Heart rate response during exercise test and cardiovascular ...

European Heart Journal (2006) 27, 582–588 

doi:10.1093/eurheartj/ehi708 

Clinical research 

Prevention and epidemiology 

Heart rate response during exercise test and 

cardiovascular mortality in middle-aged men 

Kai P. Savonen 1 , Timo A. Lakka 1,2,3 , Jari A. Laukkanen 1,4 , Pirjo M. Halonen 5 , 

Tuomas H. Rauramaa 1 , Jukka T. Salonen 4,6,7,8 , and Rainer Rauramaa 1,9 * 

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 

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 HR 13,14 and inability to reach a fixed percentage 

value of an age-adjusted predicted maximal HR 15 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: rainer.rauramaa@messi.uku.fi 

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. 

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 

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HR response during exercise test and cardiovascular mortality 583 

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 

(VO 2max ) 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 

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 

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584 K.P. Savonen et al. 

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 VO 2max , 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 

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 VO 2max 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 VO 2max and HR40–100 were included in the 

model but VO 2max 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 death 13,16 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 



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 Mean/median (SD/range) or proportion P-value 

for difference 

All men 

(n ¼ 1378) 

Men who died 

of CVD during 

follow-up (n ¼ 56) 

Survivors 

(n ¼ 1322) 

between groups a 

Age (years) 54 (42–61) 54 (42–61) 52 (42–61) 0.003 

BMI (kg/m 2 ) 26.5 (3.4) 27.8 (3.9) 26.5 (3.3) 0.01 

Cigarette smoking (cigarette-years) b 147 (301) 315 (465) 140 (290) 0.02 

Alcohol consumption (g/week) 74 (113) 120 (191) 72 (108) 0.12 

CVD history (%) c 14.7 28.6 14.1 0.01 

Diabetes (%) d 3.7 8.9 3.5 0.18 

Serum LDL-cholesterol (mmol/L) 3.98 (0.97) 4.30 (1.04) 3.97 (0.96) 0.001 

Systolic blood pressure at rest 

133 (16) 143 (19) 132 (15) ,0.001 

(mmHg) 

Maximal oxygen uptake (L/min) 2.6 (0.6) 2.3 (0.5) 2.6 (0.6) 0.03 

Exercise test duration (s) 627 (137) 543 (121) 631 (137) 0.002 

Myocardial ischaemia during 

13.8 33.9 12.9 ,0.001 

exercise (%) e 

Systolic blood pressure 

76 (24) 77 (25) 76 (24) 0.50 

response (mmHg) f 

Systolic blood pressure 

7.5 (2.7) 8.6 (3.1) 7.5 (2.6) 0.02 

response in relation to test 

duration (mmHg/min) 

Resting HR (b.p.m.) 74 (13) 78 (15) 74 (13) 0.02 

Chronotropic incompetence (%) g 10.1 14.3 9.9 0.55 

Maximal HR (b.p.m.) 163 (17) 154 (18) 163 (17) 0.003 

HR reserve (b.p.m.) h 89 (20) 76 (19) 89 (19) ,0.001 

HR at 40% of maximal workload 108 (13) 109 (14) 108 (13) 0.34 

(b.p.m.) 

HR increment between 40 and 

100% of maximal workload 

(b.p.m.) 

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 ischaemia 31 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


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 

baseline a 

Risk factor Death due to CVD Death due to coronary heart disease All-cause death 

Relative risk 

(95% CI) 

P-value 

Relative risk 

(95% CI) 

P-value 

Relative risk 

(95% CI) 

P-value 

Age (for each increment 

1.08 (1.02–1.16) 0.02 1.04 (0.97–1.12) 0.31 1.08 (1.04–1.13) ,0.001 

of 1 year) 

Alcohol consumption 

1.14 (0.62–2.09) 0.68 0.97 (0.45–2.09) 0.94 1.52 (1.06–2.19) 0.02 

91 g/week (highest 

fourth vs. others) 

BMI (for each increment 

1.20 (0.93–1.54) 0.16 1.19 (0.88–1.60) 0.26 1.07 (0.91–1.26) 0.42 

of 3.4 kg/m 2 ) 

CVD history (yes vs. no) 1.81 (0.98–3.34) 0.06 1.66 (0.77–3.57) 0.20 1.02 (0.66–1.58) 0.93 

Cigarette smoking (for each 1.43 (1.19–1.72) ,0.001 1.41 (1.11–1.78) 0.004 1.43 (1.29–1.60) ,0.001 

increment of 301 

cigarette-years) 

Diabetes (yes vs. no) 1.29 (0.48–3.47) 0.62 1.14 (0.33–4.00) 0.84 1.25 (0.64–2.45) 0.52 

Myocardial ischaemia during 2.35 (1.32–4.19) 0.004 3.32 (1.68–6.59) 0.001 1.25 (0.83–1.90) 0.29 

exercise (yes vs. no) 

Serum LDL-cholesterol 

1.16 (0.89–1.51) 0.28 1.26 (0.92–1.72) 0.15 1.01 (0.86–1.18) 0.92 

(for each increment of 

0.97 mmol/L) 

Systolic blood pressure at rest 1.36 (1.09–1.70) 0.008 1.19 (0.89–1.58) 0.24 1.28 (1.11–1.49) 0.001 

(for each increment of 

16 mmHg) 

HR increment between 40 and 

100% of maximal workload 

(for each increment of 13 b.p.m.) 

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 

baseline a 

Risk factor Death due to CVD Death due to CHD All-cause death 

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.) 

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


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 baseline a 

Stratifying variable 

Relative risk 

(95% CI) 

P-value 

P-value for 

interaction 

All men (n ¼ 1378) 3.57 (2.09–6.09) ,0.001 

Alcohol consumption 

91 g/week, the highest 

3.04 (1.19–7.80) 0.02 0.37 

fourth (n ¼ 344) 

,91 g/week (n ¼ 1034) 3.89 (2.02–7.49) ,0.001 

BMI 

30.0 kg/m 2 (n ¼ 195) 3.71 (1.18–11.65) 0.03 1.00 

,30.0 kg/m 2 (n ¼ 1183) 3.43 (1.86–6.32) ,0.001 

CVD history 

Yes (n ¼ 203) 4.57 (1.64–12.76) 0.004 0.48 

No (n ¼ 1175) 3.13 (1.66–5.93) ,0.001 

Cigarette smoking 

Yes (n ¼ 384) 3.13 (1.29–7.56) 0.01 0.62 

No (n ¼ 994) 3.76 (1.90–7.45) ,0.001 

Maximal oxygen uptake ,2.35 L/min 

2.35 L/min, the lowest 

2.90 (1.42–5.94) 0.003 0.64 

third (n ¼ 460) 

.2.35 L/min (n ¼ 918) 3.73 (1.61–8.64) 0.002 

Myocardial ischaemia during exercise 

Yes (n ¼ 190) 4.84 (1.75–13.38) 0.002 0.49 

No (n ¼ 1188) 2.67 (1.37–5.19) 0.004 

Serum LDL-cholesterol 

3.5 mmol/L (n ¼ 950) 4.27 (2.33–7.83) ,0.001 0.15 

,3.5 mmol/L (n ¼ 428) 1.57 (0.41–5.96) 0.51 

Systolic blood pressure at rest 

140 mmHg (n ¼ 389) 2.82 (1.39–5.76) ,0.001 0.48 

,140 mmHg (n ¼ 989) 3.75 (1.68–8.37) 0.001 

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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