Background In asymptomatic populations, physical activity is inversely associated with the risk of cardiovascular death, but it is not known if physical activity compensates for adverse effects of multiple cardiovascular risk factors.
The aim of this study was to assess if the positive association of a clustering of cardiovascular risk factors (CRFs) with cardiovascular disease (CVD) mortality could be weakened by exercise training.
Methods We followed 53 542 individuals who were free from known CVD, among which 3751 had CRF, from baseline between 1984 and 1986 until the date of death from any cause, or until the end of follow-up (31 December 2004). We used the Cox proportional hazards model to estimate HR of cardiovascular death.
Results The HR of death from CVD among people with CRF was 1.38 (95% CI 1.28 to 1.48) compared to those without CRF. The association was stronger among women than in men. In people with CRF, cardiovascular mortality was inversely related to physical activity: risk was 24% lower (HR 0.76, 95% CI 0.61 to 0.95) in the physically active compared to the inactive group. Compared to inactive people without CRF, people with CRF who reported no activity had 41% higher risk of cardiovascular death (HR 1.41, 95% CI 1.16 to 1.70).
Conclusion These data show that individuals with CRF are at greater risk of premature cardiovascular death compared to people without CRF, and that the risk of people with CRF who were physically active appears to be comparable to that of inactive individuals without CRF.
- Metabolic clustering
- physical activity
- cardiovascular mortality
- HUNT-1 study
- mortality SI
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Combining several factors associated with cardiovascular disease (CVD) gives a more powerful predictor of premature CVD death than assessing separate effects of each factor.1 This approach is particularly useful, since clustering of cardiovascular risk factors (CRFs), including high blood pressure, high cholesterol, low cardiorespiratory fitness, impaired endothelial function, obesity and a high level of blood glucose, is prevalent in at least 25% of the US adult population.1 2
Physical activity has been inversely associated with incidence and mortality from CVD in several studies.3–7 Whereas some studies suggest that a moderate amount of exercise is sufficient to reduce the risk of CVD,3 5 7 others have found a gradually decreased risk with increased training volume.6 Previous studies have also suggested that physical activity may, at least in part, counteract the adverse effects of obesity and high blood pressure on CVD risk and mortality.8 However, it is not known if physical activity also compensates for the adverse effect of multiple CRFs. One study reported that men with CRF had a twofold higher risk of death from CVD compared to healthy men,9 but that in men with CRF who exercised regularly there was no increase in risk.
Thus, the aim of this prospective study was to determine whether the positive association of a clustering of CRFs with CVD mortality could be weaker among people who engage in exercise training.
Material and methods
In Nord Trøndelag County in Norway, the total adult population aged 20 y and older was invited to participate in the Nord Trøndelag Health Study (HUNT) from 1984–1986. Of 85 100 individuals who were eligible to participate, 74 994 (88.1%) accepted the invitation. They filled in the questionnaire that was included with the invitation and attended a clinical examination. At the clinical examination, the participants received a second questionnaire that was to be filled in from home and returned in a pre-stamped envelope. The study has been described in detail elsewhere.10 Briefly, information was collected on a range of health and lifestyle-related topics, such as physical activity, diabetes, smoking status, alcohol consumption, educational attainment and marital status. The clinical examination included standardised measurements of blood pressure, body height and body weight. Among participants aged 40 y or older, blood glucose was measured non-fasting from capillary whole blood (Reflochech Glucose test strips and reflectance photometer, Boehringer Mannheim GmbH, Mannheim, Germany).11
The study was approved by the regional ethical committee in Trondheim, Norway.
In this study, we excluded 14 432 participants due to incomplete information on physical activity and 2909 participants with incomplete data from the clinical examination. We also excluded 4114 subjects with known CVD at baseline, leaving 53 542 participants available for analysis.
Clustering of CRVs
The data collection in the present study was performed 2–4 y before the condition of metabolic syndrome was described; therefore, we therefore used a modified definition that we termed ‘clustering of cardiovascular risk factors’ to make sure that most individuals with the metabolic syndrome became included in the analysis. CRF was defined as a combination of the most used criteria for the metabolic syndrome12–14; a non-fasting glucose ≥6.0 mmol/L,15 systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg,13 and body mass index ≥25 kg/m2.
