High frequency home-based exercise decreases levels of vascular endothelial growth factor in patients with stable angina pectoris

Abstract

Background

In coronary artery disease (CAD), circulating angiogenic factors have been seen to increase, possibly as a response to ischaemia. Regular physical activity (PA) is recommended for prevention and treatment of CAD, but more research is needed to optimise PA regimes. We investigated the effect of home-based high frequency exercise (HFE) on angiogenic cytokines and cardiac markers in patients with stable CAD.

Design

This was a randomised case-control study

Methods

Sixty-two patients, with stable CAD, were randomised to HFE (n = 33), (aerobic exercise 70% of max, 30 min, five times/week and resistance exercise three times/week), performed at home, or usual lifestyle (control, n = 29). After eight weeks, percutaneous coronary intervention (PCI) was performed in both groups, and the HFE group continued another six months of exercise. Serum vascular endothelial growth factor (VEGF) and stromal derived factor-1 (SDF-1), plasma N-terminal-brain natriuretic peptide (NT-proBNP), high-sensitive troponin T (TnT) and copeptin were analysed.

Results

Data are presented as median (25^th, 75^th percentile) of relative changes (%) from baseline. Values of p are given for the difference between the HFE and controls. HFE decreased circulating VEGF levels, before PCI (−5% (−15%, −2%)), while VEGF levels increased in the control group (5% (−3%, 20%) p = 0.004). A significant difference in VEGF remained at three months post-PCI (HFE (−1%(−12%, 5%), control (7% (0%, 14%), p = 0.04), but not at six months after PCI. SDF-1, NT-proBNP, TnT and copeptin levels did not differ significantly. In addition, VEGF levels were positively correlated to NT pro-BNP.

Conclusions

Home-based HFE decreased circulating VEGF in patients with stable CAD, suggesting a reduced ischaemic burden. HFE does not increase markers of cardiac dysfunction, suggesting that it is a safe therapeutic intervention in these patients.

Keywords

Angiogenesis vascular endothelial growth factor stromal derived factor-1 exercise coronary artery disease

Introduction

In primary prevention, regular physical activity (PA) is associated with reduced cardiovascular morbidity and mortality.^1,2 A recent systematic review investigating the effectiveness of the combination of percutaneous coronary intervention (PCI) and exercise compared with PCI alone in coronary artery disease (CAD), reported the incidence of non-fatal coronary events to be lower in the exercise group. Moreover, significant differences in restenosis rate or residual diameter of the stenosis were also reported with exercise.³ Exercise also reduces the risk of developing cardiovascular events and being re-hospitalised after PCI.^4,5

The mechanisms behind these clinical results, may be explained by exercise having multiple effects by itself or in combination with other life-style changes, including reducing classical risk factors of CAD.⁶ In addition, regular exercise seems to have an effect on the atherosclerosis progression itself,^7,8 on endothelial function,⁹ myocardial perfusion,^10,11 collateral blood flow¹² as well as important angiogenic factors,^13,14 all contributing to decreasing myocardial ischaemia.

Vascular endothelial growth factor (VEGF) and stromal derived factor-1 (SDF-1) are crucial in angiogenesis. Both factors are induced by myocardial ischaemia.^15–17 VEGF induces proliferation of endothelial cells and both VEGF and SDF-1 are of great importance in order to recruit endothelial progenitor cells (EPCs).^18,19 In patients with CAD, higher levels of circulating angiogenic cytokines are seen when compared to healthy controls.¹⁵ This is usually considered secondary to myocardial ischaemia, but might also suggest plaque growth and progression.¹⁵ In one study, a supervised, post-myocardial infarction exercise programme decreased circulating angiogenic cytokines, as well as the infarction size, corresponding to improved myocardial blood flow.¹⁵

In a study by Hambrecht et al., it was seen that a 12 months exercise programme, in patients with stable CAD, was associated with a higher event-free survival, better maximal oxygen uptake as well as lower costs due to reduced hospitalisations and repeat revascularisations.²⁰

Earlier studies, showing exercise-induced effects on angiogenic factors in patients with CAD, have often used very intensive, and frequent, in-hospital supervised exercise programmes. However, for the large number of patients with CAD, that kind of supervised exercise is not practically or economically feasible, especially not in the long run. Thus, complementary, possibly home-based, individually tailored exercise programmes as an alternative to traditional hospital-based exercise training are needed.

