramaa,
R. (2008). Chronotropic incompe-
tence and mortality in middle-aged
men with known or suspected coro-
nary heart disease. Eur. Heart J. 29,
Savonen, K. P., Lakka, T. A., Laukka-
nen, J. A., Halonen, P. M., Raura-
maa, R. (2006). Heart rate response
during exercise test and cardiovas-
Eur. Heart J. 27, 582–588.
Siscovick,D. S.,Weiss,N. S.,Fletcher,R.
H., and Lasky, T. (1984). The inci-
dence of primary cardiac arrest dur-
Siscovick, D. S., Weiss, N. S., Hall-
D. R. (1982). Physical activity and
primary cardiac arrest. JAMA 248,
Smith, L. L., Kukielka, M., and Billman,
G. E. (2005). Heart rate recovery
after exercise: a predictor of ventric-
ular fibrillation susceptibility after
myocardial infarction. Am. J. Phys-
iol. Heart Circ. Physiol. 288, H1763–
Task Force of the European Society of
Cardiology and the NorthAmerican
Society of Pacing and Electrophysi-
ology. (1996). Heart rate variability.
Standards of measurement, physi-
ological interpretation, and clinical
use. Eur. Heart J. 17, 354–381.
Makikallio, T. H., Airaksinen, K.
E., Seppanen, T., and Huikuri, H.
V. (2001). Effects of exercise and
passive head-up tilt on fractal and
complexity properties of heart rate
dynamics. Am. J. Physiol. Heart Circ.
Physiol. 280, H1081–H1087.
S., Mäkikallio, T. H., and Huikuri,
H. (2011). Sympatho-vagal interac-
tion in the recovery phase of exer-
Tulppo, M. P., Kiviniemi, A. M., Hau-
tala, A. J., Kallio, M., Seppanen,
T., Makikallio, T. H., and Huikuri,
H. V. (2005). Physiological back-
ground of the loss of
Tulppo, M. P., Makikallio, T. H., Sep-
panen, T., Airaksinen, J. K., and
Huikuri, H. V. (1998a). Heart rate
dynamics during accentuated sym-
pathovagal interaction. Am. J. Phys-
iol. 274, H810–H816.
Tulppo, M. P., Makikallio, T. H., Sep-
panen, T., Laukkanen, R. T., and
Huikuri, H. V. (1998b). Vagal mod-
ulation of heart rate during exercise:
effects of age and physical fitness.
Am. J. Physiol. 274, H424–H429.
Tulppo, M. P., Makikallio, T. H., Takala,
T. E., Seppanen, T., and Huikuri,
H. V. (1996). Quantitative beat-to-
beat analysis of heart rate dynamics
during exercise. Am. J. Physiol. 271,
von Klot, S., Mittleman, M. A., Dock-
ery, D. W., Heier, M., Meisinger,
C., Hormann, A., Wichmann, H.
E., and Peters, A. (2008). Inten-
sity of physical exertion and trig-
gering of myocardial infarction: a
classification of diabetes mellitus
and its complications, part 1: diag-
nosis and classification of diabetes
mellitus. Geneva: WHO.
Wykretowicz, A., Guzik, P., Bartkowiak,
maga, M., Wesseling, K. H., and
Wysocki, H. (2005). Endothelial
function and baroreflex sensitivity
according to the oral glucose tol-
erance test in patients with coro-
nary artery disease and normal
fasting glucose levels. Clin. Sci. 109,
Yamamoto, Y., and Hughson, R. L.
analysis: new method for studying
Yamamoto, Y., Hughson, R. L., and
Peterson, J. C. (1991). Autonomic
control of heart rate during exer-
cise studied by heart rate variability
spectral analysis. J. Appl. Physiol. 71,
Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any
commercial or financial relationships
that could be construed as a potential
conflict of interest.
Received: 09 June 2011; accepted: 18
August 2011; published online: 05 Sep-
tala AJ, Karjalainen J, Piira O-P, Catai
AM, Mäkikallio TH, Huikuri HV and
Tulppo MP (2011) Heart rate dynamics
without type 2 diabetes. Front. Physio.
2:57. doi: 10.3389/fphys.2011.00057
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