Download Heart rate response during exercise test and cardiovascular

Clinical research
European Heart Journal (2006) 27, 582–588
doi:10.1093/eurheartj/ehi708
Prevention and epidemiology
Heart rate response during exercise test and
cardiovascular mortality in middle-aged men
Kai P. Savonen1, Timo A. Lakka1,2,3, Jari A. Laukkanen1,4, Pirjo M. Halonen5,
Tuomas H. Rauramaa1, Jukka T. Salonen4,6,7,8, and Rainer Rauramaa1,9*
1
Kuopio Research Institute of Exercise Medicine, Haapaniementie 16, 70100 Kuopio, Finland; 2 Department of Physiology,
University of Kuopio, Kuopio, Finland; 3 Pennington Biomedical Research Center, Baton Rouge, LA, USA; 4 Research Institute
of Public Health, University of Kuopio, Kuopio, Finland; 5 IT Service Centre, University of Kuopio, Kuopio, Finland;
6
Department of Community Health and General Practise, University of Kuopio, Kuopio, Finland; 7 Inner Savo Health Centre,
Suonenjoki, Finland; 8 Oy Jurilab Ltd, Kuopio, Finland; and 9 Department of Clinical Physiology and Nuclear Medicine,
Kuopio University Hospital, Kuopio, Finland
Received 2 April 2005; revised 15 November 2005; accepted 8 December 2005; online publish-ahead-of-print 6 January 2006
KEYWORDS
Exercise testing;
Heart rate;
Cardiovascular diseases
Aims The objective is to study whether a heart rate (HR) response during exercise test independently
predicts cardiovascular disease (CVD) mortality.
Methods and results The subjects were a representative sample of 1378 men, 42–61 years of age, from
eastern Finland with neither prior coronary heart disease (CHD) nor use of b-blockers at baseline. HR
was measured at rest and during a maximal, symptom-limited exercise test at 20, 40, 60, 80, and
100% of maximal workload. During an average follow-up of 11.4 years, there were 56 deaths due to CVD.
The slope of HR increase during exercise test was steeper in survivors when compared with those who
died due to CVD during follow-up (P , 0.001), and the difference in the steepness of HR slope between
the groups was the strongest at interval 40–100% (P , 0.001). In Cox-multivariable models, maximal
HR 2 HR at 40% workload as a continuous variable was inversely associated with CVD (P ¼ 0.04), CHD
(P ¼ 0.004), and all-cause (P ¼ 0.002) mortality after adjustment for known risk factors for CVD death.
Conclusion By considering an HR response throughout an exercise test, we found that a blunted HR
increase at 40–100% of maximal workload was associated with increased CVD mortality.
Introduction
A high resting heart rate (HR) has been associated with
increased cardiovascular disease (CVD) mortality and
increased risk of sudden death from myocardial infarction
in apparently healthy individuals.1–12 In contrast, a low
maximal HR13,14 and inability to reach a fixed percentage
value of an age-adjusted predicted maximal HR15 have
been related to an increased risk of CVD death. On
the basis of these findings, it is not surprising that a low
HR reserve (HRR), defined as a difference between resting
HR and maximal HR, has been associated with increased
CVD mortality and increased risk of sudden death from myocardial infarction.12,13,16 Moreover, an impaired increment
of HR from rest to an age-adjusted predicted submaximal
workload, which was based on maximal HR, was associated
with an increased risk of incident coronary heart disease
(CHD).17 Instead, HR increment from rest to unadjusted
submaximal workload did not predict CVD mortality.18
All these studies have used only HR at rest or HR at rest
and one time point during exercise. To the best of our knowledge, there are no studies in which the whole HR data from
* Corresponding author. Tel: þ358 17 2884444; fax: þ358 17 2884488.
E-mail address: [email protected].fi
rest to maximal workload would have been explored systematically to find parameters associated with CVD mortality.