In this study our primary aim was to investigate the effect of home-based high frequency exercise (HFE) before and after PCI in patients with stable angina pectoris, specifically looking at the response in the angiogenic factors, VEGF and SDF-1. We also wanted to look at the correlation between these angiogenic factors and the prognostic markers troponin-T (TnT), N-terminal pro-brain-natriuretic-peptide (NT-proBNP) and copeptin.

Methods

Patients

The study was performed as described earlier.²¹ The initial study group consisted of 62 patients with stable angina pectoris, recruited from the waiting lists for elective PCI from three PCI-centres in the western part of Sweden. Inclusion criteria were for selection of patients with expected reduced endothelial function; diabetes, hypercholesterolemia, previous coronary artery bypass grafting (CABG) or angiographic signs of atherosclerosis in at least four of 18 coronary segments. Exclusion criteria were left main stem disease, completely occluded target vessel, Canadian Cardiovascular Society class IV, New York Heart Association class IV, handicaps that prevent physical exercise, or if the patient already exercised ≥3 days per week. The study was approved by the ethics committee of Gothenburg University and written informed consent was obtained.

Patients were randomised to HFE (n = 33) or usual care controls (n = 29) groups. The controls were instructed to continue with their usual lifestyle. In addition, both groups were also offered to take part in the regular exercise-based cardiac rehabilitation care, which consisted of group-based lifestyle education and aerobic, as well as resistance, exercise twice a week. However, only two patients from the control group participated. The exercise programme in the regular rehabilitation programme was based according to the guidelines from the American Heart Association, 2007.²² Results on fitness levels, from this study, have been published earlier.^21,23

For the purpose of this study, blood samples could be obtained from 45 of the subjects, making up the final study population. In total, serum from 24 patients in the exercise group and 21 patients from the control group were analysed.

Exercise intervention

The exercise intervention was performed as previously described, including both aerobic and resistance exercise.²¹ The HFE group started the exercise programme eight weeks before scheduled PCI and continued until six months after PCI. A submaximal exercise test was performed and the exercise level was set below the individual angina level, aimed at being performed at approximately 70% of the individual maximum working capacity according to Borg’s rate of perceived exertion (RPE) scale, for at least five days a week, 30 min a day, using an ergometer cycle (Monark 915E, Monark Exercise AB, Varberg, Sweden). The patients were allowed to switch the cycling to another type of aerobic exercise with corresponding intensity level; such as jogging or swimming twice a week. Instructions were given to reduce exercise intensity, in case angina was precipitated. The patients in the HFE group were tested once a month during the intervention period at a submaximum level by a physiotherapist on a bicycle ergometer, to upgrade the intensity level corresponding to 13–15 on the Borg RPE-scale,²⁴ adjusting the exercise intensity when necessary.

Resistance exercise with resistive elastic bands (JPM Products, Hertsfordshire, United Kingdom), including unilateral shoulder flexion, unilateral shoulder abduction, bilateral rowing and unilateral heel-lift (without elastic band) were also included in the exercise programme. The resistance of the elastic band was determined and adjusted after performing a maximum of 10 repetitions.²⁵ The patients performed the resistance exercise three times a week, each exercise with three sets of 10 repetitions with intensity level of 75% of one repetition maximum. To increase motivation and adherence to the exercise programme, the patients documented their exercise activity in a diary, which was controlled by the physiotherapist during the monthly follow up visits.

Blood samples

Blood samples were obtained at baseline, after eight weeks (pre-PCI), three months after PCI and six months after PCI. Blood samples were collected, using a standardised procedure after an overnight fast and 15 min rest. The serum was centrifuged, frozen and stored at −80℃. High-sensitivity Enzyme-Linked Immunosorbent Assay (ELISA) kit (Quantikine) was used to measure the serum-levels of VEGF and SDF-1 according to the manufacturers’ protocol. NT-proBNP, and high-sensitive TnT were analysed on Cobas e602 (Roche) with a coefficient of variation (CV) < 5% at the levels obtained in the patient samples. Copeptin US Kryptor assay were performed on the Brahms Kryptor Compact Plus with a CV < 5% at the levels obtained in the patient samples.