At baseline, the participants were asked to complete a questionnaire that included frequency, duration and intensity of recreational physical activity in a week (ie, walking, skiing, swimming, or other sports). The frequency question allowed five response options (0, <1, 1, 2–3 and ≥4 times; coded 1–5), and participants who reported exercising at least once a week were also asked about the average duration (<15, 15–30, 31–60 and >60 min; coded 1–4) and intensity (light, moderate and vigorous; coded 1–3) of the activity. Among people who exercised once a week or more, we constructed a summary score of frequency, duration and intensity. The score summarised each participant's responses to give equal weight to each measure according to the following equation: 1/5×frequency+1/4×duration+1/3×intensity. This approach gave a maximum score of 1.0 for each of the three components of the summary score. The median score value was 2.02 for men and 1.83 for women (range 1.18–3.00). A summary score below the median was classified as low activity, whereas a score at the median or above was classified as high activity.
Endpoints and follow-up
The mandatory reporting of deaths by physicians and public health officers to the national Cause of Death Registry in Norway constitutes the basis for the coding of the underlying cause of death. Mortality follow-up to the Cause of Death Registry is virtually complete,16 and the primary endpoint in this study was death caused by CVD (International Classification of Disease (ICD) 9: 390–459; ICD 10: I 00–I 99) with specific emphasis given to deaths from ischaemic heart disease (ICD 9: 410–414; ICD 10: I 20–I 25) and stroke (ICD 9: 430–438; ICD 10: I 60–I 69). Each participant contributed person years from the date of the clinical examination until the date of death from any cause or until the end of follow-up (31 December 2004), whichever came first. Attendance was voluntary and each participant signed a written consent. The mortality follow-up of the HUNT cohort was approved by the regional committee for ethics in medical research and by the Norwegian Data Inspectorate.
We used the Cox proportional hazards model to estimate HR of death from cardiovascular causes (ischaemic heart disease and stroke) among people with CRFs compared to people without CRFs. Among participants with CRFs we also estimated HRs for different categories of physical activity compared to the group with no activity. In a separate analysis, we assessed the combined effect of CRF and physical activity on cardiovascular death. Precision of the estimates was assessed by 95% CIs. Our basic models were adjusted for age (using attained age as the time variable) and sex, and in additional multivariable analyses we adjusted for smoking status (never, former, current and unknown), marital status (married, unmarried, widowed, divorced/separated) and education (<10, 10–12, ≥13 years and unknown). We also assessed the modifying effect of age and sex using a likelihood ratio test. All statistical tests were two-sided and all statistical analyses were performed using Stata for Windows (Version 10.0 StataCorp LP, 1985–2007).
Baseline characteristics of the study population are presented in table 1. At baseline (1984–86), 3751 (8%) individuals had a clustering of CRFs for CVD. During 18 y of follow-up (more than 945 000 person years), a total of 4958 participants (4109 without CRF (8.3%) and 849 with CRF (22.6%)) had died from CVD. Of these, 2971 deaths were caused by ischaemic heart disease and 1678 by stroke.
CRF and cardiovascular mortality
Compared to people without CRFs, people with CRFs had 38% higher mortality rate from CVD (HR 1.38, 95% CI 1.28 to 1.48). Interaction tests showed that this association was dependent on age (p values of interaction: <0.001 for CVD and IHD; <0.03 for stroke); and therefore, the age-specific associations of CRF with CVD mortality are given in table 2. Among people with CRF who were younger than 60 y at baseline, the risk of dying from CVD was 55% (HR 1.55, 95% CI 1.28 to 2.21) higher compared to people without CRF. In older age groups this association was weaker; among people 60–79 y, the analogous HR was 1.36 (95% CI 1.25 to 1.48), and for people 80 y and older the HR was 1.26 (95% CI 0.98 to 1.56).
The association of CRF with CVD also differed by sex (p values for interaction: <0.001 for CVD and IHD; <0.02 for stroke). Thus, in age groups younger than 60 years, the HR of death from CVD associated with CRF was 1.35 (95%, 1.08 to 1.69) among men and 2.66 (95% CI, 1.83 to 3.87) in women. The associations showed similar strengths for IHD and stroke, but the consistently stronger associations in women diminished with increasing age (data not shown).
