Atherosclerosis 235 (2014) 150e161
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Review
The effect of physical activity or exercise on key biomarkers in atherosclerosis e A systematic review Henning Palmefors a, Smita DuttaRoy a, Bengt Rundqvist a, Mats Börjesson b, * a b
Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Göteborg, Sweden Swedish School of Sports and Health Sciences and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 July 2013 Received in revised form 12 April 2014 Accepted 21 April 2014 Available online 1 May 2014
Objective: This systematic review aimed to summarize published papers on the effect of physical activity (PA)/exercise on key atherosclerotic factors in patients with risk factors for or established cardiovascular disease (CVD). Methods: Studies involving PA and cytokines, chemokines, adhesion molecules, CRP and angiogenic factors were searched for in Medline and Cochrane library. Original human studies of more than 2 weeks of PA intervention were included. Study quality was assessed according to the GRADE system of evidence. Results: Twenty-eight papers fulfilled the inclusion criteria. PA decreases the cytokines, tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interferon-y IFN-y (high, moderate and low evidence, respectively). The effect of PA on chemokines; stromal derived factor-1 (SDF-1), interleukin-8 (IL-8) (insufficient evidence) and monocyte chemoattractant protein-1 (MCP-1) (low evidence) was inconclusive. Aerobic exercise decreased the adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) (moderate and high evidence, respectively), while effects of PA on E- and P-selectin were inconclusive. PA decreases C-reactive protein (CRP) (high evidence). The angiogenic actors, endothelial progenitor cells (EPCs) are increased (high evidence) and VEGF is decreased (moderate evidence) by PA. The effect of PA on these factors seems to depend on the type and duration of exercise intervention and patient factors, such as presence of ischemia. Conclusion: As presented in this review, there is a high level of evidence that physical activity positively affects key players in atherosclerosis development. These effects could partly explain the scientifically proven anti-atherogenic effects of PA, and do have important clinical implications. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Atherosclerosis Physical activity Exercise Molecular biology
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1. Search history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2. Evaluating the quality of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1. Cytokines (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.2. Chemokines (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.3. Adhesion molecules (Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.4. Angiogenic factors (Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.5. C-Reactive protein (CRP) (Table 5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
* Corresponding author. Tel.: þ46 705 298360. E-mail address: [email protected] (M. Börjesson). http://dx.doi.org/10.1016/j.atherosclerosis.2014.04.026 0021-9150/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161
4. 5. 6.
151
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1. Introduction Atherosclerosis is a progressive inflammatory artery disease, which is responsible for about 50% of deaths in the western world, mainly due to cardiovascular disease (CVD), including heart disease and stroke [1,2]. Risk factors to develop atherosclerotic diseases include smoking, diabetes, hypertension, hyperlipidemia and lack of physical activity (PA) [3]. Atherosclerosis is a complex process involving a number of factors and inflammatory cells interacting throughout different stages of the development. The atherosclerotic process is initiated by circulating plasma low-density lipoprotein (LDL) entering the sub-endothelial space in the blood vessel. The LDL is oxidized by reactive oxygen species (ROS) and upregulates adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin on the endothelium and induce the expression of chemotactic agents, such as monocyte chemoattractant protein-1 (MCP-1) in endothelial cells. The activated endothelium also causes influx of coagulation proteins [4]. The upregulation of adhesion molecules leads to recruitment of monocytes and T-lymphocytes to the vessel wall, which are key actors in maintaining the inflammatory process [5]. Macrophages and T-lymphocytes, in turn, express chemokines such as MCP-1, cytokines such as interferon Gamma (IFN-y), tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) [1,2]. In response to these mediators, smooth muscle cells (SMC) migrate from the tunica media into the intimal or subendothelial space and a fibrous cap is built [6]. The inflammatory cells in the plaque also produce angiogenic factors such as vascular endothelial growth factor (VEGF) [7,8], which leads to growth of microvessels in the plaque providing nutrition for the plaque, but it can also lead to hemorrhage and thrombosis. The chemokine stromal derived factor-1 (SDF-1) and endothelial progenitor cells (EPCs) are involved in plaque angiogenesis as well as vascular function [9]. Another very important actor in