Statistics

Data are presented using the median (25^th, 75^th percentile) for continuous variables and percentages for proportions. Baseline characteristics between groups were compared using Fisher’s exact test and Mann-Whitney U test for dichotomous and continuous/ordered variables, respectively. With the exception of copeptin, data of effects on angiogenic factors are presented as relative changes from baseline and comparisons between groups regarding relative changes were performed using Mann-Whitney U test. Since several of the copeptin measurements were below detection level, we only compared proportions of patients with decreased or increased levels, using Fisher’s exact test. Correlations between variables were analysed using Spearman’s rank correlation. All tests are two-sided and p-values below 0.05 were considered statistically significant. All analyses were performed using SAS 9.3 for Windows 7.

Results

Patient characteristics

The male/female ratio was 20/4 in the HFE group and 17/4 in the control group. There were no significant differences in age, baseline blood pressure, weight, medical history, creatinine levels, fasting blood glucose, fasting lipids, intake of statins, beta-blockers, antithrombotic medication, angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers between the groups (Tables 1 and 2). Haemoglobin values at baseline were significantly higher in the exercise group 144 (139, 152) vs 140 (134, 144) in the control group (p = 0.02) (Table 2). An improvement in exercise capacity was found in the HFE group versus the control group, although this difference was non-significant in the present study population (23 W vs 10.5 W, p not significant).

Table 1.

Baseline characteristics of the study population

	HFE (n = 24)	Ctrl (n = 21)	p
Age (years)	62 (58, 68)	66 (62, 71)	0.11
Gender (male/female; n)	20/4	17/4	1.00
BP systolic (mm Hg) (0/1)^a	140 (130, 140)	140 (132, 152)	0.13
BP diastolic (mm Hg) (0/1)	80 (80, 80)	80 (75, 85)	0.60
Weight (kg)	82 (80, 90)	80 (75, 90)	0.14
Medical history (%)
AMI	38	24	0.36
Stroke	4	5	1.00
PCI	29	10	0.14
CABG	8	5	1.00
Hypertension	50	67	0.37
Hyperlipidaemia	79	71	0.73
Diabetes	25	14	0.47
Heart failure	8	5	1.00
Smoking	0	10	0.21
Angina pectoris	92	95	1.00
Duration of CAD (3/0)	18 (8, 36)	14 (12, 36)	0.84
CCS-class (I/II/III/; n) (3/0)	0/9/12	2/7/12	0.81
Medication (%)
ASA	88	86	1.00
Clopidogrel	21	10	0.42
β-Blockers	92	90	1.00
Statins (1/0)	74	76	1.00
Nitroglycerine	50	38	0.55
ACE-inhibitors	33	43	0.55
Ca-channel blockers	17	10	0.67

ACE: angiotensin-converting enzyme; AMI: acute myocardial infarction; ASA: acetylsalicylic acid; BP: blood pressure; CABG: coronary artery bypass grafting; CAD: coronary artery disease; CCS: Canadian Cardiac Society; Ctrl: control; HFE: home-based high frequency exercise; PCI: percutaneous coronary intervention

Data presented as median (25^th, 75^th percentile), unless otherwise stated

number of patients with missing information in the two groups, respectively.

Table 2.

Baseline characteristics of metabolic markers in the study population

	HFE (n = 24)	Ctrl (n = 21)	p
Hb (mmol/l)	144 (139, 152)	140 (134, 144)	0.02
Creatinine (µmol/l)	96 (82, 106)	97 (79, 109)	0.82
Cholesterol (mmol/l)	4.4 (3.8, 5.0)	4.7 (3.8, 5.2)	0.58
Triglycerides (mmol/l) (1/0)^a	1.4 (1.1, 1.9)	1.0 (0.8, 1.4)	0.07
HDL (mmol/l)	1.2 (1.0, 1.6)	1.5 (1.2, 1.6)	0.13
LDL (mmol/l) (2/0)	2.4 (1.9, 2.7)	2.4 (2.0, 2.9)	0.63
Fasting glucose (mmol/l)	5.8 (5.0, 6.7)	5.1 (4.9, 5.7)	0.05
HbA1c (%)	4.9 (4.4, 5.5)	4.7 (4.5, 5.0)	0.56

Ctrl: control; Hb: haemoglobin; HbA1c: glycosylated hemoglobin, type A1C; HDL: high density lipoprotein; HFE: home-based high frequency exercise; LDL: low-density lipoprotein

Data presented as median (25^th, 75^th percentile). ^aNumber of patients with missing information in the two groups, respectively.

