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Comparison of two treadmill training programs on walking ability and endothelial function in intermittent claudication
International Journal of Cardiology 168 (2013) 838–842
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparison of two treadmill training programs on walking ability and endothelial function in intermittent claudication☆ Piotr Mika a,⁎, Anita Konik a, Rafal Januszek b, Tomasz Petriczek b, Anna Mika a, Roman Nowobilski c, Rafal Nizankowski b, Andrzej Szczeklik b a b c
Department of Clinical Rehabilitation, University School of Physical Education, Cracow, Poland Department of Internal Medicine, Jagiellonian University School of Medicine, Cracow, Poland Institute of Physiotherapy, Faculty of Health Sciences, Jagiellonian University, School of Medicine, Cracow, Poland
a r t i c l e
i n f o
Article history: Received 8 February 2012 Received in revised form 3 July 2012 Accepted 7 October 2012 Available online 30 October 2012 Keywords: Atherosclerosis Claudication Treadmill training Endothelial function
a b s t r a c t Background: In this randomized trial we compared two treadmill trainings, based on exercises performed to moderate claudication pain vs pain-free training, with respect to their effects on walking ability and endothelial function. Methods: A total of sixty patients with stable intermittent claudication were randomized to the pain-free treadmill training (repetitive intervals to onset of claudication pain) or moderate treadmill training (repetitive intervals to moderate claudication pain). In both groups exercises were performed 3 times a week for 3 months. Changes in flow mediated dilatation (FMD) and treadmill walking performance as well as plasma levels of C-reactive protein (hs-CRP) and fibrinogen were assessed before and after the program. Results: Fifty-two patients completed the training program. Post-training maximal walking time was prolonged by 100% (pb 0.001) vs 98% (pb 0.001), and pain-free walking time by 120% (pb 0.001) vs 93% (pb 0.001) in the moderate training group as compared to the pain-free training group, respectively. FMD increased by 56% (pb 0.001) in the moderate training group and by 36% (pb 0.01) in the pain-free training group. No significant changes in the levels of hs-CRP and fibrinogen were seen after treadmill program in either group. Conclusions: Both pain-free treadmill training and the moderate treadmill training have similar efficacy on walking ability in patients with claudication. The improvement of post-training FMD indicates systemic effect of both treadmill programs on endothelial function. Both programs appear to be safe therapeutic modes, since none of them escalates the inflammation. Pain-free treadmill training seems useful and effective therapeutic option for patients with claudication. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Intermittent claudication is the leading symptom of peripheral arterial disease (PAD). It is usually defined as pain or muscle discomfort in the lower limb reproducibly produced by exercise, due to imbalance of oxygen supply and demand, and relieved by rest [1]. An impairment of endothelial function is usually observed in patients with claudication [2]. This early event of atherogenesis, which leads to increased leukocyte adhesion and platelet aggregation, may be observed many years before appearance of atheromatous plaque [3]. The more severe PAD, the greater impairment of endothelial
☆ The study was supported, in part, by grant no NN404026035 from the Ministry of Science and Higher Education, Poland. ⁎ Corresponding author at: Department of Clinical Rehabilitation, University School of Physical Education, Al. Jana Pawla II 78, 31-571 Cracow, Poland. Tel.: +48 12 6831134; fax: +48 12 6831300. E-mail address: [email protected] (P. Mika). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.10.003
function [2]. The endothelial dysfunction, manifested by impairment of the endothelial-dependent vasodilatation contributes to the increased peripheral resistance, decreased blood flow rate, limited tissue oxygenation and walking intolerance that occur in this disease [3]. Therefore, impaired endothelial function, besides atherosclerotic stenosis is a potential contributor to phenomenon of intermittent claudication. It has been suggested, that the interventions which improve endothelial function increase walking capacity of the affected individuals [2]. Changes in endothelial reactivity are one of the physiological responses to physical exercise. Regular exercise has been shown to enhance endothelial function in healthy individuals as well as in patients with coronary artery disease and with PAD [3–6]. Walking programs have long been considered the best option to improve walking distance in patients with claudication [7]. Based on the meta-analysis summarizing 21 exercise trials in this group of patients, Gardner et al. [8] suggested that the optimal program to improve walking distance should use intermittent walking to near-maximal leg pain.