atherosclerosis, C-reactive protein (CRP), is produced in response to IL-6 and its pro-atherogenic effects are exerted mainly through causing endothelial dysfunction [5]. The focal thickening of the vessel that is caused by the resulting atherosclerotic plaque consisting of SMC and inflammatory cells can block the blood flow and cause ischemia. A plaque rupture leads to exposure of subendothelial factors and thrombotic factors, causing an immediate aggregation of platelets and to the formation of a local thrombus, potentially leading to an acute event, such as myocardial infarction or stroke [1,2,4]. Regular PA has been shown to decrease levels of cardiovascular risk factors [10] and improve endothelial function [11e13], as well as protect against myocardial ischemia [14]. These effects possibly contribute to PA reducing cardiovascular morbidity and mortality [13,15,16]. Specifically, exercise has been proposed to affect many key atherosclerotic factors and angiogenic factors, thereby having an effect on the progression of coronary atherosclerosis [14]. However, existing studies vary greatly regarding study quality, duration and type of PA-intervention as well as in outcome measures, and many results are actually based on animal studies. Consequently, the large body of study results is also conflicting, at least partly due to the heterogenous palette of studies. There is a
need for a more uniform scientific approach to the question regarding the evidence for the effects of PA/exercise on atherosclerosis. Therefore, the aim of this review was to systematically review the existing literature for the effects of PA on key components in atherosclerosis development. 2. Method In this systematic review, a literature search in the Medline and Cochrane library was carried out, with the purpose to evaluate the quality of evidence for the effect of PA/exercise on individuals with underlying cardiovascular risk factors and/or established cardiovascular disease. The literature search spanned the years 1999e 2011, and used the search terms presented in Fig. 1. 2.1. Search history In step 1 the basic search terms were “physical activity” OR “exercise”. These terms were then paired with additional search terms for the different biomarkers; cytokines (TNF-a, IFN-y, IL-6), chemokines (SDF-1, IL-8, MCP-1), adhesion molecules (ICAM-1, VCAM-1, E-/P-selectin), angiogenic factors (EPC, VEGF) and CRP, respectively. Any additional relevant studies identified from the literature from the reference lists of available studies, were added. In a first selection, abstracts for each subgroup were analyzed. Abstracts of studies not concerning physical activity, those analyzing different biomarkers or whose aim did not correlate to this literature study, were excluded. Out of 1006 articles reviewed, 114 articles were taken to step 2 of the study selection. These articles, were arranged in tables, divided into the five different subgroups. The number of subjects, the use of control groups, follow-up, results, human/animal trials and whether the study studied the effect of acute or chronic physical activity were noted. Thereafter, a second selection process was performed, where the remaining articles were reviewed against the following inclusion criteria: 1. Being human studies 2. 2 weeks of physical activity 3. original studies (no reviews, case reports) 4. only including patients with cardiovascular risk factors or established CVD. Articles not fulfilling these inclusion criteria were excluded. Of the 114 articles, 51 were excluded, due to studying only the effect of acute physical exercise, 18 for being reviews, 12 due to being animal trials, 3 due to being studies of healthy subjects and 2 due to studies in patients with heart failure where the cause was unknown or other than atherosclerotic disease. Thus, a total of 86 papers were excluded in step 2 of the selection process, and the remaining 28 articles were finally included in this review and subjected to further and detailed scrutiny, regarding quality of evidence. 2.2. Evaluating the quality of evidence We used the state-of-the art GRADE system, to evaluate the quality of evidence [17], of included papers. Firstly, each study was scientifically graded, according to GRADE [17]. As the starting point, a randomized controlled study (RCT) was considered being of highquality (4 points) and an observational study was considered being of low evidence (2 points). However, these initial scores could be
152
H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161
Search terms (physical acƟvity OR
Hits 273
Excluded 247
Cause of exclusion Not regarding
exercise) and cytokines
physical acƟvity
AND (interferon-gamma
Wrong cytokine
OR tnf-a)
analyzed
(physical acƟvity OR
109
87
Not regarding
exercise) AND adhesion
physical acƟvity
molecules AND (vcam-1 OR
Wrong adhesion
icam* OR selecƟn*)
molecule
Remaining 26
22
analyzed
(physical acƟvity OR
495
455
Not regarding
exercise) AND (vegf OR
physical acƟvity
EPC)
Wrong angiogenic
40
factor analyzed
(physical acƟvity OR
129
103
Not regarding
exercise) AND chemokines
physical acƟvity
AND (c OR cc OR cxc OR
Wrong chemokine
cx3c OR sdf-1 OR rantes)
analyzed
Totally
1006
892
26
114
Fig. 1. Compilation of the first selection process, after analyzing abstracts of the studies.