We tested the hypothesis that an HR increase at a certain
phase of the exercise test better predicts CVD and CHD mortality than overall HR increase from rest until the end of the
test or other previously established HR variables in middleaged men free of CHD.
Methods
Subjects
We studied participants in the Kuopio Ischaemic Heart Disease Risk
Factor Study, an ongoing population study designed to investigate
risk factors for CVD and related outcomes. The study involves men
from east Finland,19 an area known for its high prevalence and incidence of CVD.20 The subjects are a representative sample of men
who lived in the town of Kuopio or neighbouring rural communities,
stratified according to age, who were 42, 48, 54, or 60 years of age
at baseline examinations between March 1984 and December 1989.
Of 3235 eligible men, 2682 (83%) participated in the study.
Complete data on exercise test variables were available for 2240
men. Of these men, 712 had a prevalent CHD, defined as either a
history of myocardial infarction or angina pectoris, angina pectoris
on effort based on the London School of Hygiene Cardiovascular
Questionnaire,21 or the use of nitroglycerine for chest pain once a
& The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: [email protected]
HR response during exercise test and cardiovascular mortality
week or more frequently. Of these men, 595 used b-blockers that
reduce HR at rest and during exercise. After excluding these
subjects, the final study sample included 1378 men free of CHD
and not using b-blockers. None of the subjects reported using
HR-blunting calcium blockers, such as verapamil and diltiazem.
The study protocol was approved by the Research Ethics Committee
of the University of Kuopio, and it complies with the Declaration of
Helsinki. Each participant gave a written informed consent.
Assessment of HR and other exercise test variables
A maximal, symptom-limited exercise test was performed at
baseline using an electrically braked cycle ergometer as described
previously.22,23 The primary aim of the study was to explore HR
data from rest to maximal workload systematically instead of
using arbitrarily chosen parts of recorded HR data. For that
purpose, each subject’s exercise test was divided into five consequent periods of equal duration, and HR value was extracted from
corresponding time points, i.e. rest, 20, 40, 60, 80, and 100% of
maximal workload. For 556 men examined before June 1986, the
testing protocol comprised a 3-min warm-up at 50 W followed by
a step-by-step increase in the workload by 20 W/min. The remaining
822 men were tested with a linear increase in the workload by
20 W/min. Because two different protocols were used during the
first 50 W, only the values at or .50 W were included into the analysis. Relative intensities of 20% were not considered in final
analyses, because for 528 men examined before June 1986, the
first workload of 50 W exceeded 20% of their maximal workload.
For safety reasons and to obtain reliable information, the test was
supervised by an experienced physician with the assistance of a
trained nurse. The most common reasons for stopping the exercise
test were leg fatigue (787 men), exhaustion (237), breathlessness
(128), and pain in the leg muscles, joints, or back (51). The test
was discontinued because of cardiorespiratory symptoms or abnormalities in 98 men. These included dyspnoea (39), arrhythmias (37), a
marked change in systolic or diastolic blood pressure (8), dizziness
(6), chest pain (4), and ischaemic electrocardiographic changes (4).
HR was recorded from electrocardiogram (ECG) at rest, at the end
of each 30-s interval during the exercise test, and at peak exercise.
To express HR as a relative value, HRR was calculated as maximal
HR 2 resting HR. Resting HR was expressed as the lowest HR
value, whether measured in lying position before the test or while
sitting on bicycle at the initiation of the test. Systolic blood pressure
response to exercise was calculated as maximal systolic blood
pressure 2 resting systolic blood pressure, and the response was
also related to the duration of the test. Maximal oxygen uptake
(VO2max) was defined as the highest value recorded over a 30-s interval. The criteria for myocardial ischaemia during exercise test were
ischaemic changes in ECG defined as horizontal or downsloping ST
depression .1.0 mm at 80 ms after the J-point.