Effects of home-based training on angiogenic factors prior to PCI

Results are presented as relative change (%) from baseline. While circulating VEGF-levels increased in the control group (5% (−3%, 20%)), levels decreased (−5% (−15%, 2%)) in the HFE group (p = 0.004 for difference in relative change) prior to PCI (Table 3). Although not statistically significant, during the same time period there was a tendency of difference in change also regarding circulating SDF-1 levels (4 (0, 7) in control patients, compared to −2% (−4%, 4%) in HFE patients, (p = 0.06), Table 3).

Table 3.

Angiogenic cytokines and cardiac markers. Data are presented as relative change (%) from baseline

	HFE (n = 24)	Ctrl (n = 21)	p
VEGF pre-PCI	−5 (−15, 2)	5 (−3, 20)	0.004
VEGF 3 months post-PCI	−1 (−12, 5)	7 (0, 14)	0.04
VEGF 6 months post-PCI	4.4 (3.8, 5.0)	4.7 (3.8, 5.2)	0.58
SDF-1 pre-PCI	−2 (−4, 4)	4 (0, 7)	0.06
SDF-1 3 months post-PCI	1.2 (1.0, 1.6)	1.5 (1.2, 1.6)	0.13
SDF-1 6 months post-PCI	2.4 (1.9, 2.7)	2.4 (2.0, 2.9)	0.63
TnT pre-PCI	1 (−3, 8)	3 (−4, 6)	0.81
TnT 3 months post-PCI	11 (1, 24)	10 (0, 22)	0.49
TnT 6 months post-PCI	9 (−3, 13)	1 (−3, 15)	0.71
NT-proBNP pre-PCI	−15 (−28, 17)	−28 (−37, −21)	0.23
NT-proBNP 3 months post-PCI	−8 (−23, 15)	−5 (−35, 29)	0.89
NT-proBNP 6 months post-PCI	−2 (−44, 51)	−4 (−18, 42)	0.80

Ctrl: control; HFE: home-based exercise training group; NT-proBNP: N-terminal- pro-brain-natriuretic peptide; PCI: percutaneous coronary intervention; SDF-1: stromal-derived factor-1; TnT: troponin T; VEGF: vascular endothelial growth factor. Data presented as median (25^th, 75^th percentile). *Number of patients with missing information in the two groups, respectively.

Effects of home-based training on angiogenic factors post-PCI

Results are presented as relative change (%) from baseline. Following PCI there was still a statistically significant difference in change from baseline at three months regarding VEGF levels (7 (0, 14) in the control group and −1 (−12, 5) in the HFE group, p = 0.04). At six months no significant difference was seen (Table 3).

Regarding SDF-1 levels, no significant difference in change from baseline comparing the two groups were seen (Table 3).

Correlation of angiogenic factors and markers of cardiac dysfunction

There was no significant difference in change from baseline regarding NT-proBNP, TnT or copeptin levels between the groups at any time point (Table 3 and Supplementary Material). There was a significant correlation regarding relative changes from baseline between NT-proBNP and VEGF before PCI (r = 0.43, p = 0.02) and also at six months after PCI (r = 0.40, p = 0.02).

Discussion

The main finding of this study, is that in patients with CAD prior to PCI, a home-based HFE programme, (aerobic and resistance exercise), reduces VEGF levels. In addition, there is a positive correlation between relative changes in the prognostic marker NT-proBNP and VEGF changes. However, no convincing effect of HFE on SDF-1 levels in CAD-patients, prior to or after PCI, could be seen.

