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Relation of Physical Activity to Cardiovascular Disease Mortality and the Influence of Cardiometabolic Risk Factors

      Physical activity can improve several metabolic risk factors associated with cardiovascular disease (CVD) and is associated with a lower risk of CVD mortality. We sought to evaluate the extent to which metabolic risk factors mediate the association between physical activity and CVD mortality and whether physical activity provides protective effects against CVD mortality in healthy adults and those with metabolic risk factors. A sample of 10,261 adults from the Third National Health and Nutrition Examination Survey with public-access mortality data linkage (follow-up 13.4 ± 3.9 years) was used. Physical activity was assessed by questionnaire and classified into inactive, light, and moderate/vigorous activity categories. Metabolic risk factors (dyslipidemia, type 2 diabetes mellitus, obesity, hypertension, inflammation, and insulin resistance) were categorized using clinical thresholds. After adjusting for basic confounders, engaging in light or moderate/vigorous physical activity was associated with a lower risk of CVD mortality (p <0.05). Adjustment for each risk-factor set only slightly attenuated this relation. When all risk-factor sets were added to the model simultaneously, light (hazard ratio 0.72, 0.62 to 0.84) and moderate/vigorous (hazard ratio 0.72, 0.62 to 0.85) activity remained at lower risk of CVD mortality. In addition, physical activity provided protective effects for CVD mortality in healthy subjects and those with metabolic risk factors in isolation or in clusters. In conclusion, physical activity was associated with a lower risk of CVD mortality independent of traditional and inflammatory risk factors. Taken together these results suggest that physical activity may protect against CVD mortality regardless of the presence of metabolic risk factors.
      Physical activity is a therapeutic option often prescribed to patients as a means of improving metabolic risk factors, which include high-density lipoprotein (HDL) cholesterol, excess adiposity, high blood pressure, and glucose metabolism and control.
      • Warburton D.E.
      • Nicol C.W.
      • Bredin S.S.
      Health benefits of physical activity: the evidence.
      Accordingly, physical activity is also associated with a decreased risk of cardiovascular disease (CVD) mortality,
      • Warburton D.E.
      • Nicol C.W.
      • Bredin S.S.
      Health benefits of physical activity: the evidence.
      • Barengo N.C.
      • Hu G.
      • Lakka T.A.
      • Pekkarinen H.
      • Nissinen A.
      • Tuomilehto J.
      Low physical activity as a predictor for total and cardiovascular disease mortality in middle-aged men and women in Finland.
      • Leitzmann M.F.
      • Park Y.
      • Blair A.
      • Ballard-Barbash R.
      • Mouw T.
      • Hollenbeck A.R.
      • Schatzkin A.
      Physical activity recommendations and decreased risk of mortality.
      which may in part be influenced by these improvements in metabolic risk factors. The purpose of the present analysis is to examine the extent to which metabolic risk factors mediate the association between leisure time physical activity and CVD mortality. This will further be examined by investigating the protective effects of physical activity intensity on CVD mortality risk in metabolically healthy adults and in those with individual or clusters of metabolic risk factors.

      Methods

      The study sample was obtained from the Third National Health and Nutrition Examination Survey (NHANES III), which is a nationally representative cross-sectional survey of the United States conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. Data were collected from 1988 through 1994 in 33,994 subjects ≥2 months old using a multistage stratified probability cluster design. Complete details of the study design and procedures are reported elsewhere.
      Centers for Disease Control and Prevention and National Center for Health Statistics
      Plan and operation of the Third National Health and Nutrition Examination Survey, 1988–94 Series 1: programs and collection procedures.
      Analytic and Reporting Guidelines for the Third National Health and Nutrition Examination Survey, NHANES III (1988–94).
      Data from the public-access mortality linkage file were used with follow-up through December 31, 2006. Mortality status was determined primarily through probabilistic matching with the National Death Index death certificate records. The National Death Index has a high sensitivity and specificity generally exceeding 95%.
      • Cowper D.C.
      • Kubal J.D.
      • Maynard C.
      • Hynes D.M.
      A primer and comparative review of major US mortality databases.
