The effect of physical activity or exercise on key biomarkers in atherosclerosis – A systematic review

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* (<0.001)

Y* (<0.001)

68

Yes

12 months

Obese, breast cancer

High

Y* (<0.05)

/

157

Yes

6 months

Hypercholesterolemia

Goldhammer E 2005, [21]

28

No

3 months

CAD

Astengo M 2010, [22]

56

Yes

8 months

CAD

Cesari F 2009, [23]

86

No

2 weeks

Cardiac rehabilitation

Reed JL 2010*, [24]

24

No

4 months

Sedentary women

Smith JK 1999, [25]

43

No

6 months

CVRF

Ogawa 2010, [26]

21

No

3 months

Elderly subjects

Bruun JM 2006, [27]

27

No

15 weeks

Obese

Niessner A 2006, [28]

32

No

3 months

CAD/CVRF

Gatta L 2010, [29]

14

No

3 weeks

CHF

RCT to lifestyle intervention program or usual care. Training: 6 weekse3 times/week. 9 weekse2 times/week. Remaining e individual training. Weight loss discussion sessions, promoting increased physical activity and diet modification. Weekly 4 months, monthly thereafter. Verbal and written single point advice about diet and/or exercise. Aerobic exercise (bicycle, treadmill). 3 times/week, 45 min each time. 70e80% maximum heart rates. Bicycle ergometer. 5 times/week. 30 min each time. 70% maximal capacity. Bicycle ergometer 6 times/week Training and caloric restriction diet intervention promoting a weight loss. Training 4 times/week, 40e90 min each time. About 80% of max heart rate. Treadmill, cycling, weight lifting. Mean: 2.5 h/week, 70 min each time. Low-intensity resistance exercise training. 1 times/week. Hypocaloric diet and physical activity. 2e3 h training 5 times/week. Endurance training.  3 times/week. 30 min each time. Bicycle ergometer. 85% of heart rate. 2 times/day, 6 days/week

Pakiz B 2011, [19]

Sjögren P 2010, [20]

IFN-y

IL-6

/

High

Y (<0.001)

Moderate

Y (0.002)

Moderate

/

Moderate

Y (<0.0001)

Low

/

Y (0.03)

Low

Y (0.003)

Y (0.007)

Low

/

Y (0.025)

/

Low

Y (<0.01)

Low

/

Low

Y (<0.05)

H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161

Author

/

Compilation of the effects from regular physical activity on serum levels of cytokines. * ¼ decrease is also detected in the control group. CHD ¼ coronary heart disease, CAD ¼ coronary artery disease, CVRF ¼ cardiovascular risk factors.

153

154

Table 2 Effects of PA on chemokines. n¼

RCT

Follow up

Client base

Intervention - Type - Amount

GRADE

Adamopoulos S 2001, [30]

12

Yes

3 months

CHF

High

Schlager O 2011, [31]

40

Yes

12 months

PAD

Van Craenenbroeck EM 2010, [32] Pakiz B 2011, [19]

48

No

6 months

CHF

68

Yes

12 months

Obese, breast cancer

Lee BC 2009, [33]

58

Yes

3 months

Postinfarct

Cesari F 2009, [23]

86

No

2 weeks

Astengo M 2010, [22]

56

Yes

8 months

Cardiac surgery CAD

Bicycle exercise. 5 times/week 30 min each time. Heart rate 70e80%. Intermittent walking. 2 times/week for 6 months. 35e50 min each time. 90% of heart rate. 3 times/week (60 min). Weight loss discussion sessions, promoting increased physical activity and diet modification. Weekly 4 months, monthly thereafter. Bicycle ergometer. 55e75% of VO2-max. 3 times/week. Bicycle ergometer 6 times/week.

Ogawa 2010, [26]

21

No

3 months

Elderly

Niessner A 2006, [28]

32

No

3 months

CAD/CVRF

Bruun JM 2006, [27]

27

No

15 weeks

Obese

Roberts CK 2006, [34]

31

No

3 weeks

Obese

Bicycle ergometer. 5 times/week. 30 min each time. 70% maximal capacity. Low-intensity resistance exercise training. 1 times/week. Endurance training. 3 times/week. 30 min each time. Hypocaloric diet and physical activity. 2e3 h training 5 times/week. Diet and daily treadmill walking. 45e60 min each time.