Exercise-based cardiac rehabilitation has been shown to be beneficial in secondary prevention of CAD morbidity and mortality,^1,2,26 by reducing traditional risk factors, but also more directly by positively affecting the atherosclerotic disease progression,^7,8 myocardial perfusion,^10,11 and angiogenesis.²⁷ Several angiogenic factors, such as VEGF and SDF-1, have previously been shown to be positively affected by hospital-based, supervised exercise programmes.¹⁵ While previous studies in cardiac rehabilitation mainly investigated the effects of aerobic exercise, the HFE programme in this study, included both aerobic and resistance exercise, as recommended in the secondary prevention guidelines for patients with CAD.²² Such a regime has been shown to improve body composition, strength and indicators of cardiovascular fitness more than aerobic exercise alone, in patients with CAD.²⁸ Therefore, we chose to study the effects of a HFE programme, including resistance exercise on angiogenic cytokines and cardiac markers.

In order to release VEGF, hypoxia-inducible factor-1 (HIF-1) needs to be induced. HIF-1 acts as a transcription-factor and is induced by ischaemia.²⁹ In the presence of significant stenosis, there is an ischaemic stimulus that can induce the release of VEGF, parallel to that seen in the control group in this study.

Indeed, patients with CAD seem to have higher levels of VEGF. When compared to healthy controls, patients that have a history of myocardial infarction have higher levels of circulating angiogenic factors. In response to exercise, myocardial blood flow increases, in individuals with a history of myocardial infarction, and concomitantly reduces the levels of angiogenic factors.¹⁵ Our results are in line with these findings and suggest that HFE might reduce the ischaemic burden in patients with stable CAD, as suggested by the decreased circulating angiogenic growth factors.

When the ischaemic stimulus was removed by PCI, the increased VEGF-levels in the non-trained individuals slowly normalised. No additional effects were seen in the exercising individuals, which could possibly be explained by the fact that these patients already had lower levels of circulating cytokines and thus less ischaemic burden, compared to the non-trained individuals.

Although VEGF-levels have also been reported to increase in response to exercise, we found no such response in our study. The majority of studies that presented VEGF-release in response to exercise, studied acute effects as well as effects of performance above the ischemic level.^4,30–33 After PCI, the ischaemic burden is removed and exercise of higher frequency or intensity may be needed to induce growth factors.

SDF-1 release is stimulated by ischaemia and is known to be one the most potent activators of endothelial progenitor cells (EPCs). Previous studies have shown increase in EPC levels following exercise in both non-ischaemic individuals and in patients with CAD.^30,34 One paper studied the effect of exercise on SDF-1-levels in post-infarct patients, showing reduced levels, corresponding to increased myocardial blood flow.¹⁵ In our study, SDF-1 levels pre-PCI showed a tendency to increase over time in non-trained individuals which is in line with the effects seen on VEGF. In the exercise-trained individuals they remained unchanged. The effect was however not convincing and PCI did not provide any additional effect. The main effect of SDF-1 is to recruit EPCs for myocardial repair.³⁵ Our patients had stable angina and the troponin levels were also in the normal ranges, ruling out myocardial damage. This could partly explain why no statistically significant effect on circulating levels of SDF-1 was seen in our study.

In patients with stable angina, higher NT-proBNP, TnT and Copeptin levels are associated with increased risk for major cardiovascular events.^36,37 NT-proBNP in these patients is associated with increased cardiovascular mortality.³⁸ We found a low positive correlation between VEGF levels and NT-proBNP, suggesting that exercise can induce reduction in VEGF as well as NT-proBNP levels in these patients.

Home-based exercise has previously shown to be as effective as centre-based exercise when improving cardiac risk factors such as systolic blood pressure, diastolic blood pressure, total cholesterol, exercise capacity and psychological status.³⁹ An individually home-based HFE programme, including aerobic and resistance exercise, might represent an attractive option to broaden access and participation. Therefore, it is of great clinical significance that in addition to improving exercise capacity, as reported earlier, HFE performed at home with guidance from a physiotherapist, as described in this study, can also positively modulate angiogenic factors in patients with CAD.

Although, in physiologically normal conditions it is unlikely that a slight difference in haemoglobin level make any difference, in patients with ischaemic heart disease, it cannot be ruled out that the observed difference (144 vs 140 mmol/l), might have had some marginal influence on the results, thus being a possible limitation.

Summary

In conclusion, we have shown that home-based HFE can reduce the level of the circulating angiogenic cytokine, VEGF, in patients with CAD, suggesting a reduced ischaemic burden. PCI, in non-trained individuals, may achieve comparable levels of cytokine reduction as exercise. These findings have clinical implications as individualised exercise prescription in patients with CAD may be initiated in the hospital setting, ideally as part of cardiac rehabilitation, but could be continued in the home-based setting with follow-up guidance by a physiotherapist.

