Physical Activity and Markers of Inflammation and Thrombosis Related to Coronary Heart Disease
Demosthenes B. Panagiotakos, 46 Paleon Polemiston
Street, Glyfada, 166 74, Attica, Greece
Epidemiologic studies have provided strong evidence of the beneficial effects of physical activity in patients with coronary heart disease; however, the mechanisms for the cardioprotective effect of physical activity are not fully understood. The more favorable changes in coronary risk profiles of physically active individuals and the favorable changes observed on several of the established coronary risk factors in exercise intervention studies must play a partial role in that protection. In more recent years, inflammatory and thrombotic factors have been implicated in the development and progression of atherosclerosis. Physical activity has been associated with lower levels of several inflammatory markers; however, the effect of physical activity on coagulation markers remains controversial. The authors summarize the studies on the effect of physical activity on several inflammatory and thrombotic variables. The importance of physical activity in the prevention of cardiovascular disease through modification of the inflammatory and thrombogenic processes is also addressed.
Prevention of cardiovascular disease (CVD) through the evaluation and modification of several risk factors has been the emphasis of health care professionals in recent years. Physical inactivity is considered one of the major risk factors that promotes the development and progression of CVD.1,2,3 Sedentary lifestyles increase all causes of mortality, double the risk of CVD, diabetes, and obesity, and substantially increase the risk of colon cancer, high blood pressure, osteoporosis, depression, and anxiety. Preliminary data from the World Health Organization (WHO) suggest that inactivity, or sedentarism, is one of the 10 leading global causes of death and disability.1 More than 2 million deaths each year are attributable to lack of physical activity.
About 60%–85% of adults in countries around the world are simply not active enough to benefit their health. Unfortunately, the situation is not improving; in the rapidly growing cities of the developing world-crowding, poverty, crime, traffic, poor air quality, a lack of parks, sidewalks, sports and recreation facilities, and other safe areas make physical activity a difficult choice. Regular physical activity that is performed on most days of the week reduces the risk of developing or dying from some of the leading causes of illness and death. According to the WHO,1 physical activity improves health in the following ways: 1) reduces the risk of developing diabetes; 2) reduces the risk of developing high blood pressure; 3) helps reduce blood pressure in people who already have high blood pressure; 4) reduces feelings of depression and anxiety; 5) promotes psychological well-being; 6) helps control weight; and 7) helps build and maintain healthy bones, muscles, and joints. However, several investigators underline that the exact mechanisms by which physical activity may benefit human health, and especially CVD, are not fully understood.
Because atherosclerotic vascular disease has been associated with thrombotic events and there exists a clear link between atherosclerosis, inflammation, and thrombosis, the development of markers that have pathobiologic, prognostic, and treatment-related relevance has taken on a role of considerable importance. In this work we summarized the effect of physical activity on several inflammatory and thrombotic markers, based on a systematic review in the literature.
TYPES OF PHYSICAL ACTIVITY
The two principal categories of physical activity are occupational physical activity (OPA) and leisure-time physical activity (LTPA). OPA usually refers to 8 hours per day, whereas the duration of LTPA is quite variable. LTPA includes all forms of aerobic activities, structured endurance exercise programs, resistance-training programs, and sports. Endurance-type physical activity involves repeated use of large muscles, such as in walking or bicycling. The health benefits of such activities have been extensively studied. Resistance exercise (to increase muscle strength, such as by lifting weights), is increasingly being recognized as a means to preserve and enhance muscular strength and endurance and to prevent falls and improve mobility in the elderly.2 It is now recognized that the volume and intensity of exercise needed to produce health benefits is considerably less than the requirements to improve physical fitness.4,5,6 Several studies3,4,5,6,7,8,9,10,11,12 have shown that low-to-moderate intensity physical activity, typical of everyday life, is adequate to favorably influence cardio-metabolic health.4,5,6,7,8,9,10,11,12,13 The benefits include improved glucose hemostasis, blood lipid-lipoprotein levels, abdominal fat distribution, and blood pressure in the absence of significant gains in physical fitness or substantial weight loss.
PHYSICAL ACTIVITY AND INFLAMMATORY MARKERS
Recent studies have determined that inflammatory mechanisms couple dyslipidemia to atheroma formation. Leukocyte recruitment and expression of proinflammatory cytokines characterize early atherogenesis and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a complication of atherosclerosis responsible for myocardial infarctions and most strokes. Increasing evidence indicates the substantial role that inflammation has in plaque progression and rupture.