      In addition, a calibration study using the NHANES I Follow-Up Survey reported that the National Death Index correctly classified the vital status of 98.5% of participants in the cohort. Underlying cause of death was based on the International Statistical Classification of Diseases, Ninth Revision for deaths occurring from 1988 through 1998 and the International Statistical Classification of Diseases, 10th Revision for deaths occurring from 1999 through 2006. Death was classified for cardiovascular causes from codes 390 to 398, 401 to 404, 410 to 414, 420 to 438, 440 to 448, and 451 to 459 from the ninth revision and codes 100 to 109, 111, 113, 125 to 151, 160 to 178, and 180 to 199 from the tenth revision. All study participants gave their informed written consent before participation in the examination and the study protocol was approved by the National Center for Health Statistics. Subjects were excluded if they were pregnant (n = 196), were <20 or >90 years of age (n = 15,190), had a body mass index (BMI) <18.5 kg/m2 (n = 1,123), or had missing data for age, mortality follow-up, metabolic risk factors, or physical activity (n = 7,224). This left a final sample of 10,261 men and women.
      Participants completed a questionnaire on whether they participated in leisure-time physical activity and, if so, the frequency of their participation in the following activities: walking, jogging, bicycling or bicycling on an exercise bicycle, swimming, aerobics or aerobic dancing, other dancing, calisthenics or exercises, gardening or yard work, and weight lifting. Subjects could also list up to 4 additional activities. Information on duration of physical activity was not assessed. A metabolic equivalent (MET) value was assigned to each activity based on the standardized coding scheme by Ainsworth et al.
      • Ainsworth B.E.
      • Haskell W.L.
      • Whitt M.C.
      • Irwin M.L.
      • Swartz A.M.
      • Strath S.J.
      • O'Brien W.L.
      • Bassett Jr, D.R.
      • Schmitz K.H.
      • Emplaincourt P.O.
      • Jacobs Jr, D.R.
      • Leon A.S.
      Compendium of physical activities: an update of activity codes and MET intensities.
      Physical activity was classified into inactive, light, moderate, and vigorous using standardized methods
      • Crespo C.J.
      • Keteyian S.J.
      • Heath G.W.
      • Sempos C.T.
      Leisure-time physical activity among US adults Results from the Third National Health and Nutrition Examination Survey.
      • Ford E.S.
      Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults.
      consistent with American College of Sports Medicine guidelines.
      • Haskell W.L.
      • Lee I.M.
      • Pate R.R.
      • Powell K.E.
      • Blair S.N.
      • Franklin B.A.
      • Macera C.A.
      • Heath G.W.
      • Thompson P.D.
      • Bauman A.
      American College of Sports Medicine, American Heart Association
      Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association.
      Vigorously active was defined as engaging ≥3 times/week in activities with a MET value of 6 for subjects >60 years old and a MET value of 7 for subjects <60 years old.
      • Crespo C.J.
      • Keteyian S.J.
      • Heath G.W.
      • Sempos C.T.
      Leisure-time physical activity among US adults Results from the Third National Health and Nutrition Examination Survey.
      • Arroll B.
      • Beaglehole R.
      Potential misclassification in studies of physical activity.
      Moderately active was engaging ≥5 times/week in activities of which ≤2 could be considered vigorous. Lightly active was engaging in activity that was considered neither moderate nor vigorous. Inactive was defined as engaging in no leisure-time physical activity.
      Age, gender, income (<$10,000, $10,000 to $29,999, $30,000 to $39,999, ≥$40,000), ethnicity (non-Hispanic White or non-White), smoking status (current smoker, former smoker, or never smoked), alcohol intake (≥3 or <3 drinks/day), dietary fat intake (>30% or ≤30%), medications (lipid, blood pressure, diabetes), and a self-reported physician diagnosis of hypertension, heart attack, stroke, and congestive heart failure were assessed by questionnaire. Participants were classified as having CVD if a physician previously told them they had a heart attack, stroke, or congestive heart failure. BMI was calculated using measured height and weight.
      Blood was drawn from the antecubital vein after ≥6-hour fast for assessment of triglycerides, HDL cholesterol, total cholesterol, plasma glucose, serum insulin, glycated hemoglobin, and C-reactive protein.