SDF-1

MCP-1

Y (<0.001)

High

/

High

/ /

High

High

IL-8

Y (0.02)

Moderate

Y (<0.05)

Moderate

/

/

Low Low

Y (0.002)

Y (0.03)

Low

Y (<0.05)

Y (<0.01)

Low

Y (<0.05)

Compilation of the effects from regular physical activity on serum levels of chemokines. CAD ¼ coronary artery disease, CHF ¼ chronic heart failure, CVRF ¼ cardiovascular risk factors, PAD ¼ peripheral arterial disease.

H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161

Author

Table 3 Effects of PA on adhesion molecules. n¼

RCT

Follow up

Client base

Intervention - Type - Amount

GRADE

sVCAM-1

sICAM-1

E-selectin

Schumacher A 2006, [18]

197

Yes

6 months

CHD

High

Y* (<0.001)

Y* (0.043)

Olson TP 2007, [39]

28

Yes

12 months

Obese women

High

/

/

Sjögren P 2010, [20]

157

Yes

6 months

Hypercholesterolemia

High

/ Y* (<0.005)

** Y (<0.05)

Lara Fernandes J 2011, [36]

34

Yes

4 months

CAD

High

/

Adamopoulos S 2001, [30]

12

Yes

3 months

CHF

High

Y (<0.01)

Y (<0.01)

Hatunic M 2007, [35]

21

No

3 months

Low

/

/

/

Saxton JM 2008, [37]

104

Yes

6 months

Obese women, early onset T2DM PAD

Low

/

/

/

Saetre 2011, [38]

29

No

2 months

PAD

Low

/

Y (0.016)

Y (0.013)

Roberts CK 2006, [34]

31

No

3 weeks

Obese

RCT to lifestyle intervention program or usual care. Training: 6 weekse3 times/week. 9 weekse2 times/week. Remaining e individual training. Resistance training. 2 times/week. Verbal and written single point advice about diet and/or exercise. Bicycle exercise. 3 times/week, 60 min each time. Bicycle exercise. 5 times/week 30 min each time. Heart rate 70e80% Bicycle/treadmill. 4 times/week 60 min each time. Arm/leg-cranking exercise. 40 min, 2 times/week Walking (cycling, strength training). 2 times/week 30e60 min each time. Diet and daily treadmill walking. 45e60 min each time.

Low

Y (<0.01)

Y (<0.05)

P-selectin

/

/

H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161

Author

Y (<0.01)

Compilation of the effects from regular physical activity on serum levels of adhesion molecules. * ¼ reduction also detected in sedentary control group. ** ¼ significant reduction in diet and exercise group, compared to exercise group only. CHD ¼ coronary heart disease, CAD ¼ coronary artery disease, CHF ¼ chronic heart failure, T2DM ¼ type 2 diabetes, PAD ¼ peripheral arterial disease.

155

156

Table 4 Effects of PA on angiogenic factors. Author

n¼

Follow up

Client base

Intervention - Type - Amount

GRADE

EPC type

EPC

VEGF

Intermittent walking. 2 times/week for 6 months. 35e50 min each time. Bicycle ergometer. 55e75% of VO2-max. 3 times/week Weight loss discussion sessions, promoting increased physical activity and diet modification. Weekly 4 months, monthly thereafter. 90% of heart rate. 3 times/week, (60 min). Bicycle ergometer 6 times/week. Running exercise. 5 times/week 30e60 min each time. Treadmill exercise. 98  47 min/week. Habitual Physical Activity Level was measured using an International PAL Questionnaire. Habitual PAL was obtained by estimating the total weekly energy expenditure (Metabolic equivalents/week). Cycling/running 2 times/day, 6 times/week Low-intensity resistance exercise training. 1 times/week. 8 week of exercise training. Bicycle ergometer, 3 times/week.