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The recent Intersociety Consensus for the Management of PAD (TASC II) states that in optimal program exercise should be performed to the point “when claudication pain is considered moderate” [1]. It was suggested previously that repeated episodes of leg muscle pain followed by rest may lead to cumulative inflammatory response and disease progression in patients with claudication [9]. The acute inflammatory response to strenuous exercise may also exacerbate endothelial function in patients with claudication which paralleled with an increase of inflammation markers [2,3]. In light of these, the pain-free treadmill training with exercises interrupted at the onset of claudication pain seems most safe, effective option for the treatment of patients with claudication [10]. However, it has also been noticed that less optimal training response occurs when the patients stop at the onset of claudication [1,8]. To date, no direct comparison between treadmill programs applying various claudication pain intensities has been reported. Thus, identifying the most appropriate level of submaximal exercise for this group of patients is still an important issue which needs more clarification. The purpose of this randomized trial was to compare the efficacy of two treadmill training programs for patients with claudication. The training using exercises performed to moderate claudication pain vs pain-free treadmill training were compared in the context of their effects on endothelial function, walking performance, as well as plasma level of fibrinogen and CRP (the stable biochemical markers of inflammation and disease severity). 2. Methods 2.1. Study population Sixty patients with PAD and intermittent claudication, aged 50–75 years, in stage II of PAD (Fontaine classification), have been recruited from the vascular outpatient clinic. The diagnosis of PAD was confirmed by Doppler ultrasound and an ankle/brachial index (ABI) of less than 0.9 at rest. All patients had stable claudication distance and were able to walk at least 150 m without pain. None of the enrolled patients had a history of unstable angina pectoris, recent myocardial infarction, or vascular surgery within the previous year. Patients affected by impaired cardiac or lung function, cancer, kidney and liver disease, or arthritis that limited walking were excluded. Patients who were unable to walk on the treadmill at a speed of at least 3.2 km/h were also excluded. Pharmacological treatment of all patients (anti-platelet therapy, anti-hypertensive therapy, cholesterol-lowering agents) was stable within 6 months before the enrolment and remained unchanged during the study. None of the participants in the study was taking pentoxifylline, cilostazol or selective cox-2 inhibitors. The study complied with the Declaration of Helsinki. All subjects provided written informed consent before the investigation. Local ethical committee approval was obtained for this study.
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2.4. Treadmill testing Walking abilities (PFWT and MWT) were assessed during morning hours according to the graded treadmill protocol [13]. Subject walked on the treadmill (Gait Trainer, Biodex, USA) at an initial workload of 3.2 km/h, 0% grade for 2 min. Subsequent stages increased 2% in grade every 2 min. The speed was set constant (3.2 km/h) throughout the test. The PFWT was determined when the patient reported first pain feeling, discomfort, or numbness in the calf (level 2 on pain scale) whereas the MWT was recorded when the patient refused to continue the test because of severe claudication pain (level 5 on pain scale) [11]. Patients were instructed not to use handrail support during the treadmill test. The treadmill was calibrated prior to each testing. The test was repeated on the next day and the best of the two measurements was used in the data analysis. 2.5. Endothelial function assessment The endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was assessed using a high resolution echo-Doppler ultrasound (Sequoia 512, Acuson, linear probe 7 MHz). The examination was performed in a quiet, temperature-controlled room (23°–24 °C) after 15 min resting period. The subjects reported to the laboratory between 7 and 8 a.m. after overnight fasting. Patients were instructed to refrain from physical exercises, caffeine beverages, and tobacco use for 12 h prior to the test. All temporary medications were withheld for 24 h before testing [12]. The subject was positioned supine with the arm fixed in a comfortable position for imaging the brachial artery 2 cm above the antecubital fossa in the longitudinal plane. A segment with clear anterior and posterior intimal interfaces between the lumen and vessel wall was selected for imaging [14]. The images were recorded for 30 s at rest. Thereafter, arterial occlusion was produced with the pneumatic sphygmomanometric cuff placed below the antecubital fossa and inflated 50 mm