The association between LTPA and inflammatory markers has been examined by a number of investigators.14,15,16,17 Results of the National Health and Nutrition Examination Survey III14 demonstrated that in a study of 13,748 US adults age 20 years or older, time devoted to physical activity is inversely associated with C-reactive protein (CRP), fibrinogen concentrations, and white blood cell count. In particular, after adjusting for several confounding factors, the risk reduction for elevated CRP concentrations (dichotomized at the ≥85th percentile of the sex-specific distribution) were 2%, 15%, and 47% for participants who engaged in light, moderate, and vigorous physical activity, respectively.
King et al.15 also reported a lower likelihood of inflammatory markers in those engaging in the more physically demanding activities of jogging and aerobic dancing, but not in less demanding activities. Similarly, in 875 individuals aged 70–79, only high levels of housework and yard work activity were inversely and independently associated with favorable levels of interleukin (IL)-6 and CRP.18 A strong, inverse and independent association with LTPA and inflammatory markers, but not with work-related physical strain, was also reported by Rothenbacher et al.16 These findings suggest a likely threshold of exercise volume and/or intensity necessary for favorable changes in the inflammatory markers.
In another study of the Third National Health and Nutrition Examination Survey, Abramson and Vaccarino17 reported that of 3638 healthy US men and women age 40 years and older studied, a graded reduction in elevated CRP levels resulted from the number of times the participants engaged in physical exercise. The reduction in the risk of those engaging in physical activity 4–21 times per month was 23%, while the reduction of those engaging 22 or more times per month was 47%. Similar associations were seen for white blood cell count and fibrinogen levels.
Similarly, Geffken et al.19 reported consistent findings in the Cardiovascular Health Study cohort of 5888 men and women. Compared with those in the lowest quartile of self-reported physical activity, those in the highest quartile had 19%, 6%, 4%, and 3% lower concentrations of CRP, white blood cells, fibrinogen, and factor VIII activity, respectively, after adjustment for gender, presence of CVD, age, race, smoking, body mass index (BMI), diabetes, and hypertension. It was also suggested by the same investigators19 that the association of higher levels of physical activity with lower levels of inflammation markers may be mediated by BMI and glucose. Some support for the latter hypothesis is provided by a report on the association between BMI and CRP, IL-6, and soluble tumor necrosis factor receptors (sTNF-Rs) 1 and 2.20 Further biomarkers were measured in 405 healthy men and 454 healthy women from two large ongoing prospective studies. After adjustment for other predictors of inflammation, physical activity was inversely associated with plasma levels of sTNF-R1, sTNF-R2, IL-6, and CRP (p=0.07, p=0.004, p=0.04, and p=0.009, respectively). After further adjustment for BMI and leptin, most of these associations were insignificant surrogates for fat mass.20 Obesity can interfere with achieving the level of physical activity necessary for cardiovascular health; therefore, based on the findings of the study, an independent effect of physical activity on the inflammatory markers cannot be excluded.
In a study by Reuben et al.,18 870 persons aged 70–79 years in the top 33% of community-dwelling older persons with respect to physical and cognitive functioning observed an association between high levels of recreational activity and lower levels of the inflammatory markers, i.e., IL-6 and CRP. Their findings suggest a mechanism for the protective effect of physical activity and support interventions that increase physical activity in older persons.
Intensive physical activity induces an inflammatory reaction as demonstrated by the delayed increase in blood of acute phase proteins, including CRP. There is also evidence of a diminished acute phase reaction due to regular exercise, suggesting a suppression of the inflammatory response through training. With this information, Mattusch et al.21 measured CRP before and after 9 months of training in 14 subjects preparing for a marathon, studying the outcome effect of training on the baseline CRP concentration. Although training intensity was continuously increased, baseline CRP diminished in 10 of the 12 runners. The CRP median fell from 1.19 mg/L before training to 0.82 mg/L after training (p<0.05). Since intense physical activity is known to be associated with an inflammatory reaction of muscles and tendons, the CRP decrease was unexpected. The decrease of CRP concentration after intense training suggests that intensive regular exercise has a systemic anti-inflammatory effect, contrary to the effect on muscles and tendons.