      Centers for Disease Control and Prevention
      The Third National Health and Nutrition Examination Survey (NHANES III 1988–94) Reference Manuals and Reports [CD-ROM].
      Blood pressure was assessed by a physician or trained interviewer after the participant had been seated quietly for 5 minutes. Homeostasis model assessment was used to evaluate insulin resistance.
      • Matthews D.R.
      • Hosker J.P.
      • Rudenski A.S.
      • Naylor B.A.
      • Treacher D.F.
      • Turner R.C.
      Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
      Metabolic risk factors were grouped into risk-factor sets based on their pathophysiologic effects. Dyslipidemia was defined as triglycerides ≥2.06 mmol/L, HDL cholesterol <1.04 mmol/L for men and <1.29 mmol/L for women, or total cholesterol ≥6.0 mmol/L.
      National Cholesterol Education Program (NCEP) Expert Panel
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or a physician diagnosis of hypertension.
      National Cholesterol Education Program (NCEP) Expert Panel
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      Inflammation was defined as C-reactive protein ≥0.3 mg/dl
      • Windgassen E.B.
      • Funtowicz L.
      • Lunsford T.N.
      • Harris L.A.
      • Mulvagh S.L.
      C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians.
      and insulin resistance was defined as homeostasis model assessment ≥2.5.
      • Matthews D.R.
      • Hosker J.P.
      • Rudenski A.S.
      • Naylor B.A.
      • Treacher D.F.
      • Turner R.C.
      Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
      Type 2 diabetes mellitus was defined as glycated hemoglobin ≥6.5% or a fasting plasma glucose ≥7.0 mmol/L
      American Diabetes Association
      Diagnosis and classification of diabetes mellitus.
      and obesity was defined as a BMI ≥30 kg/m2.
      National Cholesterol Education Program (NCEP) Expert Panel
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      Baseline characteristics were reported stratified by physical activity and were weighted to be representative of the Unites States population. Because of the small number of deaths in the vigorous category, moderate and vigorous activity groups were collapsed. Differences in participant characteristics among physical activity levels were assessed using 1-way analysis of variance and chi-square tests. Hazard ratios (HRs) for CVD mortality risk were estimated by Cox proportional hazard regressions. No violation of the proportional hazards assumption was observed. No significant gender or age interactions were found; therefore analyses were conducted with men and women of all ages together. The basic multivariate model was adjusted for age, gender, income, ethnicity, smoking status, alcohol intake, high dietary fat intake, and pre-existing CVD. To examine the extent to which metabolic risk factors mediate the association between CVD mortality and physical activity, each risk-factor set (dyslipidemia, type 2 diabetes mellitus, obesity, hypertension, inflammation, and insulin resistance) was added to the basic model individually and then simultaneously with inactive as the referent. Further analysis examined CVD mortality risk in subjects stratified by physical activity and number of metabolic risk factors present. Analyses were performed using SAS 9.2 (SAS Institute, Cary, North Carolina).

      Results

      Baseline characteristics stratified by physical activity group are presented in Table 1. Most of the population reported engaging in light (42.1%) or moderate/vigorous (35.7%) activity. Active subjects were younger, were more likely to be of a high socioeconomic status, be nonsmokers, and have a more favorable metabolic profile than inactive subjects. During follow-up of 13.4 ± 3.9 years there were 2,433 deaths, 1,095 of which were due to cardiovascular causes. Unadjusted survival curves for each physical activity category are shown in Figure 1. Unadjusted mortality rates per 1,000 person-years were 13.2, 6.2, and 7.6 in the inactive, light, and moderate/vigorous physical activity groups, respectively.
      Table 1Baseline characteristics according to physical activity intensity
      VariablePhysical Activity Intensity
      Inactive (n = 2,077)Light (n = 4,431)Moderate/Vigorous (n = 3,753)
      Age (years)49.9 ± 0.643.7 ± 0.5
      Significantly different from inactive (p <0.05).
      45.2 ± 0.6
      Significantly different from inactive (p <0.05).
      Men34.0%48.2%
      Significantly different from inactive (p <0.05).
      54.0%
      Significantly different from inactive (p <0.05).
      White64.6%79.5%
      Significantly different from inactive (p <0.05).