Assessment of other risk factors
CVD history was defined as a history of cardiomyopathy, heart
failure, stroke, or claudication. Cigarette smoking was defined as
cigarette-years, which denotes the lifelong exposure to smoking
and was estimated as the product of years smoked and the
number of cigarettes smoked daily at the time of examination.24
Diabetes was defined as a history of taking medication for diabetes
or fasting blood glucose 6.7 mmol/L. The collection of blood
specimens and the assessment of other risk factors, including
alcohol consumption, body mass index (BMI), serum lipoproteins,
and systolic and diastolic blood pressure at rest, have been
described elsewhere.22–24
Ascertainment of follow-up events
Deaths were ascertained by computer linkage to the national death
registry using a social security number that every Finn has. There
were no losses to follow-up. All deaths that occurred between
583
study enrolment from 20 March 1984 to 5 December 1989 and 31
December 1998 were included. CVD and CHD deaths were coded
according to the Ninth International Classification of Diseases
(code nos 390–459 and 410–414, respectively) or the Tenth
International Classification of Diseases (code nos I00–I99 and
I20–I25, respectively). CVD and CHD deaths were used as the
primary endpoints and all-cause death as the secondary endpoint.
We used CVD and CHD deaths as the primary endpoints because
HR response during exercise primarily reflects cardiovascular
status and most likely predicts CVD mortality.
Statistical analysis
The analysis of variance (ANOVA) for repeated measures, adjusted
for age and the length of follow-up, was used to detect whether
the slopes of HR increase of men who died during follow-up and
survivors differed from the beginning of the test or only later
during the test. In order to eliminate dispersion from compound
symmetry assumption (equal correlations between measurements),
Greenhouse-Geisser corrected degrees of freedom were used when
testing the effects in ANOVA. The Helmert contrasts, which compare
HRs at each relative workload with the mean HRs of the next
relative workloads, were used to locate the phase of the test
(rest, 40, 60, 80, and 100% of maximal workload) where the HR
slopes of men who died during follow-up and survivors started to
diverge. The statistically most significant contrast was used to
construct a new variable. Differences in baseline data between
those who died and survivors were tested with linear- and logisticregression analyses and Mann–Whitney U test by adjusting for age
and length of follow-up.
The new HR variable constructed according to ANOVA for
repeated measures was entered into forced Cox-proportional
hazards’ regression models. If possible, covariates were entered
as uncategorized into Cox models. Two different sets of covariates
were used: (i) age and examination year; (ii) age, examination
year, alcohol consumption, BMI, cigarette smoking, CVD history,
diabetes, serum LDL-cholesterol, systolic blood pressure at rest,
and myocardial ischaemia during exercise. To compare the predictive value of HR40–100 and other exercise test variables, a stepwise
Cox-regression analysis was used. Relative hazards, adjusted for risk
factors, were estimated as antilogarithms of coefficients from
multivariable models. Their confidence intervals (CIs) were estimated under the assumption of asymptotic normality of the
estimates. To detect the best cut-off point for a new variable,
the dichotomization cut-off point that maximized the log-rank
test statistics was sought, and the predictive power of this categorized variable was tested by using Cox models. Finally, we tested
potential interactions of the new HR variable with other risk
factors for death with Cox models by adjusting for age and examination year. All tests for statistical significance were two sided.
Statistical analyses were performed by using SPSS 11.5. for
Windows (SPSS, Inc., Chicago, IL, USA).
Results
At the beginning of the follow-up, the median age of the
subjects was 54 years (range 42–61 years). In ANOVA for
repeated measures, the slope of HR increase was steeper
in survivors when compared with those who died due to
CVD during follow-up (F ¼ 12.9; df ¼ 1.757; P , 0.001 for
interaction effect adjusting for age and length of followup) (Figure 1). By using Helmert contrasts, the difference
in the steepness of HR slope between the groups was the
strongest at interval 40–100% (F ¼ 19.6; P , 0.001). On
the basis of these results, a new variable called HR40–100
was constructed as maximal HR 2 HR at 40% workload. The
average HR40–100 was 54 b.p.m. (SD 13 b.p.m.) in the
whole study population, 55 b.p.m. (SD 13 b.p.m.) in
584
Figure 1 Heart rate (mean + SD) as a function of relative intensity
(percentage of maximal workload reached in exercise test) in those who died
due to CVD during follow-up (dashed line) and survivors (continuous line).