Hg over the systolic blood pressure. After 5 min of ischemia, the cuff was deflated. The diameter of the brachial artery was measured for 60 to 90 s after deflation. The mean of 3 maximal end-diastolic diameter measurements was assumed to calculate FMD value. The percent change in artery diameter during postocclusive reactive hyperemia was taken as the value of FMD [3]. The measurement was performed at rest and repeated 15 min after the treadmill test to maximal claudication pain. 2.6. Biochemical analyses On the next day blood samples were collected at rest, after overnight fasting. Patients were asked to refrain from smoking 12 h prior to the blood test. Blood samples for the analysis of fibrinogen, high-sensitivity C-reactive protein (hs-CRP) and lipid profile: total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides, were drawn from the forearm vein (between 9.00 and 10.00 a.m.) after a 30 min rest (sitting in a comfortable chair) and immediately sent to the laboratory. Total cholesterol, HDL-C, and triglycerides concentration were measured by photometric dry chemistry method using Vitros-350 analyzer (Johnson & Johnson, Hempstead, Hertfordshire, UK). The LDL-C was calculated by the Friedewald formula. Serum hs-CRP concentration was determined using nephelometric method on the Behring Nephelometer BN II (Simens, Marburg, Germany). Plasma fibrinogen concentration was measured using the method of Clauss [15] on Sysmex CA-500 analyzer (Sysmex, Kobe, Japan). 2.7. Other measures
2.2. Study design After initial familiarization with treadmill exercise patients were randomized to either the moderate training (MT) group, (n = 30) or the pain-free training (PFT) group (n = 30). All patients were evaluated at baseline and after 12 weeks of the study. Each time pain-free (PFWT) and maximal walking time (MWT) were measured during treadmill test. Additionally, each time endothelial function and ABI were assessed, blood analyses were performed, and smoking status of all patients was obtained. The testing and analyses were conducted by qualified medical staff blinded to the subject's group assignment.
2.3. Treadmill training Both exercise programs consisted of 12 weeks of supervised, intermittent treadmill walking. Exercise sessions were conducted three times a week. During each exercise session, treadmill walking was at the speed of 3.2 km/h and the grade was individually determined for each patient that will induce claudication within 3 to 5 min [1]. The exercise was interrupted when claudication pain was considered moderate (MT group) or the patient stopped at the onset of claudication (PFT group). The severity of claudication pain experienced by the patient was determined on a scale, where 1 = no pain, 2 = onset of claudication pain, 3 = mild pain, 4 = moderate pain, and 5 = maximal pain [11]. After exercise, the patient was resting until claudication has abated and then walking was resumed. This cycle of intermittent walking exercise was applied for 35 min at the start of the program with progressive increase of session time by 5 min per 2 weeks until a total of 60 min was accomplished. At subsequent visits, the grade of the treadmill was increased (for the new session), if the patient was able to walk for 8 min or longer at the previous workload [12].
ABI was measured at rest according to the standard procedure [1]. Smoking status was determined as the daily amount of smoked cigarettes reported by the patient, height and weight were measured before and after the program, and BMI (body mass index) was calculated. 2.8. Statistical analysis Changes in variables over 12 weeks of the program were analyzed by repeated measures ANOVA (within subjects, between groups). One-way ANOVA was used to determine initial between-group differences. Stepwise multiple regression analysis was performed to identify the variables independently related to the changes in FMD and walking ability. The statistical analyses were performed using Statistica 10.0 software. The data are expressed as means and SD. Statistical significance was accepted at 0.05 level of probability.
3. Results Of the 60 patients who entered the program, 3 were withdrawn from the moderate training group and 5 from the pain-free training group. One patient was excluded because of gastric ulcer surgery, one developed diabetic foot ulceration, one was disinterested in the final examination, five patients refused to continue for unspecified, but not health-related, reasons. The clinical characteristics of the 52 patients completing the 12-week program are shown in Table 1.
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Table 1 Subjects' characteristics and baseline clinical data.
Male:female Age, years Weight, kg BMI, kg/m2 ABI Smoking history Never, n (%) Former, n (%) Current, n (%) Smoking, years Cigarettes/d Claudication, years Diabetes, n (%) Treatment, n ACEi ASA Statins
Table 3 The rest and post-exercise changes in FMD after 12 weeks of the treadmill training.
