Exercise training: only if needed?

Joep Perk*

Kalmar County Public Health Centre, Garvaregatan 11, S-572 32 Oskarshamn, Sweden

* Corresponding author. Tel: +46 491 782000; fax: +46 491 782494. E-mail address: joep{at}ltkalmar.se

This editorial refers to ‘Effect of exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study’{dagger} by T.A. Lakka et al., on page 2018

Over the past decade, the role of inflammation in developing atherosclerotic cardiovascular disease (CVD) has been clearly demonstrated. In virtually all phases, from initiation to plaque rupture, cytokines, other bioactive molecules, and inflammatory cells are involved. The analysis of these factors could theoretically be used for diagnostic purposes. Among the cytokines and acute-phase reactants, high-sensitivity (hs) C-reactive protein has proved to be most suitable for clinical use. C-reactive protein can play an active role in the inflammatory process, which includes enhancing the uptake of damaged cells by macrophages, activating endothelial cells to express adhesion molecules, and decreasing the release of endothelial nitric oxide.

Hs-C-reactive protein has shown a dose–response relationship to ischaemic heart disease, independent of known major risk factors. Three levels of hs-C-reactive protein have been proposed in the recommendations by the Centers for Disease Control and the American Heart Association (AHA): low, <1 mg/L; average, 1.0–3.0 mg/L; and high, >3.0 mg/L.1 In a meta-analysis of prospective population-based studies, when the upper tertile was compared with the lower tertile, the relative odds ratio for a major coronary event was 2.0 (95% CI: 1.6–2.5).2 The interrelationship between C-reactive protein and the metabolic syndrome is strong: median baseline C-reactive protein levels rose linearly from 0.68 mg/L in individuals without signs of the metabolic syndrome to 5.75 mg/L in those with all five characteristics of the syndrome.3

However, several questions regarding the role of hs-C-reactive protein in clinical practice remain unanswered: for which major events it has predictive value; does it include cerebral, coronary, and peripheral vascular beds; does it reflect the degree of vascular wall inflammation; is it sensitive to change; does it measure the effect of lifestyle intervention or drug treatment; is the incremental predictive value cost effective. Clearly, more scientific evidence is needed.

Physical fitness and cardiovascular health are closely related in the general population. Observational studies have shown that physical inactivity together with poor cardiovascular fitness predicts CVD. Increased physical activity and cardiorespiratory fitness may lead to decreased CVD mortality. In the recent European guidelines on CVD prevention, healthy persons are recommended to choose enjoyable physical activities which fit into their daily routine, preferably 30–45 min, four to five times weekly at 60–75% of the average maximum heart rate.4 Can we expect that this recommendation leads to lower hs-C-reactive protein values, which suggests an attenuation of the inflammatory burden on the vascular wall?

Physical activity can reduce inflammation and suppress C-reactive protein levels as it is associated with several factors that are independently related to C-reactive protein levels: age, blood pressure, smoking, BMI, cholesterol levels, triglyceride levels, and apolipoprotein B levels. It appears that exercise has a range of effects on cytokine production, thus transforming the resting cytokine balance into an anti-inflammatory state.5 In a multidisciplinary lifestyle programme for obese women, including caloric restriction and physical training, reduced cytokine production [interleukin-6 (IL-6) and TNF-alpha] was observed. This diminishes C-reactive protein levels as hepatic C-reactive protein production is stimulated by IL-6.6

Insulin sensitivity is enhanced by physical activity. Physical training improves endothelial function: it reduces peripheral inflammatory markers (a.o. soluble adhesion molecules) and augments the endothelial-derived release of nitric oxide. Thus, regular physical activity lowers C-reactive protein levels directly via the cytokine pathway and indirectly via weight reduction and improvement of insulin sensitivity and endothelial function.

C-reactive protein levels respond differently to acute or chronic physical exercise. Acute heavy physical exercise leads to an inflammatory response with a marked rise in C-reactive protein levels, suggesting muscular damage proportional to the amount of exercise and muscles engaged. However, longer term exercise training produces an opposite effect, as a parallel protective anti-inflammatory counter response in cytokine production occurs during the course of the training.