Oral hormone replacement therapy (HRT) increases plasma CRP concentrations in postmenopausal women. Stauffer et al.22 tested the hypothesis that HRT-related increases in CRP would either be blunted or absent in postmenopausal women who regularly perform endurance exercise. The investigators reported that physically active postmenopausal women exhibit lower plasma CRP concentrations than sedentary controls. In contrast, in a study by Pitsavos et al.,23 891 men (48±14 years old) and 965 women (47±14 years old) with no clinical evidence for CVD (the ATTICA study) reported that the beneficial effect of physical activity on CRP level is significant in men but not in women. A summary of the effect of physical activity on inflammation markers is illustrated in Table I.
Table I. Summary of Studies That Evaluated the Effect of Physical Activity on Inflammation Markers
|Ford,14 2002||13,748 Adults, NHANES III||CRP||Vigorous exercise was associated with a 47% lower likelihood of being in the|
85th percentile of CRP compared with the <85th percentile.
|King et al.,15 2003||4072 Adults, NHANES III||CRP, fibrinogen, WBC||Only participants in jogging and aerobic dancing remained significantly less|
likely to have elevated cardiovascular markers.
|Rothenbacher et al.,16 2003||312 Patients aged 40–68 years with stable CHD and 479 age- and sex-matched controls||CRP, SAA, IL-6, intercellular adhesion|
|Leisure time, but not work-related physical activity, is associated with a|
decreased risk of CHD, effective at even moderate levels of exercise.
|Abramson and Vaccarino,17|
|3638 Adults 40 years and older||CRP, fibrinogen, WBC||More frequent physical activity is independently associated with lower risk of|
elevated inflammation levels.
|Geffken et al.,19 2001||5888 Men and women aged >65 years||CRP, fibrinogen, factor VIII activity,|
|Compared with persons in the lowest quartile, those in the highest quartile of|
physical activity had 19%, 6%, 4%, and 3% lower concentrations of CRP,
WBC, fibrinogen and factor VIII activity, respectively.
|Pischon et al.,20 2003||405 Men and 454 women||CRP, IL-6, and soluble tumor necrosis|
factor receptors (sTNF-Rs) 1 and 2
|Physical activity was inversely associated with plasma levels of sTNF-R1, sTNF-|
R2, IL-6 and CRP.
|Reuben et al.,18 2003||870 Persons aged 70–79 years||IL-6, CRP||High levels of house/yard work and recreational activity were independently|
associated with lower risk of high CRP.
|Mattusch et al.,21 2000||14 Subjects preparing for a marathon||CRP||CRP median fell 31% after training.|
|Stauffer et al.,22 2004||114 Postmenopausal women||CRP||LTPA may prevent the elevation in CRP concentrations due to hormone|
|Pitsavos et al.,23 2003||1856 Adult men and women without|
|CRP, SAA||Vigorous activity vs. sedentary lifestyle was associated with 33% reduction in|
CRP and 17% reduction in SAA levels.
NHANES III=Third National Health and Nutrition Survey; CRP=C-reactive protein; IL=interleukin; SAA=serum amyloid—A; WBC=white blood cells; CHD=coronary heart disease;
LTPA=leisure-time physical activity
PHYSICAL ACTIVITY AND THROMBOTIC MARKERS
Activation markers of coagulation and fibrinolysis are increased in individuals at risk of coronary-artery disease and other thrombotic disorders—a condition defined as the prethrombotic state. Fibrinogen has been convincingly shown to be an independent cardiovascular risk factor. Several observational studies reported an inverse relationship between measures of time devoted in exercise or LTPA and plasma fibrinogen.24,25,26,27,28,29 Wannamethee et al.30 examined the relationship between physical activity and hemostatic and inflammatory variables. Physical activity showed a significant and inverse dose-response relationship with fibrinogen, plasma and blood viscosity, platelet count, coagulation factors VIII and IX, von Willebrand factor, fibrin D-dimer, tissue plasminogen activator antigen, CRP, and white blood cell count, even after adjustment for possible confounders. The effects were similar in men with and without prevalent CVD. An examination of changes in physical activity between baseline and 20 years later showed that inactive men who engaged in at least light physical activity had levels of blood variables approaching those who remained at least lightly active. Those who became inactive showed levels more similar to those who remained inactive. However, Carroll et al.31 reported that the relationship between both LTPA and predicted maximum oxygen consumption with plasma fibrinogen concentration within a cohort of 635 nonsmoking middle-aged men were no longer significant after adjustment for the confounding effect of other ischemic heart disease risk factors.
Cerneca et al.28 studied the behavior of the coagulation system before and after near-maximum, specific, and standardized exercise tests in three groups of males participating in sporting activities (seven rowers using the rowing machine, 12 marathon runners using the treadmill, seven weightlifters using their own exercise equipment, and seven healthy subjects [controls] using the cycle ergometer).