      80.2%
      Significantly different from inactive (p <0.05).
      Black14.3%9.2%
      Significantly different from inactive (p <0.05).
      9.3%
      Significantly different from inactive (p <0.05).
      Hispanic8.4%4.7%
      Significantly different from inactive (p <0.05).
      3.8%
      Significantly different from inactive (p <0.05).
      Other ethnicity12.7%6.6%
      Significantly different from inactive (p <0.05).
      6.7%
      Significantly different from inactive (p <0.05).
      Income
       <$10,00025.1%13.9%
      Significantly different from inactive (p <0.05).
      13.6%
      Significantly different from inactive (p <0.05).
       $10,000–$29,00043.1%34.5%
      Significantly different from inactive (p <0.05).
      34.2%
      Significantly different from inactive (p <0.05).
       $30,000–$39,00012.7%16.0%14.1%
       ≥$40,00019.2%35.6%
      Significantly different from inactive (p <0.05).
      38.1%
      Significantly different from inactive (p <0.05).
      Smoking status
       Never44.7%45.2%45.2%
       Former23.5%25.4%30.8%
      Significantly different from inactive (p <0.05).
       Current31.8%29.4%24.0%
      Significantly different from inactive (p <0.05).
      Pre-existing cardiovascular disease10.3%4.0%
      Significantly different from inactive (p <0.05).
      5.4%
      Significantly different from inactive (p <0.05).
      Hypertension31.9%22.6%
      Significantly different from inactive (p <0.05).
      21.3%
      Significantly different from inactive (p <0.05).
      Type 2 diabetes mellitus7.6%5.5%
      Significantly different from inactive (p <0.05).
      4.1%
      Significantly different from inactive (p <0.05).
      Obesity
      Body mass index ≥30 kg/m2.
      28.2%24.5%18.0%
      Significantly different from inactive (p <0.05).
      Hypercholesterolemia
      Total cholesterol ≥6.0 mmol/L.
      24.6%19.2%
      Significantly different from inactive (p <0.05).
      18.0%
      Significantly different from inactive (p <0.05).
      Low high-density lipoprotein cholesterol
      High-density lipoprotein cholesterol <1.04 mmol/L for men and <1.29 mmol/L for women.
      40.4%39.4%33.3%
      Significantly different from inactive (p <0.05).
      Hypertriglyceridemia
      Triglycerides ≥2.06 mmol/L.
      18.5%18.2%16.0%
      Homeostasis model assessment–estimated insulin resistance
      Homeostasis model assessment ≥2.5.
      40.0%33.8%
      Significantly different from inactive (p <0.05).
      26.2%
      Significantly different from inactive (p <0.05).
      C-reactive protein ≥3 mg/L37.9%29.6%
      Significantly different from inactive (p <0.05).
      23.4%
      Significantly different from inactive (p <0.05).
      Values are presented as mean ± SE or percentage of patients.
      low asterisk Body mass index ≥30 kg/m2.
      Total cholesterol ≥6.0 mmol/L.
      High-density lipoprotein cholesterol <1.04 mmol/L for men and <1.29 mmol/L for women.
      § Triglycerides ≥2.06 mmol/L.
      Homeostasis model assessment ≥2.5.
      Significantly different from inactive (p <0.05).
      Figure thumbnail gr1
      Figure 1Unadjusted survival curves according to physical activity intensity. *All curves are significantly different from each other (p <0.05). DR = death rate; py = person-year.
      Dyslipidemia (HR 1.16, 1.03 to 1.32), type 2 diabetes mellitus (HR 1.66, 1.42 to 1.94), hypertension (HR 1.39, 1.23 to 1.57), inflammation (HR 1.30, 1.15 to 1.47), and insulin resistance (HR 1.22, 1.09 to 1.38) were significantly associated with CVD mortality after adjustment for age, gender, income, ethnicity, smoking status, alcohol intake, high dietary fat intake, and pre-existing CVD. Surprisingly, obesity alone was not found to be significantly associated with CVD mortality (HR 1.12, 0.97 to 1.30) and adjustment for physical activity did not substantially attenuate the results (data not shown). The more metabolic risk factors that were present, the higher the risk for CVD mortality; subjects with ≥3 metabolic risk factors had the highest CVD mortality risk (HR 1.70, 1.35 to 2.15) compared to subjects free of metabolic risk factors. After adjustment for all other CVD metabolic risk factors and physical activity, type 2 diabetes mellitus (HR 1.53, 1.30 to 1.81), hypertension (HR 1.33, 1.17 to 1.50), and inflammation (HR 1.22, 1.08 to 1.38) remained significantly associated with CVD mortality.