modified according to several factors, increasing or lowering the score. Rating was modified (1 point) downwards by study limitations, imprecision, inconsistency of results, indirectness of evidence and if publication bias was being likely. On the other hand, the score of a specific study could be increased (þ1 point) by showing a large magnitude of effect, by a doseeresponse association, and if confounders likely minimized the effect [17]. In summary, all included studies, for each specific outcome, were, rated as being of very low quality (1 point), low quality (2 points), moderate quality (3 points) and high quality (4 points). In the second step of the quality control, the overall quality of evidence for each outcome was summarized in the Results section. In this part, mainly the high quality studies (4 points), were included, complemented by some studies of moderate quality. For each outcome, the overall quality of evidence was summarized as having very low, low, moderate or high evidence, according to GRADE [17]. In the case that studies of high/medium quality did not show any effect of PA/exercise on a chosen outcome, for the purpose of this review, we defined this as ”insufficient evidence” for the effect of PA/exercise on that particular modality existing at present. 3. Results The 28 included studies fulfilling the inclusion criteria, encompassed 12 studies on the effects of PA on cytokines [18e29], 11 studies on the PA-effects on chemokines [19,22,23,26e28,30e34], 9 on PA and adhesion molecules [18,20,30,34e39], 11 on PA and angiogenic factors [12,19,23,26,31e33,40e43] and 17 on PA effects on CRP [12,18,20e28,34e37,39,41]. Some of the papers studied
more than one factor, and thus were included in more than one subgroup. The results from, and the final evidence grading for each study, are presented in Tables 1e5, for the effect of PA on cytokines, chemokines, adhesion molecules, angiogenetic factors and CRP, respectively. The overall quality of evidence for each outcome, is summarized in Table 6 and the main results are illustrated in Fig. 2. 3.1. Cytokines (Table 1) Overall 12 studies involving cytokines were identified to fulfill the inclusion criteria [18e29] (Table 1). Three of these studies were rated as being of high quality, according to GRADE, and three being of moderate quality. There is high evidence, that PA/exercise decreases TNF-a in cardiovascular risk patients, based on two high quality studies [18,19]. There is moderate evidence that PA/exercise will decrease the levels of IL-6, based on one high quality study [18] and two studies of medium quality [21,23]. Finally, there is low evidence that PA/exercise decreases IFN-y, as shown by three observational studies, one of moderate quality [21] and two of low quality [24,25]. It seems that information/discussion on lifestyle changes, may not be enough, since two high quality studies, showed no effect on IL-6, by such intervention alone [19,20,31,32]. 3.2. Chemokines (Table 2) Overall 11 studies fulfilling the inclusion criteria regarding chemokines were identified [19,22,23,26e28,30e34] (Table 2). Five of these studies were rated as being of high quality, according to GRADE, and two more being of moderate quality.