Moderate training Group (n = 27)
Pain-free training Group (n = 25)
16:11 64.8 ± 7.2 75.8 ± 13.8 26.9 ± 3.7 0.52 ± 0.15
16:9 65.2 ± 8.0 72.2 ± 8.5 25.1 ± 2.8 0.47 ± 0.16
1 (3.7) 13 (48.1) 13 (48.1) 34 ± 12.1 6.7 ± 7.8 8.3 ± 6.7 5 (18.5)
1 (4) 10 (40) 14 (56) 35 ± 12.0 5.4 ± 7.7 9 ± 5.5 3 (12)
21 26 27
17 25 24
Table 2 Changes in pain-free walking time (PFWT) and maximal walking time (MWT) in moderate and pain-free training groups (mean ± SD). Baseline
PFWT (s)
MT PFT MT PFT MT PFT
140 ± 72 169 ± 62 441 ± 178 489 ± 147 0.52 ± 0.15 0.47 ± 0.16
MWT (s) ABI
p1 0.12 0.29 0.22
Week 12
p2
Change
307 ± 182 327 ± 155 881 ± 326 969 ± 376 0.58 ± 0.18 0.48 ± 0.20
b0.001 b0.001 b0.001 b0.001 0.02 0.70
167 ± 158 157 ± 117 440 ± 262 479 ± 333 0.06 ± 0.12 0.01 ± 0.16
p1 — value between PFT group and MT group at baseline. p2 — value between 12-week and baseline. p3 — value between change in PFT group and change in MT group. MT — moderate training, PFT — pain-free training. Change — difference between 12-week and baseline.
p1
Baseline Rest Post-exercise p Rest Post-exercise p
Week 12
3.98 ± 1.90 6.22 ± 2.0 4.58 ± 2.09 6.65 ± 2.56 0.22 0.41 4.59 ± 2.14 0.29 6.27 ± 2.80 4.24 ± 2.01 0.56 5.69 ± 2.43 0.42 0.29
p2
Change
p3
b0.001 2.24 ± 2.09 b0.001 2.06 ± 2.34 b0.01 b0.01
1.68 ± 2.84 0.42 1.44 ± 2.42 0.36
p — value between rest and post-exercise (baseline or 12-week). p1 — value between PFT group and MT group at baseline (rest or post-exercise). p2 — value between 12-week and baseline (rest or post-exercise). p3 — value between change in PFT group and change in MT group (rest or post-exercise). MT — moderate training, PFT — pain-free training. Change — difference between 12-week and baseline.
Differences in baseline variables between groups were insignificant (p > 0.05). The ANOVA analyses showed significant main effect for time but group effect and group-by-time interactions were insignificant for both walking abilities and FMD which means that the groups were changing over 12 weeks in similar ways. Both groups demonstrated significant (p b 0.001) improvement in walking abilities (PFWT and MWT) after treadmill program (Table 2). The change in each measure was similar between two groups (p > 0.05). Between-group differences in PFWT and MWT were insignificant at baseline (p > 0.05). The training program resulted in significant increases in resting FMD from 4.59 ± 2.14% to 6.27 ± 2.8% (p b 0.01) in the PFT group, and from 3.98 ± 1.9% to 6.22 ± 2% (p b 0.001) in the MT group (Table 3). A significant improvement of FMD was also observed after the program in the post-exercise values (after treadmill test to the maximal claudication pain). The post-exercise FMD increased from 4.24 ± 2.01% to 5.69 ± 2.43% (p b 0.01) in the PFT group and from 4.58 ± 2.09 to 6.65 ± 2.56 (p b 0.001) in the MT group. The change in each measure was similar between two groups (p > 0.05). Between-group differences in both rest and post-exercise FMD were insignificant (p > 0.05) at baseline. The treadmill test to maximal claudication pain did not induce significant (p > 0.05) FMD changes in MT and PFT groups both at the beginning and at the end of the study. ABI values were similar (p > 0.05) at baseline in both MT and PFT groups. The significant ABI change (p b 0.05) from 0.52 ± 0.15 to 0.58 ± 0.18 was observed after exercise program in the MT group
Group
MT
PFT
Values are mean ± SD and percentages (in parentheses) when appropriate. Differences between groups for all parameters are not significant. BMI, body mass index; ABI, ankle–brachial index; ACEi, angiotensin enzyme converter inhibitors; ASA, acetylsalicylic acid.