High

CD133þ/CD34þ/KDRþ

[ (<0.01)

/

Schlager O 2011, [31]

40

Yes

12 months

PAD

Lee BC 2009, [33]

39

Yes

3 months

Postinfarction

Pakiz B 2011, [19]

68

Yes

12 months

Obese, breast cancer.

Van Craenenbroeck EM 2010, [32] Cesari F 2009, [23] Steiner S 2005, [40]***

48

No

6 months

CHF

86 20

No No

2 weeks 3 months

Cardiac rehabilitation CAD/CVRF

72 116

No No

3 months Retrospective

Obese women CAD

Czepluch FS 2011, [42] Ogawa 2010, [26]

13 21

No No

7 weeks 3 months

Sedentary subjects Elderly women

Thijssen DH 2006, [43]

24

No

2 months

Young men/old men

Lippincott MF 2008, [41] Luk TH 2009, [12]

High

Y (0.01)

High

/

High

CD34þ/KDRþ/CD3

[* (0.021)

Moderate Low

CD133þ/CD34þ/KDRþ CD133þ/CD34þ/KDRþ

[** (0.05) [ (0.0001)

Low Low

CD 133þ/VEGFR-2þ CD34/KDRþ CD133/KDRþ

[ (<0.0003) / [ (0.03)

Y**** (<0.01) /

Low Low Low

Y (0.001) /

CD34 þ VEGFR2þ

//Y***

Compilation of the effects from regular physical activity on serum levels of angiogenic factors. * ¼ significant increase also detected in the sedentary control group. ** ¼ the change is only significant in relation to observed improvement in exercise capacity. *** ¼ Eight sedentary young men compared to eight trained young men. 8 older men compared their physical exercise-induced results with baseline levels. No changes in young subjects. Small but significant decrease among older men compared to baseline levels. **** ¼ VEGF-A-induced monocyte chemotaxis being measured. PAD ¼ peripheral arterial disease, CHF ¼ chronic heart failure, CVRF ¼ cardiovascular risk factors, CAD ¼ coronary heart disease.

H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161

RCT

Table 5 Effects of PA on CRP. n¼

RCT

Follow up

Client base

Intervention - Type - Amount

GRADE

CRP

Olson TP 2007, [39] Sjögren P 2010, [20]

28 157

Yes Yes

12 months 6 months**

Obese women Hypercholesterolemia

High High

Y (<0.01) /

Schumacher A 2006, [18]*

197

Yes

6 months

CHD

High

Y* (<0.001)

Lara Fernandes J 2011, [35]

34

Yes

4 months

CAD

High

Y*** (0.05)

Goldhammer E 2005, [21]

28

No

3 months

CAD

Moderate

Y (0.001)

Astengo M 2010, [22]

62

Yes

8 months

CAD

Moderate

/a

Cesari F 2009, [23] Smith JK 1999, [25]

86 43

No No

2 weeks 6 months

Heart surgery CVRF

Moderate Low

Ya (<0.0001) /*****

Ogawa 2010, [26]

21

No

3 months

Elderly

Low

/****

Bruun JM 2006, [27]

27

No

15 weeks

Obese

Low

Y (<0.05)

Niessner A 2006, [28]

32

No

3 months

CAD/CVRF

Low

/a

Roberts CK 2006, [34]

31

No

3 weeks

Obese

Low

Y (<0.05)

Hatunic M 2007, [35]

21

No

3 months

Low

/a

Saxton JM 2008, [37]