Table 1 The effect of PA on cytokines. n¼
RCT
Follow up
Client base
Intervention - Type - Amount
GRADE
TNF-a
Schumacher A 2006, [18]
197
Yes
6 months
CHD
High
Y* (
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Review
The effect of physical activity or exercise on key biomarkers in atherosclerosis e A systematic review Henning Palmefors a, Smita DuttaRoy a, Bengt Rundqvist a, Mats Börjesson b, * a b
Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Göteborg, Sweden Swedish School of Sports and Health Sciences and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 July 2013 Received in revised form 12 April 2014 Accepted 21 April 2014 Available online 1 May 2014
Objective: This systematic review aimed to summarize published papers on the effect of physical activity (PA)/exercise on key atherosclerotic factors in patients with risk factors for or established cardiovascular disease (CVD). Methods: Studies involving PA and cytokines, chemokines, adhesion molecules, CRP and angiogenic factors were searched for in Medline and Cochrane library. Original human studies of more than 2 weeks of PA intervention were included. Study quality was assessed according to the GRADE system of evidence. Results: Twenty-eight papers fulfilled the inclusion criteria. PA decreases the cytokines, tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and interferon-y IFN-y (high, moderate and low evidence, respectively). The effect of PA on chemokines; stromal derived factor-1 (SDF-1), interleukin-8 (IL-8) (insufficient evidence) and monocyte chemoattractant protein-1 (MCP-1) (low evidence) was inconclusive. Aerobic exercise decreased the adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) (moderate and high evidence, respectively), while effects of PA on E- and P-selectin were inconclusive. PA decreases C-reactive protein (CRP) (high evidence). The angiogenic actors, endothelial progenitor cells (EPCs) are increased (high evidence) and VEGF is decreased (moderate evidence) by PA. The effect of PA on these factors seems to depend on the type and duration of exercise intervention and patient factors, such as presence of ischemia. Conclusion: As presented in this review, there is a high level of evidence that physical activity positively affects key players in atherosclerosis development. These effects could partly explain the scientifically proven anti-atherogenic effects of PA, and do have important clinical implications. Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Atherosclerosis Physical activity Exercise Molecular biology
Contents 1. 2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1. Search history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2. Evaluating the quality of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1. Cytokines (Table 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.2. Chemokines (Table 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.3. Adhesion molecules (Table 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.4. Angiogenic factors (Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.5. C-Reactive protein (CRP) (Table 5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
* Corresponding author. Tel.: þ46 705 298360. E-mail address: [email protected] (M. Börjesson). http://dx.doi.org/10.1016/j.atherosclerosis.2014.04.026 0021-9150/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161
4. 5. 6.
151
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1. Introduction Atherosclerosis is a progressive inflammatory artery disease, which is responsible for about 50% of deaths in the western world, mainly due to cardiovascular disease (CVD), including heart disease and stroke [1,2]. Risk factors to develop atherosclerotic diseases include smoking, diabetes, hypertension, hyperlipidemia and lack of physical activity (PA) [3]. Atherosclerosis is a complex process involving a number of factors and inflammatory cells interacting throughout different stages of the development. The atherosclerotic process is initiated by circulating plasma low-density lipoprotein (LDL) entering the sub-endothelial space in the blood vessel. The LDL is oxidized by reactive oxygen species (ROS) and upregulates adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin and P-selectin on the endothelium and induce the expression of chemotactic agents, such as monocyte chemoattractant protein-1 (MCP-1) in endothelial cells. The activated endothelium also causes influx of coagulation proteins [4]. The upregulation of adhesion molecules leads to recruitment of monocytes and T-lymphocytes to the vessel wall, which are key actors in maintaining the inflammatory process [5]. Macrophages and T-lymphocytes, in turn, express chemokines such as MCP-1, cytokines such as interferon Gamma (IFN-y), tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) [1,2]. In response to these mediators, smooth muscle cells (SMC) migrate from the tunica media into the intimal or subendothelial space and a fibrous cap is built [6]. The inflammatory cells in the plaque also produce angiogenic factors such as vascular endothelial growth factor (VEGF) [7,8], which leads to growth of microvessels in the plaque providing nutrition for the plaque, but it can also lead to hemorrhage and thrombosis. The chemokine stromal derived factor-1 (SDF-1) and endothelial progenitor cells (EPCs) are involved in plaque