Variables
Group
p3
only (Table 2). However, group effect and group-by-time interaction were insignificant (p > 0.05). The groups did not differ significantly (p > 0.05) in biochemical parameters at baseline (Table 4). Neither group had a significant change (p > 0.05) in hs-CRP, fibrinogen and lipid profile after treadmill training. The smoking status and BMI did not change significantly after the program in both groups (p > 0.05). No significant correlation between baseline FMD, ABI, walking abilities, smoking status, BMI or biochemical measurements and the improvement in FMD, ABI and walking abilities was observed after exercise training. The changes in FMD, ABI and walking abilities observed after the program did not correlate with each other. 4. Discussion This randomized controlled trial of the two types of exercise program demonstrates similar improvement of endothelial function and walking ability regardless of the training method. To our knowledge, this is the first direct comparison of treadmill training programs which applied claudication pain level as an end point of treadmill exercise. Coronary and cerebral events are considered the main causes of death in patients with claudication [16]. Impaired endothelial function, measured as reduced brachial artery FMD, associated with high levels of CRP and fibrinogen, has been demonstrated in PAD [17,18]. Preliminary studies suggest that restoration of normal endothelial function is coupled with reduction of cardiovascular events, as well as the improvement in walking abilities in patients with claudication [2,19]. The present study shows significant improvement of 120% PFWT and 100% MWT in the MT group as well as 93% PFWT and 98% MWT in the PFT group. This improvement of walking abilities did not statistically differ between groups and was comparable to that reported by the Cochrane Collaboration in the rigorous systematic review of 22 Table 4 Changes in biochemical variables in the moderate training (MT) and pain-free training (PFT) groups (mean ± SD). Variables
Group
Baseline
Week 12
p
total-cholesterol (mmol/l)
MT PFT MT PFT MT PFT MT PFT MT PFT MT PFT
4.87 ± 0.98 4.52 ± 0.88 2.76 ± 0.91 2.33 ± 0.97 1.33 ± 0.25 1.40 ± 0.34 1.70 ± 0.72 1.73 ± 0.90 2.45 ± 1.69 2.40 ± 2.02 4.22 ± 1.80 4.48 ± 1.18
4.64 ± 0.90 4.88 ± 1.06 2.54 ± 0.85 2.63 ± 1.02 1.31 ± 0.24 1.46 ± 0.29 1.71 ± 0.76 1.72 ± 0.77 2.41 ± 2.70 2.57 ± 2.73 4.24 ± 1.38 4.30 ± 1.12
0.14 0.08 0.10 0.11 0.65 0.14 0.80 0.90 0.94 0.78 0.90 0.46
LDL-cholesterol (mmol/l) 0.80 HDL-cholesterol (mmol/l) 0.64 Triglycerides (mmol/l) 0.26 hs-CRP (mg/l) Fibrinogen (g/l)
p — value between 12-week and baseline.
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controlled exercise trials [7]. The significant improvement of endothelial function after treadmill training has been reported previously [3,6]. Brendle et al. [6] demonstrated increase in FMD value from 4.81 to 7.97 after a 6-month training program and concluded that the improvement of FMD measured in the upper extremity after treadmill walking training confirms systemic (not only local) effects of such program on endothelial function. Similar results were obtained in our study. The mechanism of such improvement was generally attributed to enhanced endothelial synthesis of nitric oxide (NO). The release of NO may be induced by physiological stimulus such as increase in blood flow. Physical exercise augments peak limb blood flow and laminar shear stress, resulting in increased NO production and enhanced FMD [2,5,20]. Although these mechanisms were not measured in the present study, however our previous findings support this notion [21]. The improvement in walking abilities (PFWT, MWT) observed after treadmill training in both groups may then be related to positive changes in endothelial function that resulted in blood flow increase via reduction of peripheral resistance. The small but significant increase of ABI from 0.52 to 0.58, observed only in moderate training group, in which more pronounced improvement of FMD was noted, may support this thesis. However, the lack of correlation between changes in FMD, ABI and walking times (which were similar in both groups) indicates that enhanced FMD is only one among other potential factors [22,23] leading to observed changes in walking abilities in patients with claudication. Kingwell et al. [4] suggested that improved endothelium-dependent dilator reserve associated long-term endurance training is due to altered lipoprotein levels. They found that the lower total cholesterol level may contribute to better endothelium-dependent vasodilatation. Our results do not seem to confirm these findings. Almost all of our patients were treated with statins and their lipid profile had been initially modified [24]. Furthermore, we did not observed any significant changes in lipid profile after 3 months of the program in both groups. Turton et al. [25] hypothesized that exercise training confers benefit on the one hand but has a potential to enhance endothelial injury on the other. It is therefore worth to