Physical Activity and Risk of Cardiovascular Disease Events

Inflammatory and Metabolic Mechanisms

Abstract

Purpose: 

The biological mechanisms through which physical activity lowers the risk of cardiovascular disease (CVD) are incompletely understood. We examined the extent to which inflammatory/hemostatic factors (C-reactive protein and fibrinogen), metabolic factors (adiposity, total cholesterol, and HDL cholesterol), and hypertension mediate the association between physical activity and risk of CVD events.

Methods: 

Data were collected from a nationally representative sample of 7881 men and women that were linked to a patient-based database of CVD hospital admissions and deaths up to September 2006.

Results: 

A total of 226 incident CVD events (64 fatal) occurred over an average follow-up of 7.2 yr. The risk of CVD decreased in relation to physical activity groups according to current recommendations (at least 30 min of moderate activity five times per week or vigorous activity three times per week). The lowest risks for CVD were seen in participants meeting the recommendations through undertaking vigorous activity (hazard ratio = 0.47, 95% CI = 0.22-0.99), although being physically active below the guidelines also conferred protection (hazard ratio = 0.57, 0.42-0.77). Biological risk factors collectively explained between 39.4% and 22.6% of the cardioprotective effects of moderate and vigorous physical activity, respectively. Inflammation and hypertension tended to explain the largest proportion of variance.

Conclusions: 

Participation in any physical activity, irrespective of meeting current guidelines, was associated with a lower risk of CVD. The inverse association between physical activity and CVD risk is partly mediated by biological risk factors.

Regular physical activity is widely accepted as playing a crucial role in cardiovascular disease (CVD) prevention (^{6,7,14,15,20,21}). Current physical activity recommendations for the general population advocate the accumulation of at least 30 min of moderate physical activity on 5 d(middot)wk⁻¹ or vigorous activity three times per week (⁹), which is specifically associated with approximately a 30% reduction in risk of CVD death (¹³). The biological mechanisms through which physical activity lowers the risk of CVD are, however, incompletely understood. Exercise training studies demonstrate modest but consistent improvements in various risk factors such as blood pressure (⁴), HDL cholesterol (¹²), C-reactive protein (CRP), and other inflammatory markers (^8,11). Recent evidence from the Women's Health prospective study showed that inflammatory and hemostatic risk factors and blood pressure made the largest contribution to the inverse association between physical activity and CVD events (¹⁷). To extend these findings, we examined the extent to which biological factors mediate the association between physical activity recommendations and CVD risk in a sample of men and women from the Scottish Health Survey (SHS).

METHODS

Participants

The Scottish Health Survey (SHS) is a periodic survey (typically every 3-5 yr) that draws a nationally representative sample of the general population living in households. The sample was drawn using multistage stratified probability sampling with postcode sectors selected at the first stage and household addresses selected at the second stage. Different samples were drawn for each survey. The present analyses combined data from the 1998 and the 2003 SHS. Participants gave full informed consent to participate in the study, and ethical approval was obtained from the London Research Ethics Council.

Baseline assessment

Survey interviewers visited eligible households and collected data on demographics and health behaviors (physical activity, smoking, etc.). On a separate visit, nurses collected information on medical history (including medications) and took anthropometry variables (height, weight, and waist circumference) and blood samples from consenting adults. The overall response rate ranged between 60% and 76% for the different survey year, with approximately 40% of all eligible participants seeing a nurse. Detailed information on the survey method can be found elsewhere (²²).

Exposure and outcome variables

Physical activity questions inquired about participation in the 4 wk before the interview. Frequency, duration, and intensity of participation were assessed across three domains of activity: leisure time sports (e.g., cycling, swimming, running, aerobics, dancing, and ball sports such as football and tennis), walking for any purpose, and domestic physical activity (e.g., heavy housework, home improvement activities, manual and gardening work). The coding of exercise intensity was based on the compendium of physical activities (¹) (light, < 3 METs; moderate, 3-6 METs; vigorous, > 6 METs). The criterion validity of the SHS questionnaire is supported by the results of a recent study on 106 British adults from the general population (45 men), where the output of accelerometers (worn for two nonconsecutive weeks over a month period) was compared against the questionnaire output. The questionnaire appeared to be a valid measure of time spent in moderate to vigorous physical activity. Pearson correlation coefficients were 0.47 in men (P = 0.03) and 0.43 in women (P = 0.02), which is comparable in magnitude to other validation studies (⁵). In terms of test-retest reliability, the coefficients of time spent in moderate to vigorous physical activity were 0.89 for men (P < 0.001) 0.76 for women (P < 0.001).