      As presented in Table 2 engaging in light (HR 0.72, 0.62 to 0.84) or moderate/vigorous (HR 0.72, 0.61 to 0.84) activity was similarly associated with a lower risk for CVD mortality after adjustment for covariates (basic model). Adjustment for each risk-factor set resulted in little to no attenuation of the inverse relation between CVD mortality and physical activity. When all risk-factor sets were added simultaneously to the basic model, similar results were observed and no further attenuation of the HR was observed.
      Table 2Association between physical activity and cardiovascular disease mortality after adjustment for metabolic risk factors
      Physical Activity Intensity
      Inactive (n = 2,077)Light (n = 4,431)Moderate/Vigorous (n = 3,753)
      Basic model1.000.72 (0.62–0.84)0.72 (0.61–0.84)
      Basic model + dyslipidemia1.000.72 (0.62–0.84)0.72 (0.61–0.84)
      Basic model + type 2 diabetes1.000.72 (0.61–0.84)0.72 (0.61–0.84)
      Basic model + hypertension1.000.73 (0.63–0.86)0.73 (0.62–0.85)
      Basic model + inflammation1.000.72 (0.62–0.84)0.72 (0.62–0.85)
      Basic model + insulin resistance1.000.72 (0.62–0.85)0.73 (0.63–0.86)
      Basic model + obesity1.000.72 (0.62–0.86)0.72 (0.62–0.84)
      Basic model + all of above1.000.72 (0.62–0.84)0.72 (0.62–0.85)
      Basic model was adjusted for age, gender, income, ethnicity, smoking status, alcohol intake, dietary fat intake, and history of cardiovascular disease.
      Figure 2 presents further analysis of CVD mortality risk in subjects with and without a given metabolic risk factor across the 3 physical activity levels. In general, the results demonstrate that subjects with and without metabolic risk factors who engaged in light or moderate/vigorous activity were at a significantly lower risk for CVD mortality compared to inactive subjects with that metabolic risk factor. Similar findings were observed for the combined effect of physical activity and number of prevalent risk factors with CVD mortality (Figure 3) . Regardless of number of metabolic risk factors present, engaging in light or moderate/vigorous activity was associated with a significantly lower relative risk for CVD mortality compared to inactive subjects with ≥3 risk factors.
      Figure thumbnail gr2
      Figure 2Association between physical activity and presence (gray bars) and absence (white bars) of prevalent risk factors with cardiovascular disease mortality risk. Models were adjusted for age, gender, income, ethnicity, smoking status, alcohol intake, dietary fat intake, and history of cardiovascular disease. Dyslipidemia was defined as a triglyceride level ≥2.06 mmol/L, high-density lipoprotein cholesterol levels <1.04 mmol/L for men and <1.29 mmol/L for women, or total cholesterol level ≥6.0 mmol/L; type 2 diabetes mellitus was defined as a glycated hemoglobin concentration ≥6.5% or a fasting plasma glucose level ≥7.0 mmol/L; hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or physician diagnosis of hypertension; inflammation was defined as C-reactive protein level ≥0.3 mg/dl; insulin resistance was defined as homeostasis model assessment ≥2.5; and obesity was defined as a body mass index ≥30 kg/m2. *Significantly different from inactive subjects with metabolic risk factors (p <0.05). Ref = referent (hazard ratio 1.0).
      Figure thumbnail gr3
      Figure 3Association between physical activity and ≥3 risk factors (solid gray bars), 2 risk factors (striped bars), 1 risk factor (white bars), and 0 risk factor (spotted gray bars) present with cardiovascular disease mortality risk. Models were adjusted for age, gender, income, ethnicity, smoking status, alcohol intake, dietary fat intake, and history of cardiovascular disease. *Significantly different from referent category (inactive with ≥3 risk factors, p <0.05). Abbreviation as in .