underline that both these treadmill training programs are safe therapeutic modes, since none of them escalates the inflammation in patients with claudication. The elevated level of hs-CRP and fibrinogen, observed in both groups at the beginning of the program did not change significantly after 3 months of rehabilitation. It was shown that CRP has a potential use as a measure of repeated inflammatory events in claudication as well as both CRP and fibrinogen are the prognostic indicators for future cardiovascular events in person with and without clinically established atherosclerosis disease [8,26]. Additionally, the progressive rise in CRP according to disease severity has already been demonstrated [27]. It has been suggested that single exercise in patients with claudication may result in an inflammatory response [9]. However, extending these results to the regular exercise training seems, in view of our observations, too far outstretched. Moreover, it was suggested that moderate hemodynamic stress may reduce the level of inflammatory markers and increase flow-mediated vasodilatation through an ischemic preconditioning [3,22]. Based on our findings we can confirm the increase of FMD following 3 months of treadmill training, however potential changes of inflammatory markers are questionable. Tisi et al. [28] observed a significant decrease in CRP from 5.3 mg/l to 4.4 mg/l following 3 months of home-based exercise program performed every day to the limit of claudication and a mild rise to 6.6 mg/l after additional 3 months of such training. Saxton et al. [29] also reported only tendency, without statistical significance, to lowering hs-CRP level after 24 weeks of upper and lower limb exercise trainings. The influence of exercise training on fibrinogen level in patients with claudication is unclear. A significant rise in fibrinogen level (14.5%) has been observed after one month of physical training [30] however in the study of Tisi et al. [28] where exercise was performed to the limit of claudication pain fibrinogen changes were insignificant. Our results as well as those of previous researches [12]
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indicate that regardless of pain level (onset or moderate) used as an end point of treadmill exercise, there is no increase in inflammation markers (fibrinogen, hs-CRP) after treadmill program. Andreozzi et al. [3] suggested possible worsening of FMD after exercise performed to the maximal claudication pain. They concluded that physical activity in intermittent claudication should not utilize the maximal working load, in order to avoid the high inflammatory activation and the acute complication of atherosclerotic plaque. In our research, changes of post-exercise FMD were insignificant in both groups at baseline as well as at the end of our training program. The post-exercise decrease of FMD in a total group of 52 patients was observed in 26 cases at baseline and in 25 cases at the end of the program. All remaining patients presented increase of FMD value. The same type of reaction (increase or decrease of FMD) on maximal exercises before and after treadmill program was observed in almost 52% of all patients. We didn't find any predictors of the changes in FMD after exercise to the maximal claudication pain. Similarly, in the study of Andreozzi et al. [3] in 6 cases out of total of 22 examined patients no decrease (or even increase) in FMD values were observed after exercise to the maximal claudication pain irrespectively of measurement (before or after treadmill program). It seems that the single episode of low-grade ischemia related to claudication pain does not always result in worsening of endothelial function. Perhaps it depends on individual pain tolerance and the degree of ischemia at the point when the patient refuses to continue the test because of severity of claudication pain. Therefore, the effect of exercise performed to the maximal claudication pain as well as treadmill training based on such exercises, on endothelial function needs additional investigations including sensitive markers of the endothelial oxidative stress response. 4.1. Study limitation The limitation of this trial is the lack of no-training control group and potential confounding effects of patients' medication on endothelial reactivity and walking ability. Statins improve endothelial function measured by FMD and walking ability in patients with claudication in a limited range [24,31]. We believe that our results are not due to statin treatment, since there was no difference between groups in statin use. Some bias in the study may exist because of the use of angiotensin enzyme converter inhibitors (ACEi), however pharmacological treatment of all patients was stable within at least 6 months before enrolment and remained unchanged during the study. The significant changes of ABI observed in the moderate training group besides suggested improvement of the endothelial function may also be a result of better collateralization due to the ischemic stimulus during this type of treadmill training, however the data of this study are not sufficient to verify this thesis. It is possible that a few additional months of training as well as analysis of growth factors and additional inflammatory markers would provide important data to answer this question. 