survivors, and 45 b.p.m. (SD 13 b.p.m.) in those who died
due to CVD during follow-up (P , 0.001 for difference
between survivors and deceased). Baseline characteristics
in survivors and those who died of CVD during the followup are shown in Table 1. HR40–100 correlated negatively
with resting HR (r ¼ 20.33; P , 0.001) and positively
with HR reserve (r ¼ 0.79; P , 0.001) and maximal HR
(r ¼ 0.66; P , 0.001).
HR increment between 40 and 100% of maximal
workload and all-cause and CVD mortality
The average follow-up time to any death or the end of
follow-up was 11.4 years (range 0.3–14.8 years). In the
present sample, a total of 146 (10.6%) deaths occurred
during the follow-up period. There were 56 CVD deaths
(4.1%), of which 37 were due to CHD (2.7%). When adjusted
for age and examination year, CVD mortality decreased by
45% (95% CI 28–58; P , 0.001), CHD mortality decreased
by 56% (95% CI 38–68; P , 0.001), and all-cause mortality
decreased by 37% (95% CI 26–46; P , 0.001) with 1 SD
(13 b.p.m.) increment in HR40–100.
To investigate independent associations of HR40–100, it was
entered simultaneously with age, examination year, and
known risk factors for CVD death into Cox models (Table 2).
CVD mortality decreased by 26% (95% CI 1–44; P ¼ 0.04),
CHD mortality decreased by 41% (95% CI 16–59; P ¼ 0.004),
and all-cause mortality decreased by 25% (95% CI 10–37;
P ¼ 0.002) with 1 SD (13 b.p.m.) increment in HR40–100.
HR40–100 predicted also death due to non-cardiovascular
causes: mortality decreased by 24% (95% CI 5–39; P ¼ 0.02)
with 1 SD (13 b.p.m.) increment in HR40–100. HR increase
from rest to 40% of maximal workload was not associated
with CVD (P ¼ 0.65), CHD (P ¼ 0.86), or all-cause mortality
(P ¼ 0.27).
HR increment between 40 and 100% of maximal
workload, CVD mortality, and other exercise
test-derived variables
The associations of HR40–100 with mortality were compared
also with those of VO2max, resting HR, maximal HR, HR
reserve, and systolic blood pressure response. All variables
were considered as continuous variables, and relative risks
were calculated for 1 SD increment. HR40–100 significantly
K.P. Savonen et al.
predicted mortality after adjustment for known risk
factors (Table 2). When entered into the same model,
other exercise test variables had weaker associations with
CVD and CHD mortality than HR40–100 but VO2max was a
stronger predictor of all-cause death than HR40–100
(Table 3). When HR40–100 and each of the other exercise
test variables were entered into the fully adjusted model
using stepwise method, HR40–100 remained in the model
for CVD and CHD mortality, whereas other exercise test
variables did not. In the corresponding model for all-cause
mortality, both VO2max and HR40–100 were included in the
model but VO2max was a stronger predictor (P ¼ 0.008)
than HR40–100 (P ¼ 0.05).
The best cut-off point of HR40–100 for predicting CVD
mortality was 43 b.p.m., and 272 subjects (20%) had low
HR40–100 (,43 b.p.m.). When HR40–100 was entered as a
dichotomous variable into a Cox model, the strongest predictor of CVD death was smoking (P , 0.001) followed by a
low HR40–100 (RR 2.4; 95% CI 1.4–4.2; P ¼ 0.002), myocardial ischaemia during exercise (P ¼ 0.007), high systolic
blood pressure at rest (P ¼ 0.007), high age (P ¼ 0.01),
and CVD history (P ¼ 0.05). The strongest predictor of CHD
death was a low HR40–100 (RR 4.3; 95% CI 2.1–8.7;
P , 0.001) followed by myocardial ischaemia during exercise (P ¼ 0.001) and smoking (P ¼ 0.002).