angiogenesis as well as vascular function [9]. Another very important actor in atherosclerosis, C-reactive protein (CRP), is produced in response to IL-6 and its pro-atherogenic effects are exerted mainly through causing endothelial dysfunction [5]. The focal thickening of the vessel that is caused by the resulting atherosclerotic plaque consisting of SMC and inflammatory cells can block the blood flow and cause ischemia. A plaque rupture leads to exposure of subendothelial factors and thrombotic factors, causing an immediate aggregation of platelets and to the formation of a local thrombus, potentially leading to an acute event, such as myocardial infarction or stroke [1,2,4]. Regular PA has been shown to decrease levels of cardiovascular risk factors [10] and improve endothelial function [11e13], as well as protect against myocardial ischemia [14]. These effects possibly contribute to PA reducing cardiovascular morbidity and mortality [13,15,16]. Specifically, exercise has been proposed to affect many key atherosclerotic factors and angiogenic factors, thereby having an effect on the progression of coronary atherosclerosis [14]. However, existing studies vary greatly regarding study quality, duration and type of PA-intervention as well as in outcome measures, and many results are actually based on animal studies. Consequently, the large body of study results is also conflicting, at least partly due to the heterogenous palette of studies. There is a
need for a more uniform scientific approach to the question regarding the evidence for the effects of PA/exercise on atherosclerosis. Therefore, the aim of this review was to systematically review the existing literature for the effects of PA on key components in atherosclerosis development. 2. Method In this systematic review, a literature search in the Medline and Cochrane library was carried out, with the purpose to evaluate the quality of evidence for the effect of PA/exercise on individuals with underlying cardiovascular risk factors and/or established cardiovascular disease. The literature search spanned the years 1999e 2011, and used the search terms presented in Fig. 1. 2.1. Search history In step 1 the basic search terms were “physical activity” OR “exercise”. These terms were then paired with additional search terms for the different biomarkers; cytokines (TNF-a, IFN-y, IL-6), chemokines (SDF-1, IL-8, MCP-1), adhesion molecules (ICAM-1, VCAM-1, E-/P-selectin), angiogenic factors (EPC, VEGF) and CRP, respectively. Any additional relevant studies identified from the literature from the reference lists of available studies, were added. In a first selection, abstracts for each subgroup were analyzed. Abstracts of studies not concerning physical activity, those analyzing different biomarkers or whose aim did not correlate to this literature study, were excluded. Out of 1006 articles reviewed, 114 articles were taken to step 2 of the study selection. These articles, were arranged in tables, divided into the five different subgroups. The number of subjects, the use of control groups, follow-up, results, human/animal trials and whether the study studied the effect of acute or chronic physical activity were noted. Thereafter, a second selection process was performed, where the remaining articles were reviewed against the following inclusion criteria: 1. Being human studies 2. 2 weeks of physical activity 3. original studies (no reviews, case reports) 4. only including patients with cardiovascular risk factors or established CVD. Articles not fulfilling these inclusion criteria were excluded. Of the 114 articles, 51 were excluded, due to studying only the effect of acute physical exercise, 18 for being reviews, 12 due to being animal trials, 3 due to being studies of healthy subjects and 2 due to studies in patients with heart failure where the cause was unknown or other than atherosclerotic disease. Thus, a total of 86 papers were excluded in step 2 of the selection process, and the remaining 28 articles were finally included in this review and subjected to further and detailed scrutiny, regarding quality of evidence. 2.2. Evaluating the quality of evidence We used the state-of-the art GRADE system, to evaluate the quality of evidence [17], of included papers. Firstly, each study was scientifically graded, according to GRADE [17]. As the starting point, a randomized controlled study (RCT) was considered being of highquality (4 points) and an observational study was considered being of low evidence (2 points). However, these initial scores could be
152
H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161
Search terms (physical acƟvity OR
Hits 273
Excluded 247
Cause of exclusion Not regarding
exercise) and cytokines
physical acƟvity
AND (interferon-gamma
Wrong cytokine
OR tnf-a)
analyzed
(physical acƟvity OR
109
87
Not regarding
exercise) AND adhesion
physical acƟvity
molecules AND (vcam-1 OR
Wrong adhesion
icam* OR selecƟn*)
molecule
Remaining 26
22
analyzed
(physical acƟvity OR
495
455
Not regarding
exercise) AND (vegf OR
physical acƟvity
EPC)
Wrong angiogenic
40
factor analyzed
(physical acƟvity OR
129
103
Not regarding
exercise) AND chemokines
physical acƟvity
AND (c OR cc OR cxc OR
Wrong chemokine
cx3c OR sdf-1 OR rantes)
analyzed
Totally
1006
892
26
114
Fig. 1. Compilation of the first selection process, after analyzing abstracts of the studies.