The main outcome was first occurring fatal or nonfatal cardiovascular events (including myocardial infarction, coronary artery bypass, percutaneous coronary angioplasty, cerebrovascular events, and heart failure). This information was obtained from a patient-based database of CVD hospital admissions and deaths (Information Services Division, Scotland) that was linked to the surveys. The Information Services Division database has demonstrated 94% accuracy and 99% completeness when samples of computerized CVD records from the Scottish national database were compared with the original patient case notes. Classification of the underlying cause of death was based on information collected from the death certificate together with any additional information provided subsequently by the certifying doctor. Mortality from cardiovascular causes was coded according to International Classification of Diseases, Ninth Revision (ICD-9) (390-459) and ICD-10 (I01-I99). Data on CVD hospital admissions were available between 1980 and September 2006, which allowed us to exclude participants with existing CVD at baseline.

Biological risk markers

Peripheral blood was collected in citrate and serum tubes and spun at room temperature. All blood samples were frozen at −70°C until assay. The analysis of CRP levels from serum was performed using the N Latex high-sensitivity CRP mono immunoassay on the Behring Nephelometer II analyzer. The limit of detection was 0.17 mg(middot)L⁻¹, and the coefficient of variation (CV) was less than 6% for this assay. Fibrinogen levels were determined using the Organon Teknika MDA 180 analyzer, using a modification of the Clauss thrombin clotting method, with a CV of less than 10%. Total and HDL cholesterol were measured using the DAX cholesterol oxidase assay method on an Olympus 640 analyzer. All analyses were carried out in the same laboratory according to Standard Operating Procedures by State Registered Medical Laboratory Scientific Officers. Existing hypertension was confirmed from self-reported doctor's diagnosis (an elevated blood pressure reading, >140/90 mm Hg, on three separate occasions). Obesity was defined as body mass index (BMI) ≥30 kg(middot)m⁻² and central obesity as waist >102 cm in men and >88 cm in women.

Statistical analysis

Cox proportional hazards models were used with months as the time scale to estimate the risk of cardiovascular events by physical activity exposure. For participants who survived, the data were censored to September 2006. Physical activity was categorized according to existing recommendations (⁹). Groups consisted of participants who were sedentary (referent), participants who were active but not meeting guidelines, participants who met the guidelines through participating in moderate to vigorous activity (e.g., at least 30 min of moderate activity five times or more per week or 3 d of moderate activity and 1 d of vigorous activity) and those that met guidelines through predominantly participating in vigorous activity (i.e., at least 30 min vigorous activity three times or more per week). The proportional hazards assumption was examined by comparing the cumulative hazard plots grouped on exposure, although no appreciable violations were noted. Test for linear trend was obtained by entering the categorical variables as continuous parameters in the models. In the basic multivariate model, we adjusted for potential confounders, including age, gender, socioeconomic group (SEG) using the Registrar General Classification (I/II professional/intermediate, III skilled nonmanual/skilled manual, IV/V part-skilled/unskilled), and smoking (never, ex-smoker, current smoker). To test the extent to which biological risk factors mediated the association between physical activity and cardiovascular events, we grouped together CVD risk factors considered to be potential mediators on an a priori basis. This included an inflammatory/hemostatic factor (CRP and fibrinogen), a metabolic factor (adiposity measures, total cholesterol, and HDL cholesterol), and a blood pressure factor (diagnosed hypertension). We separately added these risk factors, one set at a time, into the basic model. Finally, we performed a fully adjusted analysis that included all CVD risk factors simultaneously. The proportion of CVD risk reduction explained by each set of CVD risk factors was computed as follows: (HR_{basic model} − HR_adjusted) / HR_{basic model} − 1) × 100 (¹⁷). All blood variables were included as categorical variables-cholesterol, HDL cholesterol, and fibrinogen as tertiles-and CRP were categorized according to previously defined cut points (¹⁹), representing low (<1 mg(middot)L⁻¹), medium (1 to <3 mg(middot)L⁻¹), and high-risk (≥3 mg(middot)L⁻¹) groups. Analyses were also run entering risk markers as continuous values, although this did not appreciably alter the results. We used analysis of variance with Scheffe post hoc tests and chi-square tests to examine univariable relationships of the confounders with the exposure and the outcome variables. In preliminary analysis, we fitted a gender by physical activity term into the models, although there was no evidence of any interaction. We therefore present all results for men and women combined. All analyses were performed using the Statistical Package for the Social Sciences for Windows (version 14; SPSS Inc, Chicago, IL), and all tests of statistical significance were based on two-sided probability.