Physical activity and cardiovascular mortality
In people with CRFs (table 3), there was a reduction in the risk of cardiovascular death with increased training volumes (p trend: 0.002 for CVD, 0.06 for IHD and 0.006 for stroke) and the associations did not substantially differ by sex. In the most physically active people with CRFs, the reduction was 24% (HR 0.76, 95% CI 0.61 to 0.95) compared to the inactive group with CRFs. The specific results for IHD and stroke were similar to those for CVD.
Combined effect of physical activity and CRFs on cardiovascular mortality
In a separate analysis, we assessed the combined effect of physical activity and CRF with IHD mortality (table 4). Compared to people in the reference group of no physical activity and no CRF, the combination of no activity and CRF yielded a HR of 1.41 (95% CI 1.16 to 1.70) in contrast to the combination of high physical activity without CRF that yielded a HR of 0.81 (95% CI, 0.72 to 0.92). In comparison, the HR associated with the combination of high physical activity and CRF was 1.03 (95% CI 0.82 to 1.29).
The results related to stroke mortality were fairly similar to those for ischaemic heart disease (table 5). Compared to people in the reference group of no physical activity and no CRF, the combination of no activity and CRF yielded a HR of 1.46 (95% CI 1.16 to 1.85) in contrast to the combination of high physical activity without CRF that yielded a HR of 0.71 (95% CI 0.60 to 0.84). In comparison, the HR associated with the combination of high physical activity and CRFs was 1.05 (95% CI, 0.77 to 1.43).
In this large population study we found a positive association of a clustering of CRFs with the risk of premature CVD. However, people with CRFs who engaged in physical exercise were at lower risk compared to the inactive group, and their risk was reduced with increasing amount of exercise. In people without CRFs, there was also a reduction in risk with increasing level of physical activity.
The higher relative risk of premature cardiovascular mortality associated with CRFs is in line with results of previous studies.17 18 In addition, we found that the association of CRFs with cardiovascular mortality became weaker with increasing age. Whereas there was a strong positive association with CRF in age groups younger than 60 y at baseline, both in men and women, the strength of the association declined with age. The reason for this is not fully understood, but one possibility could be selective survival and that people with low tolerance for CRFs tend to die before reaching old age. Another possibility could be effects related to different birth cohorts—that is, different conditions or lifestyles associated with the time of growing up.19 Interestingly, Vatten et al20 found a similar age-dependent tendency related to obesity and cardiovascular mortality, with a strong positive association before the age of 60 y followed by a decline of the association with age. Possibly, genomic data combined with observational data from epidemiological studies could help us better understand the weakening of the association with increasing age.
Even though clustering of CRFs is more prevalent in men than in women,21 the association of CRF with mortality was substantially stronger in women. Although data on CRFs and mortality from CVD in unselected populations are sparse, several studies have reported greater risk among women than in men with diabetes.22 23 This has been interpreted as a sex-specific of diabetes, inducing a more unfavourable cardiovascular risk profile among women, including higher blood pressure, obesity and dyslipidemia.22 Another possibility could be that physicians' management of diabetes and coronary heart disease in women is less aggressive than in men, despite greater cardiac disability in women.24
The importance of physical activity status in predicting long-term mortality has mainly been reported in studies of asymptomatic populations such as those of the Framingham study,25 the Aerobic centre longitudinal study,9 the Lipid research clinical trials,26 the HUNT study in Norway7 and in the Harvard alumni study.27 Our population was unique in allowing us to assess subjects both with and without CRF. In individuals with CRFs, physical inactivity was associated with higher risk of CVD and, specifically, with deaths from ischaemic heart disease and stroke, compared to inactive persons without CRFs. The association displayed a gradual pattern, with increased protection with increased level of physical activity. However, the main difference in cardiovascular mortality among those with CRFs was between those who reported a moderate to high level of activity and those reporting very low or no activity. We used the previously described activity index20 28 to categorise level of activity. A high level of physical activity in these data was indicated by a frequency of more than once per week, usual duration of more than 30 min and moderate to vigorous degree of intensity. We also assessed the effect of physical activity related to deaths from ischaemic heart disease and stroke among people with and without CRFs. In people with CRF with a high summary score for physical activity, the risk of dying from ischaemic heart disease was comparable to the risk of healthy inactive individuals without CRFs. These observations are in line with previous studies.4 29
The literature is not clear on whether physical activity is associated with reduced risk of stroke, and especially if physical activity could weaken the risk of stroke among people with CRFs. One meta-analysis showed that moderate to high level of physical activity was associated with reduced risk for both ischaemic and haemorrhagic stroke compared to low level of activity.30 Our results show that among people with CRFs, all levels of activity were associated with reduced risk of dying from stroke and that the level of risk was similar to that of healthy inactive individuals without CRFs. These results are in line with previous studies of obese individuals20 and healthy subjects.7 Stroke is the third leading cause of death and long-term disability in western countries, and more than half a million US adults suffer from stroke each year,31 in which 25% are fatal.32 Effective treatment is limited and survivors require lengthy rehabilitation and care. Therefore, primary prevention is imperative to reduce the burden of stroke and the current study suggests that physical activity protects against premature death due to stroke in individuals with CRFs.