The present knowledge on the relationship between physical activity and serum C-reactive protein levels is mainly derived from large observational and cross-sectional studies. There are yet few prospective controlled studies on the effect of exercise intervention on C-reactive protein but the outcomes are not equivocal. In 39 patients with claudicatio intermittens, 3 and 6 months of training resulted in a 17% reduction of C-reactive protein levels.7 Nine months of marathon training reduced C-reactive protein levels to 31% among 12 healthy volunteers when compared with 10 controls.8 In 43 subjects with high risk of ischaemic heart disease, a 35% reduction of C-reactive protein levels was reported after 6 months of physical training, but this outcome did not reach statistical significance.9 The combination of 2 years of weight reduction and physical training in obese women resulted in a 34% drop in serum C-reactive protein levels.5 However, Raurama et al.10 reported a non-significantly lower C-reactive protein level after a 6-year randomized trial of aerobic physical exercise in a population sample of 140 middle aged men. Can the differences in outcome of these studies be understood by the design, the included population, length, intensity, and supervision of the exercise training or other factors?

The present study by Lakka et al.11 from the University of Kuopio, Finland (as the study of Raurama et al.) offers an interesting novel explanation. The aim of the HERITAGE Family Study was to investigate the role of genetic factors in cardiovascular, metabolic, and hormonal responses to standardized exercise training. The population consisted of 652 sedentary individuals of different age, gender, and race, where ‘sedentary’ was defined as not having participated in regular physical activity over the past half-year. Participants were invited to join a 20-week supervised training programme on an ergometer bicycle. They trained three times weekly at a level of 75% of baseline VO2-max. Compliance was excellent with high attendance rates and low drop-out numbers. The participants increased their VO2-max with 18% in average, but the effect on weight, blood pressure, insulin sensitivity, and blood lipids was marginal.

At baseline, the population was stratified in a low, normal, and high tertile for hs-C-reactive protein according to the AHA guidelines.1 As shown in the previous studies, baseline C-reactive protein values correlated with age, gender, smoking, BMI, blood pressure, blood lipids, glucose and insulin levels, the use of hormone replacement therapy, or oral contraceptives. The authors found that exercise training did not influence C-reactive protein levels in the whole study population, but a 24% reduction of C-reactive protein levels after training was observed in the highest C-reactive protein tertile (>3 mg/L). This remained statistically significant after adjustment for all baseline correlates. The reduction was independent of age, gender, race, smoking habits, weight, blood pressure, and the remaining metabolic parameters. Remarkably, the C-reactive protein reduction was not related to the improvement of VO2-max. How may these findings be interpreted?

The outcome of the study is weakened by the lack of a control group and of objective measurements of physical activity in this sedentary population. Only serum hs-C-reactive protein was used, no other markers of vascular wall inflammation were studied.

Can the differences in C-reactive protein response to 20 weeks of exercise training between the highest tertile and the remaining population be explained by confounding factors? The authors have selected a sedentary population, on the basis of a screening question of physical activity in the past 6 months. However, individuals may have difficulties in judging their own habitual physical activity, considerable over- and under-estimation does occur. Has habitual physical activity in daily living influenced C-reactive protein levels? Have the authors obtained cohorts with significantly different levels of physical activity at baseline by stratifying the population in three groups?

If inequalities in baseline activity do not explain the differences in levels of a marker for vascular wall inflammation, may there be other protective elements such as genetic factors, environmental influence, nutritional habits, or psychological factors? If this is the case, are there persons in the low and normal tertiles who are sufficiently protected by these factors and would not benefit from any augmented physical activity as protection against CVD, no need for training?

In the tertile with C-reactive protein >3 mg/L levels fell in average from 5.60 to 4.56 mg/L but did not reach down to normal levels. It is yet impossible to state whether this decrease is clinically significant. Can it be normalized at all? Further studies will be needed to define the optimal design of an exercise training programme: need it be life-long? Which intensity and frequency is effective? One standard programme for all with elevated C-reactive protein levels?

However, the main question is: if exercise training can lower or even normalize C-reactive protein levels, suggesting attenuation of vascular wall inflammation, does this translate into a lower CVD morbidity and mortality? Lakka et al. have shown that exercise training may lead to a lowering of C-reactive protein levels in a subgroup of the sedentary population with elevated levels, which can be as much as a quarter of the adult population. The practical clinical consequence of this finding is that it opens the way for targeted lifestyle counselling, although further studies are needed. In the AHA statement,1 the use of C-reactive protein is only recommended in CVD risk assessment and restricted to individuals with moderate elevated 10-year CVD risk: 10–20% according to the Framingham score. This may correspond to a 3–5% 10-year CVD mortality risk according to SCORE. In this cohort, elevated C-reactive protein levels (>3 mg/L) may become a prognostic tool for cardiologists and general practitioners: it may identify those for whom exercise training will be effective. Keeping other beneficial effects of regular physical activity in mind, still an intriguing question remains unanswered: exercise for all or only needed if there are signs of vascular wall inflammation?

Footnotes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. Back

{dagger} doi:10.1093/eurheartj/ehi394 Back

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