Analyses stratified according to known risk factors for CVD
death are presented in Table 4. A low HR40–100 predicted
CVD death in all subgroups except in men with lower
serum LDL-cholesterol levels (,3.5 mmol/L; n ¼ 428;
P ¼ 0.51).
Discussion
The main finding of the present study is that a blunted HR
increase between 40 and 100% of maximal workload
(HR40–100) during an exercise test was associated with
increased CVD, CHD, and all-cause mortality in a
population-based sample of middle-aged men free of CHD.
The magnitude of the association was comparable with
that of other major CVD risk factors.
In the present study, CVD mortality was associated with
HR increment from 40 to 100% of maximal workload,
whereas an association was not found with HR increase
from rest to 40% of maximal workload. HR40–100 was a
better predictor of CVD death than HR reserve (HR increase
from rest to maximum) or a variable quantifying a submaximal HR increment by Lauer et al.,17 both previously established predictors of CVD death13,16 or incident CHD.17 A
possible reason for this is that HR40–100 does not include
the early portion of an HR slope, whereas HR reserve and
HR variable by Lauer et al. 17 include also HR range ,40%
of maximal workload.
During dynamic exercise, the initial rise in the HR is
mainly due to the withdrawal of vagal tone until HR
approaches 100 b.p.m., whereas from that HR level
onward, the more slowly responding sympathetic system
begins to dominate the control of HR up to maximal
values.25,26 In the present study, a mean HR at 40% of
maximal workload was 100 b.p.m. (Table 1). This suggests
that a reduced ability to increase sympathetic activity may
be the underlying factor mediating the association between
a low increment of HR .40% of maximal workload and
increased CVD mortality. Instead, a vagally mediated early
HR response during exercise test and cardiovascular mortality
585
Table 1 Baseline characteristics according to CVD death during follow-up in 1378 men with no history of CHD or use of
b-blockers at baseline
Characteristics
Age (years)
BMI (kg/m2)
Cigarette smoking (cigarette-years)b
Alcohol consumption (g/week)
CVD history (%)c
Diabetes (%)d
Serum LDL-cholesterol (mmol/L)
Systolic blood pressure at rest
(mmHg)
Maximal oxygen uptake (L/min)
Exercise test duration (s)
Myocardial ischaemia during
exercise (%)e
Systolic blood pressure
response (mmHg)f
Systolic blood pressure
response in relation to test
duration (mmHg/min)
Resting HR (b.p.m.)
Chronotropic incompetence (%)g
Maximal HR (b.p.m.)
HR reserve (b.p.m.)h
HR at 40% of maximal workload
(b.p.m.)
HR increment between 40 and
100% of maximal workload
(b.p.m.)
Mean/median (SD/range) or proportion
All men
(n ¼ 1378)
Men who died
of CVD during
follow-up (n ¼ 56)
Survivors
(n ¼ 1322)
54 (42–61)
26.5 (3.4)
147 (301)
74 (113)
14.7
3.7
3.98 (0.97)
133 (16)
54 (42–61)
27.8 (3.9)
315 (465)
120 (191)
28.6
8.9
4.30 (1.04)
143 (19)
52 (42–61)
26.5 (3.3)
140 (290)
72 (108)
14.1
3.5
3.97 (0.96)
132 (15)
P-value
for difference
between groupsa
0.003
0.01
0.02
0.12
0.01
0.18
0.001
,0.001
2.6 (0.6)
627 (137)
13.8
2.3 (0.5)
543 (121)
33.9
2.6 (0.6)
631 (137)
12.9
0.03
0.002
,0.001
76 (24)
77 (25)
76 (24)
0.50
7.5 (2.6)
0.02
7.5 (2.7)
8.6 (3.1)
74 (13)
10.1
163 (17)
89 (20)
108 (13)
78 (15)
14.3
154 (18)
76 (19)
109 (14)
74 (13)
9.9
163 (17)
89 (19)
108 (13)
0.02
0.55
0.003
,0.001
0.34
54 (13)
45 (13)
55 (13)
,0.001
a
Differences between groups were adjusted for age and length of follow-up and tested with logistic-regression analysis for CVD
history, chronotropic incompetence, diabetes, and myocardial ischaemia during exercise and with linear-regression analysis for
rest of the variables. An age difference between groups was tested with Mann–Whitney U test.