Footnotes

Acknowledgements

The authors would like to thank Rebecca Djurback, Lillemor Mattsson, Christina Johansson and associates in the Department of Clinical Chemistry at Sahlgrenska University Hospital for laboratory analysis and, Chrichan Månsson, Åsa Dahl, Susanna Wittboldt, Marco Astengo and Eva-Lena Pommer for data collection and laboratory assistance. They also want to thank Per Albertsson and Department of Cardiology, Sahlgrenska University Hospital for support.

Funding

This study was supported by the Health and Medical Care Executive Board of the Region Västra Götaland, the Sahlgrenska University Hospital, the Karolinska Hospital and Swedish Heart and Lung Foundation. OH was supported by the Swedish Cancer Society, the Swedish Research Council, the Swedish Pain Foundation (SSF), the Assar Gabrielsson Cancer Research Foundation, and by LUA/ALF Funding at the Sahlgrenska University Hospital.

Conflict of interest

The authors declare that there is no conflict of interest.

References

Petersen

Gronbaek

Helge

. Changes in physical activity in leisure time and the risk of myocardial infarction, ischemic heart disease, and all-cause mortality. Eur J Epidemiol 2012; 27: 91–99.

Myers

Prakash

Froelicher

. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 2002; 346: 793–801.

R-X

Müller-Riemenschneider

. Effectiveness of exercise after PCI in the secondary prevention of coronary heart disease: A systematic review. Eur J Integr Med 2011; 3: e63–e69.

Belardinelli

Paolini

Cianci

. Exercise training intervention after coronary angioplasty: The ETICA trial. J Am Coll Cardiol 2001; 37: 1891–1900.

Lisspers

Sundin

Ohman

. Long-term effects of lifestyle behavior change in coronary artery disease: Effects on recurrent coronary events after percutaneous coronary intervention. Health Psychol 2005; 24: 41–48.

Fagard

Cornelissen

. Effect of exercise on blood pressure control in hypertensive patients. Eur J Cardiovasc Prev Rehabil 2007; 14: 12–17.

Ornish

Scherwitz

Billings

. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998; 280: 2001–2007.

Haskell

Alderman

Fair

. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP). Circulation 1994; 89: 975–990.

Hambrecht

Wolf

Gielen

. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med 2000; 342: 454–460.

10.

Gould

Ornish

Scherwitz

. Changes in myocardial perfusion abnormalities by positron emission tomography after long-term, intense risk factor modification. JAMA 1995; 274: 894–901.

11.

Sdringola

Nakagawa

. Combined intense lifestyle and pharmacologic lipid treatment further reduce coronary events and myocardial perfusion abnormalities compared with usual-care cholesterol-lowering drugs in coronary artery disease. J Am Coll Cardiol 2003; 41: 263–272.

12.

Zbinden

Meier

. Coronary collateral flow in response to endurance exercise training. Eur J Cardiovasc Prev Rehabil 2007; 14: 250–257.

13.

Schlager

Giurgea

Schuhfried

. Exercise training increases endothelial progenitor cells and decreases asymmetric dimethylarginine in peripheral arterial disease: A randomized controlled trial. Atherosclerosis 2011; 217: 240–248.

14.

Yang

Prior

Lloyd

. Training-induced vascular adaptations to ischemic muscle. J Physiol Pharmacol 2008; 59: S57–S70.

15.

Lee

Hsu

Tseng

. Effect of cardiac rehabilitation on angiogenic cytokines in postinfarction patients. Heart 2009; 95: 1012–1018.

16.

Kranz

Rau

Kochs

. Elevation of vascular endothelial growth factor-A serum levels following acute myocardial infarction. Evidence for its origin and functional significance. J Mol Cell Cardiol 2000; 32: 65–72.

17.

Pillarisetti

Gupta

. Cloning and relative expression analysis of rat stromal cell derived factor-1 (SDF-1)1: SDF-1 alpha mRNA is selectively induced in rat model of myocardial infarction. Inflammation 2001; 25: 293–300.

18.