      Discussion

      The results of this analysis propose that the relation between physical activity and CVD mortality is independent of the many metabolic CVD risk factors suggested to mediate this relation. Further, our findings demonstrate that the protective effects of physical activity regarding CVD mortality risk can also be observed in subjects with metabolic risk factors in isolation or in clusters. These findings highlight the relative clinical importance of prescribing physical activity to prevent CVD mortality regardless of metabolic risk profile.
      Conflicting research has suggested that 0% to 59% of the activity-related decrease in CVD can be explained by metabolic risk factors.
      • Mora S.
      • Cook N.
      • Buring J.E.
      • Ridker P.M.
      • Lee I.M.
      Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms.
      • Hamer M.
      • Stamatakis E.
      Physical activity and risk of cardiovascular disease events: inflammatory and metabolic mechanisms.
      • Wennberg P.
      • Wensley F.
      • Johansson L.
      • Boman K.
      • Di Angelantonio E.
      • Rumley A.
      • Lowe G.
      • Hallmans G.
      • Jansson J.H.
      Reduced risk of myocardial infarction related to active commuting: inflammatory and haemostatic effects are potential major mediating mechanisms.
      • McGuire K.A.
      • Janssen I.
      • Ross R.
      Ability of physical activity to predict cardiovascular disease beyond commonly evaluated cardiometabolic risk factors.
      For instance, a comprehensive list of traditional (blood pressure, BMI, cholesterol), inflammatory, and hemostatic risk factors has been observed to explain a substantial proportion of the activity-related decrease in CVD morbidity,
      • Mora S.
      • Cook N.
      • Buring J.E.
      • Ridker P.M.
      • Lee I.M.
      Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms.
      • Hamer M.
      • Stamatakis E.
      Physical activity and risk of cardiovascular disease events: inflammatory and metabolic mechanisms.
      • Wennberg P.
      • Wensley F.
      • Johansson L.
      • Boman K.
      • Di Angelantonio E.
      • Rumley A.
      • Lowe G.
      • Hallmans G.
      • Jansson J.H.
      Reduced risk of myocardial infarction related to active commuting: inflammatory and haemostatic effects are potential major mediating mechanisms.
      whereas others have suggested that no attenuation of risk occurs after adjustment for such factors.
      • McGuire K.A.
      • Janssen I.
      • Ross R.
      Ability of physical activity to predict cardiovascular disease beyond commonly evaluated cardiometabolic risk factors.
      Two of these studies
      • Hamer M.
      • Stamatakis E.
      Physical activity and risk of cardiovascular disease events: inflammatory and metabolic mechanisms.
      • Wennberg P.
      • Wensley F.
      • Johansson L.
      • Boman K.
      • Di Angelantonio E.
      • Rumley A.
      • Lowe G.
      • Hallmans G.
      • Jansson J.H.
      Reduced risk of myocardial infarction related to active commuting: inflammatory and haemostatic effects are potential major mediating mechanisms.
      included fatal and nonfatal cardiovascular events in their definition of CVD. Because of the small number of deaths, these studies were unable to distinguish the mediating effects of CVD metabolic risk factors for fatal cardiac events specifically. Our results extend previous observations and suggest that engaging in light or moderate/vigorous physical activity is associated with a decrease in risk of CVD mortality of approximately 30% and that this relation is not markedly attenuated by adjustment for metabolic risk factors (dyslipidemia, type 2 diabetes mellitus, obesity, hypertension, inflammation, and insulin resistance). With very little of the risk decrease being explained by metabolic risk factors, the positive effect of physical activity on endothelial function, antioxidant function, or other factors yet to be determined may be playing a mediating role in explaining the decrease in CVD mortality risk.
      • Joyner M.J.
      • Green D.J.
      Exercise protects the cardiovascular system: effects beyond traditional risk factors.
      The present findings further demonstrate that subjects who have ≥1 metabolic risk factor may benefit from significant decreases in CVD mortality risk by engaging in light or moderate/vigorous activity. The present results are consistent with previous research demonstrating that active subjects with metabolic abnormalities such as diabetes
      • Hu G.