b
Cigarette-years denotes the lifelong exposure to smoking which was estimated as the product of years smoked and the number of
cigarettes smoked daily at the time of examination.24
c
CVD was defined as a history of cardiomyopathy, heart failure, stroke, or claudication.
d
Diabetes was defined as a history of taking medication for treatment of diabetes or fasting glucose 6.7 mmol/L.
e
The criteria for myocardial ischaemia during exercise test were ischaemic changes in ECG defined as horizontal or downsloping ST
depression 1.0 mm at 80 ms after the J-point.
f
Systolic blood pressure response was calculated as maximal systolic blood pressure 2 resting systolic blood pressure.
g
Chronotropic incompetence was defined as an inability to reach 85% of the age-predicted (220 2 age in years) maximal HR.
h
HR reserve was calculated as maximal HR 2 resting HR.
increment of HR does not seem to be informative from the
predictive point of view. In contrast, a resting HR, which is
also largely defined by vagal activity, has previously been
associated with an increased risk of premature CVD
death,1–12 and a similar trend was found also in this study.
Patients with advanced CHD and heart failure show a high
resting HR and a poor ability to increase HR during exercise.27–29 These findings have been attributed to a low
number of b-adrenergic receptors and desensitization of
myocardial b-adrenergic receptors secondary to increased
sympathetic activity.27–29 A low HR40–100 together with a
high resting HR in the present study may indicate a milder
autonomic nervous system aberration frequently found in
cardiac patients.13 Experimental data show that cardiac
autonomic regulation plays an important role in occurrence
of life-threatening arrhythmias during acute cardiac
ischaemia.30
Other mechanisms by which an impaired HR response
could be associated with increased CVD mortality include
exercise-induced myocardial ischaemia31 and a decreased
cardiorespiratory fitness.17 An impaired HR response has
also been speculated to be a parasympathetic reflex
triggered by irritation of mechanoreceptors in the left
ventricular wall (the Bezold–Jarisch reflex) subsequent to
deteriorated myocardial contractility.32,33 However, a low
HR40–100 predicted CVD and all-cause mortality independent of exercise-induced ischaemia.
First, the strength of our study is that we have a representative population-based sample of middle-aged men.
Secondly, the participation rate was high and there were
586
K.P. Savonen et al.
Table 2 Risk factor for CVD, CHD, and all-cause death in 1378 men with no history of coronary heart disease or use of b-blockers at
baselinea
Risk factor
Death due to CVD
Relative risk
(95% CI)
Age (for each increment
of 1 year)
Alcohol consumption
91 g/week (highest
fourth vs. others)
BMI (for each increment
of 3.4 kg/m2)
CVD history (yes vs. no)
Cigarette smoking (for each
increment of 301
cigarette-years)
Diabetes (yes vs. no)
Myocardial ischaemia during
exercise (yes vs. no)
Serum LDL-cholesterol
(for each increment of
0.97 mmol/L)
Systolic blood pressure at rest
(for each increment of
16 mmHg)
HR increment between 40 and
100% of maximal workload
(for each increment of 13 b.p.m.)
