European Heart Journal Advance Access originally published online on January 6, 2006
European Heart Journal 2006 27(5):582-588; doi:10.1093/eurheartj/ehi708
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Heart rate response during exercise test and cardiovascular mortality in middle-aged men
1Kuopio Research Institute of Exercise Medicine, Haapaniementie 16, 70100 Kuopio, Finland
2Department of Physiology, University of Kuopio, Kuopio, Finland
3Pennington Biomedical Research Center, Baton Rouge, LA, USA
4Research Institute of Public Health, University of Kuopio, Kuopio, Finland
5IT Service Centre, University of Kuopio, Kuopio, Finland
6Department of Community Health and General Practise, University of Kuopio, Kuopio, Finland
7Inner Savo Health Centre, Suonenjoki, Finland
8Oy Jurilab Ltd, Kuopio, Finland
9Department 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.
* Corresponding author. Tel: +358 17 2884444; fax: +358 17 2884488. E-mail address: rainer.rauramaa{at}messi.uku.fi
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Abstract |
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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 ß-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–HR at 40% workload as a continuous variable was inversely associated with CVD (P=0.04), CHD (P=0.004), and all-cause (P=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.
Key Words: Exercise testing • Heart rate • Cardiovascular diseases
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Introduction |
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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 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 middle-aged men free of CHD.
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Methods |
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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 week or more frequently. Of these men, 595 used ß-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 ß-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–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–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 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 logistic-regression 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).
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Results |
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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=12.9; df=1.757; P<0.001 for interaction effect adjusting for age and length of follow-up) (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=19.6; P<0.001). On the basis of these results, a new variable called HR40–100 was constructed as maximal HR–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 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 follow-up are shown in Table 1. HR40–100 correlated negatively with resting HR (r=–0.33; P<0.001) and positively with HR reserve (r=0.79; P<0.001) and maximal HR (r=0.66; P<0.001).
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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=0.04), CHD mortality decreased by 41% (95% CI 16–59; P=0.004), and all-cause mortality decreased by 25% (95% CI 10–37; P=0.002) with 1 SD (13 b.p.m.) increment in HR40–100.
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HR40–100 predicted also death due to non-cardiovascular causes: mortality decreased by 24% (95% CI 5–39; P=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=0.65), CHD (P=0.86), or all-cause mortality (P=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 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=0.008) than HR40–100 (P=0.05).
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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=0.002), myocardial ischaemia during exercise (P=0.007), high systolic blood pressure at rest (P=0.007), high age (P=0.01), and CVD history (P=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=0.001) and smoking (P=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=428; P=0.51).
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Discussion |
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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 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 ß-adrenergic receptors and desensitization of myocardial ß-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 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 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.
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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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