      • Jousilahti P.
      • Barengo N.C.
      • Qiao Q.
      • Lakka T.A.
      • Tuomilehto J.
      Physical activity, cardiovascular risk factors, and mortality among Finnish adults with diabetes.
      and hypertension
      • Hu G.
      • Jousilahti P.
      • Antikainen R.
      • Tuomilehto J.
      Occupational, commuting, and leisure-time physical activity in relation to cardiovascular mortality among Finnish subjects with hypertension.
      or a clustering of metabolic risk factors
      • Tjønna A.E.
      • Lund Nilsen T.I.
      • Slørdahl S.A.
      • Vatten L.
      • Wisløff U.
      The association of metabolic clustering and physical activity with cardiovascular mortality: the HUNT study in Norway.
      may be at lower mortality risk compared to inactive subjects with such conditions. However, few studies to date have attempted to simultaneously measure the combined contribution of physical activity and several CVD metabolic risk factors on CVD mortality in the same sample.
      • Hamer M.
      • Stamatakis E.
      Physical activity and risk of cardiovascular disease events: inflammatory and metabolic mechanisms.
      • Blair S.N.
      • Kampert J.B.
      • Kohl 3rd, H.W.
      • Barlow C.E.
      • Macera C.A.
      • Paffenbarger Jr., R.S.
      • Gibbons L.W.
      Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women.
      • Richardson C.R.
      • Kriska A.M.
      • Lantz P.M.
      • Hayward R.A.
      Physical activity and mortality across cardiovascular disease risk groups.
      Moreover, these studies are limited because risk factors such as inflammation and insulin resistance were not examined. Therefore, our findings extend previous knowledge and support the prescription of physical activity as a method to help improve or normalize metabolic risk factors and lower CVD mortality risk regardless of the presence of metabolic risk factors.
      Previous research has demonstrated that a dose–response relation exists between physical activity and CVD morbidity and mortality, with higher levels of physical activity being associated with lower CVD risk.
      U.S. Department of Health and Human Services
      Physical Activity Guidelines Advisory Committee report, 2008. To the Secretary of Health and Human Services. Part A: executive summary.
      However, this dose–response relation was not observed in the present analysis because subjects who reported being lightly active had a similar decrease in CVD mortality risk as those subjects who reported engaging in activity ≥5 times/week. This lack of a dose–response relation may be due to the misclassification of participants' physical activity levels because self-reported questionnaire data did not contain questions on duration of activity or total energy expenditure. However, the present findings may be in line with evidence suggesting that the largest risk decrease in mortality is observed at the lowest end of the activity scale when comparing subjects who engage in no activity to those who are lightly active.
      • Powell K.E.
      • Paluch A.E.
      • Blair S.N.
      Physical activity for health: what kind? How much? How intense? On top of what?.
      In addition, it is plausible that, for those subjects who were lightly active, the relative intensity (perceived level of exertion when exercising)
      • Lee I.M.
      • Sesso H.D.
      • Oguma Y.
      • Paffenbarger Jr, R.S.
      Relative intensity of physical activity and risk of coronary heart disease.
      of their activity was enough to provide them with the mortality benefits associated with physical activity even if physical activity recommendations were not met.
      Several limitations of the present study warrant mention. Physical activity was assessed only at baseline and individual changes in physical activity levels over the course of the follow-up period may have influenced the results. Duration of time spent in each leisure time activity was not objectively measured and the self-reported data for physical activity levels are subject to recall bias; however, misclassification would likely weaken the results observed. In addition, sudden death of unknown cause was not included as a cause of CVD mortality; thus the number of CVD-related deaths reported in this study might be lower than in actuality. It is also possible that the results observed may be explained by unmeasured confounding factors associated with physical activity. Nevertheless, a large ethnically diverse sample representative of the general United States population, a long follow-up, and a large number of deaths provide significant strengths to the study.
      Thus, we suggest that metabolic risk factors may not solely account for the CVD mortality risk decrease associated with leisure-time physical activity. These findings reinforce the importance of physical activity of any intensity for CVD mortality risk regardless of metabolic profile.

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