104

Yes

6 months

Obese women, early onset T2DM PAD

Low

/a

Lippincott MF 2008, [41] Luk TH 2009, [12]**

72 116

No No

3 months Retrospective

Obese women CAD

Low Low

/a /a

24

No

4 months

Sedentary women

Resistance training. 2 times/week. Verbal and written single point advice about diet and/or exercise. RCT to lifestyle intervention program or usual care. Training: 6 weeks e 3 times/week. 9 weeks e 2 times/week. Remaining e individual training. Bicycle exercise. 3 times/week. 60 min each time. Aerobic exercise (bicycle, treadmill). 3 times/week, 45 min each time. 70e80% maximum heart rate. Bicycle ergometer. 5 times/week. 30 min each time. 70% maximal capacity. Bicycle ergometer, 6 times/week. Treadmill, cycling, weight lifting. Mean: 2.5 h/week, 70 min each time. Low-intensity resistance exercise training. 1 time/week. Hypocaloric diet and physical activity. 2e3 h training 5 times/week. Endurance training. 3times/ week. 30 min each time. Diet and daily treadmill walking. 45e60 min each time. Bicycle/treadmill. 4 times/week, 60 min each time. Arm/leg-cranking exercise. 40 min, 2 times/week. Treadmill exercise. 98  47 min/week. Habitual Physical Activity Level was measured using an International PAL Questionnaire. Habitual PAL was obtained by estimating the total weekly energy expenditure (Metabolic equivalents/week). Training and caloric restriction diet intervention promoting a weight loss. Training 4 times/week, 40e90 min each time. About 80% of max heart rate.

Low

/a

Reed JL 2010, [24]

H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161

Author

Compilation of the effect of long-term physical activity on levels of CRP (C-reactive protein). * ¼ reduction also detected in sedentary control group. ** ¼ a single time point advice on diet and/or exercising habits, effects evaluated in each group six months later. *** ¼ comparison between CRP levels after an acute exercise before and after 4 months of endurance training. **** ¼ significant decrease (<0.05) before applying a Bonferroni correction. ***** ¼ Intervention resulted in a 35% decrease in CRP levels, p ¼ 0.12. CHD ¼ coronary heart disease, CAD ¼ coronary artery disease, CVRF ¼ cardiovascular risk factors, T2DM ¼ Type 2 diabetes, PAD ¼ peripheral arterial disease. a hsCRP (High Sensitivity C-reactive Protein) measured.

157

158

H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161

Table 6 Overall quality of evidence, for the effect of PA/exercise on different angiogenetic factors. Group

Factor

Effect

Evidence

Cytokines

TNF-a IFN-g IL-6 SDF-1

Decrease Decrease Decrease ?

High Low Moderate

IL-8

?

MCP-1 SV-CAM-1

Decrease Decrease

Low Moderate

SI-CAM-1 E/P-selectin

Decrease ?

High

EPC

Increase

High

VEGF

Decrease Decrease

Moderate High

Chemokines

Adhesion molecules

Angiogenetic factors CRP

Comment

Insufficient evidence Insufficient evidence

Insufficient evidence

There is insufficient evidence, that PA/exercise will have effect on SDF-1, based on two high quality studies [31,32] showing no effect, while the study of Lee [33], showed a significant decrease of SDF-1. In addition, there is insufficient evidence that PA/exercise will have an effect on IL-8, as one study of high quality, and one of medium quality [19,22], showed no effect, while one study of moderate quality showed a decrease in IL-8 [23]. There is low evidence, that PA/exercise will decrease MCP-1, as supported by one high quality study with only 12 participants [30], and the other three out of four, being low quality studies (Table 2). 3.3. Adhesion molecules (Table 3) Overall 9 studies were found to fulfill the inclusion criteria on the effect of physical activity/exercise on adhesion molecules [18,20,30,34e39] (Table 3). Five of these studies were rated as being of high quality, according to GRADE, and none of medium quality.

There seems to be moderate evidence that aerobic PA/exercise will reduce VCAM-1, as supported by two high quality studies [18,30], while the study by Lara Fernandez [36], could not show any effect on VCAM-1, by bicycle exercise 3 times/week, in patients with CAD. Two additional high quality studies, using resistance exercise [39] and single-point advice on PA only [20], could find no effect. There is high evidence that aerobic exercise/PA decreases ICAM-1, supported by two high quality studies [18,30]. Again, resistance exercise [39], did not show any effect. But, single-point advice on PA and diet, significantly decreased ICAM-1 [20]. Regarding the effect of PA/exercise on E-selectin there is insufficient evidence that PA/exercise will decrease the levels of Eselectin. One high quality study of diet and PA counseling [20] did show decreased levels of E-selectin, but no other high or medium quality studies exists, using aerobic PA/exercise interventions. One high quality study of resistance training showed no effect [39]. Similarly, for P-selectin, insufficient evidence exists, as no high or medium quality studies, have been performed, and the low quality studies show conflicting results.