modified according to several factors, increasing or lowering the score. Rating was modified (1 point) downwards by study limitations, imprecision, inconsistency of results, indirectness of evidence and if publication bias was being likely. On the other hand, the score of a specific study could be increased (þ1 point) by showing a large magnitude of effect, by a doseeresponse association, and if confounders likely minimized the effect [17]. In summary, all included studies, for each specific outcome, were, rated as being of very low quality (1 point), low quality (2 points), moderate quality (3 points) and high quality (4 points). In the second step of the quality control, the overall quality of evidence for each outcome was summarized in the Results section. In this part, mainly the high quality studies (4 points), were included, complemented by some studies of moderate quality. For each outcome, the overall quality of evidence was summarized as having very low, low, moderate or high evidence, according to GRADE [17]. In the case that studies of high/medium quality did not show any effect of PA/exercise on a chosen outcome, for the purpose of this review, we defined this as ”insufficient evidence” for the effect of PA/exercise on that particular modality existing at present. 3. Results The 28 included studies fulfilling the inclusion criteria, encompassed 12 studies on the effects of PA on cytokines [18e29], 11 studies on the PA-effects on chemokines [19,22,23,26e28,30e34], 9 on PA and adhesion molecules [18,20,30,34e39], 11 on PA and angiogenic factors [12,19,23,26,31e33,40e43] and 17 on PA effects on CRP [12,18,20e28,34e37,39,41]. Some of the papers studied
more than one factor, and thus were included in more than one subgroup. The results from, and the final evidence grading for each study, are presented in Tables 1e5, for the effect of PA on cytokines, chemokines, adhesion molecules, angiogenetic factors and CRP, respectively. The overall quality of evidence for each outcome, is summarized in Table 6 and the main results are illustrated in Fig. 2. 3.1. Cytokines (Table 1) Overall 12 studies involving cytokines were identified to fulfill the inclusion criteria [18e29] (Table 1). Three of these studies were rated as being of high quality, according to GRADE, and three being of moderate quality. There is high evidence, that PA/exercise decreases TNF-a in cardiovascular risk patients, based on two high quality studies [18,19]. There is moderate evidence that PA/exercise will decrease the levels of IL-6, based on one high quality study [18] and two studies of medium quality [21,23]. Finally, there is low evidence that PA/exercise decreases IFN-y, as shown by three observational studies, one of moderate quality [21] and two of low quality [24,25]. It seems that information/discussion on lifestyle changes, may not be enough, since two high quality studies, showed no effect on IL-6, by such intervention alone [19,20,31,32]. 3.2. Chemokines (Table 2) Overall 11 studies fulfilling the inclusion criteria regarding chemokines were identified [19,22,23,26e28,30e34] (Table 2). Five of these studies were rated as being of high quality, according to GRADE, and two more being of moderate quality.
Table 1 The effect of PA on cytokines. n¼
RCT
Follow up
Client base
Intervention - Type - Amount
GRADE
TNF-a
Schumacher A 2006, [18]
197
Yes
6 months
CHD
High
Y* (