Lataillade

Clay

Dupuy

. Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: Possible role in progenitor survival. Blood 2000; 95: 756–768.

19.

Kucia

Jankowski

Reca

. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol 2004; 35: 233–245.

20.

Hambrecht

Walther

Mobius-Winkler

. Percutaneous coronary angioplasty compared with exercise training in patients with stable coronary artery disease: A randomized trial. Circulation 2004; 109: 1371–1378.

21.

Astengo

Dahl

Karlsson

. Physical training after percutaneous coronary intervention in patients with stable angina: Effects on working capacity, metabolism, and markers of inflammation. Eur J Cardiovasc Prev Rehabil 2010; 17: 349–354.

22.

Balady

Williams

Ades

. Core components of cardiac rehabilitation/secondary prevention programs: 2007 update: A scientific statement from the American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee, the Council on Clinical Cardiology; the Councils on Cardiovascular Nursing, Epidemiology and Prevention, and Nutrition, Physical Activity, and Metabolism; and the American Association of Cardiovascular and Pulmonary Rehabilitation. Circulation 2007; 115: 2675–2682.

23.

Back

Wennerblom

Wittboldt

. Effects of high frequency exercise in patients before and after elective percutaneous coronary intervention. Eur J Cardiovasc Nurs 2008; 7: 307–313.

24.

Borg

. Ratings of perceived exertion and heart rates during short-term cycle exercise and their use in a new cycling strength test. Int J Sports Med 1982; 3: 153–158.

25.

Williams MA, Haskell WL, Ades PA, et al. AHA Scientific Statement. Cardiac Rehabilitation and Secondary Prevention of Coronary Heart Disease. Circulation 2007; 116(5): 572–584.

26.

Lawler

Filion

Eisenberg

. Efficacy of exercise-based cardiac rehabilitation post-myocardial infarction: A systematic review and meta-analysis of randomized controlled trials. Am Heart J 2011; 162: 571–584.

27.

Laughlin

Bowles

Duncker

. The coronary circulation in exercise training. Am J Physiol Heart Circ Physiol 2012; 302: H10–H23.

28.

Marzolini

Brooks

. Effect of combined aerobic and resistance training versus aerobic training alone in individuals with coronary artery disease: A meta-analysis. Eur J Prev Cardiol 2012; 19: 81–94.

29.

Semenza

. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 2009; 24: 97–106.

30.

Adams

Lenk

Linke

. Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia. Arterioscler Thromb Vasc Biol 2004; 24: 684–690.

31.

Steiner

Niessner

Ziegler

. Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. Atherosclerosis 2005; 181: 305–310.

32.

Sandri

Adams

Gielen

. Effects of exercise and ischemia on mobilization and functional activation of blood-derived progenitor cells in patients with ischemic syndromes: Results of 3 randomized studies. Circulation 2005; 111: 3391–3399.

33.

Sandri

Beck

Adams

. Maximal exercise, limb ischemia, and endothelial progenitor cells. Eur J Cardiovasc Prev Rehabil 2011; 18: 55–64.

34.

Thorell

Borjesson

Larsson

. Strenuous exercise increases late outgrowth endothelial cells in healthy subjects. Eur J Appl Physiol 2009; 107: 481–488.

35.

Huang

. Sca-1+ cardiac stem cells mediate acute cardioprotection via paracrine factor SDF-1 following myocardial ischemia/reperfusion. PloS One 2011; 6: e29246–e29246.

36.

Ndrepepa

Braun

Schulz

. Sensitive troponin and N-terminal probrain natriuretic peptide in stable angina. Eur J Clin Invest 2011; 41: 1054–1062.

37.

Von Haehling

Papassotiriou

Morgenthaler

. Copeptin as a prognostic factor for major adverse cardiovascular events in patients with coronary artery disease. Int J Cardiol 2012; 162: 27–32.

38.

Omland

Sabatine

Jablonski

. Prognostic value of B-Type natriuretic peptides in patients with stable coronary artery disease: The PEACE Trial. J Am Coll Cardiol 2007; 50: 205–214.

39.

Jolly

Lip

Taylor

. The Birmingham Rehabilitation Uptake Maximisation study (BRUM): A randomised controlled trial comparing home-based with centre-based cardiac rehabilitation. Heart 2009; 95: 36–42.