RESULTS

Complete data were available in 8037 participants, although participants with existing CVD were removed from the analyses (n = 156), leaving a final sample size of 7881 (45.9% men, aged 46.4 ± 15.6 yr). There were a total of 226 incident CVD events (64 fatal) over an average of 7.2 yr of follow-up. Coronary heart disease accounted for 61% of nonfatal events and 66% of fatal CVD events. Thirty-six percent of participants met the physical activity guidelines and 19% reported no physical activity at all. Sedentary participants were older, were more likely to be of lower social status and be smokers, and have higher levels of biological risk factors than the other groups (Table 1). Participants who met physical activity guidelines also had lower risk factors compared with the active/below guidelines group, with the exception of hypertension and total cholesterol, where only the vigorously active differed (see Table 1). All physically active groups demonstrated a lower relative risk of cardiovascular events during follow-up after basic adjustments for age, gender, SEG, and smoking (Table 2), but the vigorously active demonstrated the greatest risk reduction with an event rate of 1%. Medication use was slightly higher in the active/below guidelines group compared with those meeting the guidelines, although additional adjustment for medications did not appreciably modify the risk of CVD events in this group (hazard ratio [HR] = 0.61, 95% CI = 0.45-0.83). When we examined the extent to which biological risk factors mediated the association between physical activity and CVD events, each factor appeared to explain a modest amount that differed according to the physical activity category (see Table 2). For example, in the vigorous activity group, all biological risk factors collectively explained 22.6% of the association in the fully adjusted model (inflammatory/hemostatic factors explained 13.2%, metabolic factors 9.4%, hypertension 9.4%) compared with the active but below guidelines group where these factors only explained a total of 16.3% (inflammatory/hemostatic factors explained 7.0%, metabolic factors 2.3%, hypertension 11.6%).

TABLE 1: Descriptive characteristics of participants at baseline by physical activity exposure.

TABLE 2: The extent to which biological risk factors explain the association between recommended physical activity levels and cardiovascular events.

Several of the biological risk markers were independently associated with CVD events, which included HDL cholesterol >1.5 mmol(middot)L⁻¹ (HR = 0.66, 95% CI = 0.47-0.94, P = 0.022), CRP ≥3 mg(middot)L⁻¹ (HR = 1.73, 95% CI = 1.11-2.70, P = 0.016), and hypertension (HR = 2.04, 95% CI = 1.55-2.71, P < 0.001). In Table 3, we present further analyses where participants were stratified according to physical activity (none vs any) and presence of risk factors (CRP ≥3 mg(middot)L⁻¹, hypertension, HDL <1.5 mmol(middot)L⁻¹, and obesity). The results show that any physical activity was associated with lower CVD risk despite the presence of several risk factors, including inflammation, low HDL, obesity, and smoking. In contrast, participants that were physically active but diagnosed with hypertension did not have a lower risk of CVD compared with sedentary hypertensives, which suggests that physical activity that reduces hypertension is critical for cardiovascular prevention. Overall, physically active participants with no risk factors demonstrated the lowest CVD risk.

TABLE 3: Stratified analyses according to physical activity and presence of risk factors in relation to incident cardiovascular events.

There were a total of 254 deaths during follow-up, and there was a relationship between risk of all-cause mortality and physical activity levels in models adjusted for age, gender, SEG, and smoking, active but not meeting guidelines (HR = 0.55, 95% CI = 0.41-0.71), and meeting guidelines through moderate (HR = 0.36, 95% CI = 0.23-0.56) or vigorous activity (HR = 0.29, 95% CI = 0.11-0.80). The inclusion of all biological risk factors in the models mediated these associations by approximately 6%.