P-value
Death due to coronary heart disease
All-cause death
Relative risk
(95% CI)
P-value
Relative risk
(95% CI)
P-value
1.08 (1.02–1.16)
0.02
1.04 (0.97–1.12)
0.31
1.08 (1.04–1.13)
,0.001
1.14 (0.62–2.09)
0.68
0.97 (0.45–2.09)
0.94
1.52 (1.06–2.19)
0.02
1.20 (0.93–1.54)
0.16
1.19 (0.88–1.60)
0.26
1.07 (0.91–1.26)
0.42
1.81 (0.98–3.34)
1.43 (1.19–1.72)
0.06
,0.001
1.66 (0.77–3.57)
1.41 (1.11–1.78)
0.20
0.004
1.02 (0.66–1.58)
1.43 (1.29–1.60)
0.93
,0.001
1.29 (0.48–3.47)
2.35 (1.32–4.19)
0.62
0.004
1.14 (0.33–4.00)
3.32 (1.68–6.59)
0.84
0.001
1.25 (0.64–2.45)
1.25 (0.83–1.90)
0.52
0.29
1.16 (0.89–1.51)
0.28
1.26 (0.92–1.72)
0.15
1.01 (0.86–1.18)
0.92
1.36 (1.09–1.70)
0.008
1.19 (0.89–1.58)
0.24
1.28 (1.11–1.49)
0.001
0.74 (0.56–0.99)
0.04
0.59 (0.41–0.84)
0.004
0.75 (0.63–0.90)
0.002
a
From Cox-regression model adjusted for age, examination year, and all variables, as shown. Except for age, alcohol consumption, CVD history, diabetes,
and myocardial ischaemia, the relative risks were calculated for a change of 1 SD, as shown. Abbreviations as in Table 1.
Table 3 Exercise test variables as a risk factor for CVD, CHD, and all-cause death in 1378 men with no history of CHD or use of b-blockers at
baselinea
Risk factor
Maximal oxygen uptake (for each
increment of 0.6 L/min)
Systolic blood pressure response
(for each increment of 24 mmHg)
Systolic blood pressure response in
relation to test duration (for each
increment of 2.7 mmHg/min)
Resting HR (for each increment
of 13 b.p.m.)
Maximal HR (for each increment
of 17 b.p.m.)
HR reserve (for each increment
of 20 b.p.m.)
Death due to CVD
Death due to CHD
All-cause death
Relative risk (95% CI)
P-value
Relative risk (95% CI)
P-value
Relative risk (95% CI)
P-value
0.74 (0.52–1.06)
0.10
0.57 (0.36–0.90)
0.02
0.66 (0.53–0.83)
,0.001
1.18 (0.90–1.54)
0.23
1.19 (0.85–1.66)
0.31
0.90 (0.76–1.06)
0.21
1.16 (0.94–1.44)
0.17
1.24 (0.95–1.61)
0.11
1.05 (0.90–1.22)
0.56
1.21 (0.94–1.55)
0.14
1.35 (1.01–1.81)
0.04
1.08 (0.92–1.27)
0.37
0.98 (0.74–1.30)
0.90
0.90 (0.64–1.27)
0.55
0.78 (0.65–0.94)
0.007
0.84 (0.63–1.12)
0.23
0.70 (0.49–1.00)
0.05
0.76 (0.64–0.91)
0.003
a
From Cox-regression model adjusted for age, examination year, alcohol consumption, BMI, cigarette smoking, CVD history, diabetes, serum LDL-cholesterol,
systolic blood pressure at rest, and myocardial ischaemia during exercise. The relative risks were calculated for a change of 1 SD, as shown. Abbreviations as
in Table 1.
no losses to follow-up. Thirdly, we have reliable data on
mortality because deaths were ascertained by National
Death Registry using a social security number. Next,
comprehensive assessment of health habits and cardiovascular risk factors allowed us to investigate the independent
association of HR40–100 with CVD mortality. Finally,
cardiorespiratory fitness was measured objectively by
direct expiratory gas analysis instead of using predicted
values.
A limitation of the study is that only men were enrolled.