Although obesity is associated with several unfavorable derangements in the hemostatic system, data on the interactions of regular physical activity with blood coagulation in overweight or obese subjects are limited in the literature. Therefore, controlled, randomized clinical trials with adequate statistical power are needed for the evaluation of physical activity in the prevention and treatment of obesity-related atherothrombotic disorders.29 Few studies exist that focus on the effect of such isometric exercise on the hemostatic system. Rocker et al.32 examined 11 healthy male subjects (21–42 years old) of varying fitness levels before, immediately after, and 10 minutes after strenuous isometric exercise of the dominant arm. Prothrombin time and partial thromboplastin time as group tests for the plasmatic coagulation system; platelet count, as well as p-selectin expression for the platelet system; tissue plasminogen activator (t-PA) activity, and antigen for the fibrinolytic system were evaluated. The partial thromboplastin time was shortened immediately after maximal isometric exercise of the dominant arm and the prothrombin time remained unchanged. No change was found in the platelet count, but a marked p-selectin expression was observed immediately after maximal isometric exercise of the dominant arm (p<0.05) and also in the resting contralateral arm. Values returned to baseline after 10 minutes. There was a slight increase of t-PA antigen concentration and white blood cell count at maximal isometric contraction, which did not occur in the resting arm, although changes over the three time points were significant in both arms. Maximal isometric exercise resulted in platelet activation in both arms, a slight activated partial thromboplastin time (aPTT) decrease, and t-PA antigen increases in the local blood stream. As compensatory fibrinolytic changes did not occur, it was not determined whether isometric exercise increased the potential risk of thromboembolism.
In the ATTICA study, Pitsavos et al.23 observed that compared with persons who reported a sedentary lifestyle, those who were defined as highly physically active had insignificantly lower (3%) fibrinogen levels (Table II).
Table II. Summary of Studies That Evaluated the Effect of Physical Activity on Thrombotic Markers
|Seven rowers, 12|
marathon runners, seven
weightlifters and seven
healthy subjects (controls)
|Prothrombin time, partial activated|
thromboplastin time, fibrinogen,
antithrombin III, protein C, protein S,
prothrombin fragment 1 and 2, tissue
activator of plasminogen and its inhibitor
|Physical activity benefits the coagulation|
system particularly as regards
et al.,30 2002
|4252 (60–79 years old)||Platelet count, coagulation factors VIII and|
IX, von Willebrand factor, fibrin D-dimer,
tissue plasminogen activator antigen
|Physical activity showed a significant|
and inverse dose-response relationship
with all the investigated markers.
|635 Nonsmoking men|
(47±8 years old)
|Maximum oxygen consumption, fibrinogen||Data do not confirm a significant|
independent association of both physical
activity and the investigated factors.
|11 Male healthy subjects|
|Prothrombin time and partial|
thromboplastin time, platelet count, p-
selectin expression, tissue plasminogen
|Maximal isometric exercise leads to|
platelet activation in both arms, a
slight aPTT decrease and t-PA antigen
increase in local bloodstream.
|1856 Adult men and|
women without CVD,
|Fibrinogen||Compared with persons who reported|
a sedentary lifestyle, those who were
defined as highly physically active had a
3% lower fibrinogen level.
aPTT=activated partial thromboplastin time; t-PA=tissue plasminogen activator; CVD=cardiovascular disease
CONCLUSIONS AND RECOMMENDATIONS
Numerous studies have determined the positive role of physical activity in reducing overall CVD risk. Reduced BMI and control of arterial blood pressure levels are important coronary risk factors affected by physical activity; however, the exact mechanisms by which exercise may benefit human health have not been established. This review summarized the effects of physical activity on newly presented cardiovascular risk factors, i.e., inflammatory, thrombotic, and oxidative stress markers and the importance of a physically active lifestyle in the prevention of cardiovascular disease. It was determined that physical activity is associated with lower levels of several inflammatory markers. However, it is evident that the effect of physical activity on coagulation and oxidative stress markers needs further investigation since the results from various studies are controversial. Nevertheless, this review underlines the important role of the adoption of a physical active lifestyle in the prevention of CVD through the modification of the inflammatory, and thrombogenic process. Thus, public health policy makers should focus their efforts on informing the community about the crucial importance of lifestyle healthy conditions that impede the developing of acute coronary events.
The authors thank Dr. John Lentzas for his assistance in the preparation of this manuscript.