DISCUSSION

The main aim of the present study was to quantify the extent to which biological risk factors mediate the association between physical activity recommendations and CVD events, which has not been widely examined. Our data suggest that the biological factors explained between 39% and 22% of the cardioprotective effects of moderate and vigorous physical activity, respectively. The total amount of variance explained is lower than that in a previous study of US women where biological risk factors explained 59% of the activity related reduction in CVD, with inflammation/hemostatic biomarkers making the largest contribution to lowered risk, followed by blood pressure, lipids, and BMI (¹⁷). We demonstrated a similar trend showing that inflammatory biomarkers and hypertension made the largest contribution to lowered risk. However, we did not measure as many biomarkers that might be a reason for the considerably lower amount of variance explained in the present study. In a large cohort of UK participants, adjustment for traditional CVD risk factors (blood pressure, diabetes, BMI, and lipids) and CRP only slightly (less than 10%) attenuated the association between physical activity and risk of coronary artery disease (²). Thus, unmeasured mediators such as endothelial function (¹⁰), insulin sensitivity (¹⁶), and mental health (³) may also play a role.

There is surprisingly little epidemiological evidence for the cardioprotective effects of physical activity in relation to current recommendations. In a large prospective study of over 200,000 participants, those meeting the physical activity recommendations had the lowest risk of CVD, although those that met the recommendations through vigorous activity demonstrated slightly lower risks (32%) compared with those meeting recommendations through moderate activity (27%) (¹³). Our findings are consistent with these results and additionally show that participants meeting recommendations through vigorous activity had lower biological risk markers, for example, 59% lower levels of CRP than the sedentary. Being active below the recommendations also appeared to confer benefit for protection against CVD and was actually associated with a similar event rate compared with participants meeting guidelines through moderate activity (2.2% vs 2.1% for active/below guidelines and active at moderate level, respectively). This finding might be possibly explained by residual confounding from unmeasured variables. Participants meeting guidelines through moderate activity consisted of a slightly higher proportion of cigarette smokers, although smoking did not appear to appreciably diminish the protective effects of physical activity (see Table 3), which appears to be at odds with recently published data (¹⁸). However, the contribution of biological risk factors to the activity related reduction in CVD was greater for those participating in moderate to vigorous activity. Interestingly, exercise intensity has not been associated with any of the favorable training effects on HDL cholesterol and blood pressure (^4,12), although insufficient studies have been performed in relation to inflammatory/hemostatic factors. It is possible that a threshold effect may exist for some risk factors or that there is an intensity versus volume trade-off.

Several limitations of the present study warrant consideration. We have only assessed physical activity once at baseline; thus, we cannot exclude the possibility that changes in activity over time could have influenced our results. Physical activity, hypertension status, and medication use were assessed by self-report; thus, it is possible that more precise assessment of these factors may have affected the results. Given that lower levels of physical activity could reflect subclinical disease, we cannot discount reverse causality. We did, however, attempt to control for this potential bias by removing participants with existing clinical CVD events at baseline. In additional analyses, we also removed participants reporting angina symptoms (n = 150), although this did not appreciably alter the results (data not shown). We were unable to assess all of the potential biological mediators of physical activity, and these may have accounted for additional unexplained variance. However, the availability of clinically confirmed CVD events, extensive clinical biomarkers, and use of a nationally representative sample from Scotland are significant strengths of this study.

In summary, we have observed that the inverse association between physical activity and CVD risk is partly mediated by biological risk factors including inflammatory/hemostatic factors (CRP and fibrinogen), metabolic factors (adiposity, total cholesterol, and HDL cholesterol), and hypertension.

The authors receive grant funding from the British Heart Foundation, UK (MH), and the National Institute for Health Research, UK (ES). The SHS is funded by the Scottish Executive.

Disclosures: none.

The views expressed in this article are those of the authors and not necessarily of the funding bodies. The results of the present study do not constitute endorsement by the American College of Sports Medicine.

This article was presented in abstract form at the British Association of Sport and Exercise Sciences annual meeting, London, UK, September 3rd, 2008.