3.4. Angiogenic factors (Table 4) Overall, 11 studies on the effect of PA/exercise on angiogenic factors, in patients with risk factors for or established cardiovascular disease, were identified [12,19,23,26,31e33,40e43], fulfilling the inclusion criteria (Table 4). Four of these studies were rated as being of high quality, according to GRADE, and one of medium quality. There is high scientific evidence, supporting that PA/exercise will increase the levels of EPC, as supported by two high quality studies [31,32] and one of medium quality [23]. There is moderate evidence that aerobic exercise will decrease VEGF, as supported by one high quality [33] and one medium quality study [23], both using bicycle ergometer as interventions. One high quality study, using lifestyle advice only, could not show any effect [19], neither could the study by Schlager [31], using intermittent walking as intervention.

Fig. 2. An overview over the effect of physical activity/exercise on key factors in the atherosclerotic process. The green arrows show the effect of physical activity/exercise (CRP ¼ Creactive protein, LDL ¼ low density lipoprotein, OxLDL ¼ oxidized LDL, ROS ¼ reactive oxygen species, VCAM-1 ¼ vascular cell adhesion molecule-1, ICAM-1 ¼ intracellular adhesion molecule-1, MCP-1 ¼ monocyte chemoattractant protein-1, IFN-y ¼ interferon-y, TNF-a ¼ tumor necrosis factor-a, IL-6 ¼ interleukin-6, EPC ¼ endothelial progenitor cell, VEGF ¼ vascular endothelial growth factor). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

H. Palmefors et al. / Atherosclerosis 235 (2014) 150e161

3.5. C-Reactive protein (CRP) (Table 5) Overall, 17 studies on the effect of physical activity/exercise on C-reactive protein (CRP), fulfilling the inclusion criteria were identified [12,18,20e28,34e37,39,41], (Table 5). Four of these studies were rated as being of high quality, according to GRADE, and three of medium quality. In summary, there is high evidence that PA/exercise decreases the levels of CRP, as supported by two high quality studies [18,36] using aerobic exercise as intervention, and one high quality study [39], using resistance training. Two medium quality studies, using aerobic exercise, showed decreased CRP [23], and no effect [22], respectively. One high quality study on single-point advice [20], showed no effect on CRP. 4. Discussion The main result of this systematic review was that physical activity/exercise has positive non-acute effects on several key factors in the atherosclerosis process in patients with risk factors for or established cardiovascular disease. The present paper show, that a) there is good evidence that PA decreases cytokines, in particular TNF-a, and to some extent also IL-6, while there are only indications of the PA-induced effect on IFN-y. b) There is insufficient evidence or low evidence for the effect of PA on the chemokines SDF-1, MCP-1 and IL-8. c) PA induces decrease in adhesion molecules VCAM-1 and ICAM-1, while the effects on Eand P-selectin are inconclusive. d) There is strong evidence that CRP-levels are lowered by PA. e) There is moderate evidence that the angiogenic factor VEGF is reduced by PA. f) EPC is clearly shown to be increased by PA (Fig. 2). The effect of PA on TNF-a, is an important finding, as TNF-a is an important actor in atherosclerosis and vascular function in several ways. It is central in vascular inflammation, involved in oxidative stress and apoptosis and also has thrombogenic potentials [44e46]. In addition, TNF-a also increases expression of adhesion molecules [44]. Also other cytokines seem affected by PA. Although more studies need to be done to confirm the association of PA and IFN-y, there is moderate level evidence that also this cytokine which is important for SMC stimulation, macrophage activation and plaque destabilization can be lowered by PA [1,47,48]. Also IL-6 levels seem to be lowered by PA in patients with cardiovascular disease or cardiovascular risk factors. This finding is indeed interesting as IL-6 levels are increased in patients with cardiovascular risk factors and higher levels are in turn associated with an increased risk of developing CVD [49e52]. IL-6 has an important task in atherosclerosis by producing CRP [53,54]. CRP acts in atherosclerosis through increasing the levels of reactive oxygen species (ROS) and nuclear factor kappa beta (NFkB). NFkB in turn induces levels of chemokines and cytokines [55e58]. Increased levels of CRP-levels have been associated with higher cardiovascular risk [55,56]. Thus, aiming towards lowering the CRP level could affect the atherosclerotic process, vascular function as well as the prognosis in cardiovascular disease. The CRP lowering effects of PA, as shown by this review, is thus a very important finding. While the effects of PA on cytokines and CRP seem well studied, more studies need to be performed to study the effect of PA on chemokines. There are indications that PA decreases the chemokine MCP-1 [30]. Being an important chemotactic factor for monocytes and macrophages, as well as being associated with the risk of developing myocardial infarction [59], these findings are indeed interesting. However, these initial findings need to be supported by more evidence. From this review of the currently available studies, it is also questionable whether IL-8 is affected by PA.