Among people without CRFs, our results confirm those of previous studies in showing that physical fitness is a strong predictor for good cardiovascular health and that even a low level of physical activity is protective against cardiovascular mortality, although there was a tendency that higher training volumes were related to even greater cardiac protection.20 33
There exist no consensus of what is the best regimen of physical activity to achieve optimal protection against premature CVD and death in risk populations. However, although recent studies demonstrates that moderate intensity exercise two to three times a week gives favourable effects in reversing and protecting against CRFs, aerobic interval exercise at higher intensities (but isocaloric programmes) gave substantial larger effects.34 35 Limitations to these studies are small sample size and their results needs to be confirmed in large sample clinical trails.
Limitations and strength of the study
Physical activity and other predictors of mortality were assessed before follow-up, but assessment took place only once and updated information throughout the follow-up period would have been valuable. Thus, individual changes in physical activity and other predictors of disease could not be taken into account in the analysis. However, our data indicate that self-reported physical activity at the beginning of a study is associated with sufficient continued activity to reduce risk against cardiovascular mortality. Furthermore, we cannot exclude the possibility that the reported physical activity may be a marker of other health-related behaviours that were not measured and, therefore, could not be adjusted for in the statistical analysis. Whether self-reported level of physical activity is valid and reproducible is always a concern, but a recent validation study showed that the questionnaire used in the present study was reproducible and provided a good reflection of leisure time physical activity for men.36 This study also found a significant correlation between self-reported physical activity and VO2max.36 There exists several definitions of the metabolic syndrome and the most commonly used are the definitions of the World Health Organization,14 National Cholesterol Education Program12 and the one from the International Diabetes Federation.13 These definitions summarise metabolic clustering and, although the definitions diverge in some components, they are still quite similar. It is a weakness of the combined definition of CRFs used in this study that it has not been formally validated. On the other hand, it is a strength that by using this definition most people with the metabolic syndrome will be included in the CRF group.
This study shows that individuals with CRFs are at greater risk of premature CVD compared to people without CRF. It also shows that the level of physical activity may be of importance to achieve exercise-induced protection against premature cardiovascular mortality in individuals with CRFs. Thus, the risk of people with CRFs who achieved the highest activity score appear to be comparable to that of inactive individuals without CRFs.
What is already known on this subject
The importance of physical activity status in predicting long-term mortality has mainly been reported in studies of asymptomatic populations such as those of the Framingham study and the Aerobic centre longitudinal study. Our population was unique in allowing us to assess subjects both with and without cardiovascular risk factors.
What this study adds
Our large and prospective study show that individuals with cardiovascular risk factors (CRFs) are at greater risk of premature cardiovascular death compared to people without CRFs, and that the risk of people with CRFs who were physically active appears to be comparable to that of inactive individuals without CRFs.
The HUNT Study is collaboration between HUNT Research Centre, Faculty of Medicine, the Norwegian University of Science and Technology (NTNU), the Norwegian Institute of Public Health and the Nord-Trøndelag County Council. The present study was supported by Foundation for Outstanding Young Investigators from the Norwegian Research Council (UW), The Norwegian Council of Cardiovascular Disease, Funds for Cardiovascular and Medical Research at St. Olav's University Hospital, Trondheim, Ship Owner Tom Wilhelmsens Foundation, Ingerborg and Anders Nordheims Foundation, EWS Foundation and Agnes Sars legacy.
LV and UW share senior authorship.
Competing interests None.
Ethics approval This study was approved by the Regional Ethical Committee, Trondheim, Norway.
Provenance and peer review Not commissioned; externally peer reviewed.
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