Therefore, generalization of the present findings to female
populations should be done with caution. The extent to
HR response during exercise test and cardiovascular mortality
587
Table 4 Associations between a low HR increment between 40 and 100% of maximal workload and CVD death in
all men and in subgroups in 1378 men with no history of CHD or use of b-blockers at baselinea
Stratifying variable
Relative risk
(95% CI)
P-value
P-value for
interaction
All men (n ¼ 1378)
Alcohol consumption
91 g/week, the highest
fourth (n ¼ 344)
,91 g/week (n ¼ 1034)
BMI
30.0 kg/m2 (n ¼ 195)
,30.0 kg/m2 (n ¼ 1183)
CVD history
Yes (n ¼ 203)
No (n ¼ 1175)
Cigarette smoking
Yes (n ¼ 384)
No (n ¼ 994)
Maximal oxygen uptake ,2.35 L/min
2.35 L/min, the lowest
third (n ¼ 460)
.2.35 L/min (n ¼ 918)
Myocardial ischaemia during exercise
Yes (n ¼ 190)
No (n ¼ 1188)
Serum LDL-cholesterol
3.5 mmol/L (n ¼ 950)
,3.5 mmol/L (n ¼ 428)
Systolic blood pressure at rest
140 mmHg (n ¼ 389)
,140 mmHg (n ¼ 989)
3.57 (2.09–6.09)
,0.001
3.04 (1.19–7.80)
0.02
3.89 (2.02–7.49)
,0.001
3.71 (1.18–11.65)
3.43 (1.86–6.32)
0.03
,0.001
1.00
4.57 (1.64–12.76)
3.13 (1.66–5.93)
0.004
,0.001
0.48
3.13 (1.29–7.56)
3.76 (1.90–7.45)
0.01
,0.001
0.62
2.90 (1.42–5.94)
0.003
0.64
3.73 (1.61–8.64)
0.002
4.84 (1.75–13.38)
2.67 (1.37–5.19)
0.002
0.004
0.49
4.27 (2.33–7.83)
1.57 (0.41–5.96)
,0.001
0.51
0.15
2.82 (1.39–5.76)
3.75 (1.68–8.37)
,0.001
0.001
0.48
0.37
a
From Cox-regression model adjusted for age and examination year. If not otherwise specified, cut-off values are based on
commonly used recommendations. Abbreviations as in Table 1.
which age, underlying diseases, regular physical activity,
and cardioactive medications influence HR40–100 or
modify its association with CVD mortality deserves further
studies. It is possible that part of the association is explained
by residual confounding due to other risk factors. However,
we adjusted for the most important risk factors and the
results remained similar. We do not know whether
HR40–100 changed during the long follow-up period and
how the possible changes have affected our results. It is
likely that HR40–100 decreases with ageing as a consequence of a decrease in maximal HR. However, age was
controlled for in the statistical analyses. We could not
investigate whether relative intensities ,40% predict CVD
mortality, because for 528 men, such low intensities could
not be assessed owing to a testing protocol. Therefore, we
cannot state whether the association of a blunted
HR increase with increased CVD mortality manifests
already at relative workloads ,40%. Finally, the association
between HR40–100 and mortality should be confirmed in
other populations before any definitive conclusions can be
made regarding its applicability as a predictor of CVD death.
HR40–100 was a strong predictor of premature CVD and
all-cause mortality in middle-aged men free of CHD. A low
HR40–100 can identify persons with an increased risk of CVD
death independent of parameters measured at rest
or maximal exertion. Our findings suggest that an assessment
of HR response to exercise between 40 and 100% of maximal
workload may be useful in the prediction of CVD death.
Acknowledgements
This study was supported by grants from the Ministry of Education in
Finland (74/722/2003), from the Finnish Cultural Foundation of
Northern Savo, and from the Foundation of Sports Institutes in Finland.
Conflict of interest: no conflict of interests exists including any
financial or other kinds of associations.
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