159

SDF-1 is a chemokine that is mainly involved in the chemotaxis of progenitor cells and is important in angiogenesis. The only highquality study that showed PA-induced increase in SDF-1 was done post-myocardial infarction, when there is a higher need of vascular and myocardial repair [33]. The study by Lee also showed exerciseinduced decrease in VEGF [33] and found that the levels of these factors were inversely correlated to myocardial blood flow in these cardiac rehabilitation patients [33]. Thus, three months aerobic exercise training reduced ischemia in these patients. Both SDF-1 and VEGF are important in angiogenesis and stimulated by ischemia, and the presence of ischemia may be required, for PA to have an effect on these factors. EPC acts in angiogenesis through vascular repair and is activated by SDF-1 and VEGF. Low levels of circulating EPCs are strongly connected to an increased risk of cardiovascular disease and impaired endothelial function [60]. Importantly, EPC was increased in response to exercise in a majority of studies included in this review. The clinical implication of these findings may be particularly important in the future, with increasing problems of lifestyle related disorders being anticipated worldwide. It is essential that the role of PA in prevention and treatment of atherosclerosis and its complications, is implemented in the clinical health care setting. This great challenge, will necessitate individualized prescribed PA/exercise to each patient with underlying cardiovascular risk factors and/or cardiovascular disease. In this context, it is very important that the present review suggests that the effects on key players in the atherosclerostic process by PA/exercise, may be dependent on the type of activity, as well as on the duration and intensity. For example, VCAM-1 and ICAM-1 seemed to be affected by aerobic exercise [18,30], while resistance training showed no effect [39]. Also, other atherogenic factors respond differently depending on exercise intensity. Aerobic exercise interventions, had an effect on VEGF, but intermittent walking did not elicit any response [31]. In the studies that reported decreased IL-8 levels by PA, the intensity of activity was higher compared to the studies that showed no effect. 5. Limitations In the present systematic review, we have studied the effect of PA/exercise only in patients with cardiovascular disease or cardiovascular risk factors. Including other patient groups, studies of longer duration as well as animal studies, may have shown different results on the key players in atherosclerosis. 6. Summary In summary, atherosclerosis is a complex process. In this systematic review, we have summarized the studies on the effect of PA on important atherosclerotic factors in patients with risk factors for, or established CAD. It is clear that PA reduces the levels of many factors that are crucial in vascular inflammation and function, including cytokines, CRP and angiogenic factors, probably explaining part of the antiatherogenic effects of physical activity. This evidence further motivates the implementation of already existing guidelines on secondary prevention of cardiovascular disease, using PA as an intervention. The clinical challenge of implementing PA as a regular treatment option in ordinary health care, still remains. Results of studies like the ones summarized in this review, will hopefully aid in this process. Acknowledgments The authors want to thank Eva-Lotte Daxberg at the medical library in Sahlgrenska University Hospital/Östra for introduction to the search engines.

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