4.2. Conclusion In conclusion, based on the improvement of both endothelial function and walking ability the efficacy of pain-free training and moderate exercise training is similar. Moreover, both programs appear safe, since none of them escalates the inflammation in patients with claudication. The post-training FMD improvement indicates systemic effects of the programs on endothelial function. The amelioration of endothelial function may be among the potential factors leading to the increase in walking ability in patients with claudication. The program with exercise interrupted at onset of claudication should be considered an effective therapeutic option. The question whether the ischemic stimulus during a training beyond the ischemic threshold would lead to a better
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functional response has not been solved in this study and requires further investigation. Acknowledgments We wish to thank Professor Stefan Chłopicki for his suggestions on endothelial function assessment. The authors of this manuscript have certified that they comply with the principles of Ethical Publishing in the International Journal of Cardiology. References [1] Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-society consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 2007;33:S1–S70. [2] Brevetti G, Schiano V, Chiariello M. Endothelial dysfunction: a key to the pathophysiology and natural history of peripheral arterial disease? Atherosclerosis 2008;197:1–11. [3] Andreozzi GM, Leone A, Laudani R, Deinite G, Martini R. Acute impairment of the endothelial function by maximal treadmill exercise in patients with intermittent claudication, and its improvement after supervised physical training. Int Angiol 2007;26:12–7. [4] Kingwell BA, Tran B, Cameron JD, Jennings GL, Dart AM. Enhanced vasodilation to acetylcholine in athletes is associated with lower plasma cholesterol. Am J Physiol 1996;270:H2008–13. [5] Katz SD, Yuen J, Bijou R, LeJemtel TH. Training improves endothelium-dependent vasodilation in resistance vessels of patients with heart failure. J Appl Physiol 1997;82:1488–92. [6] Brendle DC, Joseph LJ, Corretti MC, Gardner AW, Katzel L. Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease. Am J Cardiol 2001;87:324–9. [7] Watson L, Ellis B, Leng GC. Exercise for intermittent claudication. Cochrane Database Syst Rev 2008(CD000990). [8] Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain: a meta-analysis. JAMA 1995;274:975–80. [9] Tisi PV, Shearman CP. Biochemical and inflammatory changes in the exercising claudicant. Vasc Med 1998;3:189–98. [10] Mika P, Spodaryk K, Cencora A, Unnithan VB, Mika A. Experimental model of pain-free treadmill training in patients with claudication. Am J Phys Med Rehabil 2005;84:756–62. [11] Regensteiner JG, Meyer TJ, Krupski WC, Cranford LS, Hiatt WR. Hospital versus home-based exercise rehabilitation for patients with peripheral arterial occlusive disease. Angiology 1997;48:291–300. [12] Mika P, Wilk B, Mika A, Marchewka A, Nizankowski R. The effect of pain-free treadmill training on fibrinogen, haematocrit, and lipid profile in patients with claudication. Eur J Cardiovasc Prev Rehabil 2011;18:754–60. [13] Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP. Clinical trials for claudication. Assessment of exercise performance, functional status, and clinical end points. Circulation 1995;92:614–21. [14] Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a
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report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257–65. Whitton CM, Sands D, Hubbard AR, Gaffney PJ. A collaborative study to establish the 2nd international standards for fibrinogen, plasma. Thromb Haemost 2000;84: 258–62. Meru AV, Mittra S, Thyagarajan B, Chugh A. Intermittent claudication: an overview. Atherosclerosis 2006;187:221–37. Brevetti G, Silvestro A, Di Giacomo S, et al. Endothelial dysfunction in peripheral arterial disease is related to increase in plasma markers of inflammation and severity of peripheral circulatory impairment but not to classic factors and atherosclerotic burden. J Vasc Surg 2003;38:374–9. De Haro J, Acin F, Lopez-Quintana A, et al. Direct association between C-reactive protein serum levels and endothelial dysfunction in patients with claudication. Eur J Vasc Endovasc Surg 2008;35:480–6. Kitta Y, Obata JE, Nakamura T, et al. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol 2009;53:323–30. Di Francescomarino S, Sciartilli A, Di Valerio V, Di Baldassarre A, Gallina S. The effect of physical exercise on endothelial function. Sports Med 2009;39:797–812. Mika P, Spodaryk K, Cencora A. Effects of treadmill training on walking distance and lower limb blood flow in patients with intermittent claudication. Med Rehabil 2005;9:3–9. Tan KH, De Cossart L, Edwards PR. Exercise training and peripheral vascular disease. Br J Surg 2000;87:553–62. Mika P, Spodaryk K, Cencora A, Mika A. Red blood cell deformability in patients with claudication after pain-free treadmill training. Clin J Sport Med 2006;16: 335–40. Mohler ER, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patient with peripheral arterial disease. Circulation 2003;108:1481–6. Turton EP, Coughlin PA, Kester RC, Scott DJ. Exercise training reduces the acute inflammatory response associated with claudication. Eur J Vasc Endovasc Surg 2002;23:309–16. Ridker PM, Hennekens CH, Rifai N. Novel risk factor for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a) and standard cholesterol screening as predictors of peripheral vascular disease. JAMA 2001;285:2481–5. Silvestro A, Scopacasa F, Ruocco A, et al. Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease. Vasc Med 2003;8:225–32. Tisi PV, Hulse M, Chulakadabba A, Gosling P, Shearman CP. Exercise training for intermittent claudication: does it adversely affect biochemical markers of the exercise-induced inflammatory response? Eur J Vasc Endovasc Surg 1997;14: 344–50. Saxton JM, Zwierska I, Hopkinson K, et al. Effect of upper- and lower-limb exercise training on circulating soluble adhesion molecules, hs-CRP and stress proteins in patients with intermittent claudication. Eur J Vasc Endovasc Surg 2008;35: 607–13. Pancera P, Prior M, Zannoni M, Lucchese L, De MS, Arosio E. Micro- and macrocirculatory, and biohumoral changes after a month of physical exercise in patients with intermittent claudication. Scand J Rehabil Med 1995;27:73–6. Reriani MK, Dunlay SM, Gupta B, et al. Effects of statins on coronary and peripheral endothelial function in humans: a systematic review and meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil 2011;18:704–16.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparison of two treadmill training programs on walking ability and endothelial function in intermittent claudication☆ Piotr Mika a,⁎, Anita Konik a, Rafal Januszek b, Tomasz Petriczek b, Anna Mika a, Roman Nowobilski c, Rafal Nizankowski b, Andrzej Szczeklik b a b c
Department of Clinical Rehabilitation, University School of Physical Education, Cracow, Poland Department of Internal Medicine, Jagiellonian University School of Medicine, Cracow, Poland Institute of Physiotherapy, Faculty of Health Sciences, Jagiellonian University, School of Medicine, Cracow, Poland
a r t i c l e
i n f o
Article history: Received 8 February 2012 Received in revised form 3 July 2012 Accepted 7 October 2012 Available online 30 October 2012 Keywords: Atherosclerosis Claudication Treadmill training Endothelial function
a b s t r a c t Background: In this randomized trial we compared two treadmill trainings, based on exercises performed to moderate claudication pain vs pain-free training, with respect to their effects on walking ability and endothelial function. Methods: A total of sixty patients with stable intermittent claudication were randomized to the pain-free treadmill training (repetitive intervals to onset of claudication pain) or moderate treadmill training (repetitive intervals to moderate claudication pain). In both groups exercises were performed 3 times a week for 3 months. Changes in flow mediated dilatation (FMD) and treadmill walking performance as well as plasma levels of C-reactive protein (hs-CRP) and fibrinogen were assessed before and after the program. Results: Fifty-two patients completed the training program. Post-training maximal walking time was prolonged by 100% (pb 0.001) vs 98% (pb 0.001), and pain-free walking time by 120% (pb 0.001) vs 93% (pb 0.001) in the moderate training group as compared to the pain-free training group, respectively. FMD increased by 56% (pb 0.001) in the moderate training group and by 36% (pb 0.01) in the pain-free training group. No significant changes in the levels of hs-CRP and fibrinogen were seen after treadmill program in either group. Conclusions: Both pain-free treadmill training and the moderate treadmill training have similar efficacy on walking ability in patients with claudication. The improvement of post-training FMD indicates systemic effect of both treadmill programs on endothelial function. Both programs appear to be safe therapeutic modes, since none of them escalates the inflammation. Pain-free treadmill training seems useful and effective therapeutic option for patients with claudication. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Intermittent claudication is the leading symptom of peripheral arterial disease (PAD). It is usually defined as pain or muscle discomfort in the lower limb reproducibly produced by exercise, due to imbalance of oxygen supply and demand, and relieved by rest [1]. An impairment of endothelial function is usually observed in patients with claudication [2]. This early event of atherogenesis, which leads to increased leukocyte adhesion and platelet aggregation, may be observed many years before appearance of atheromatous plaque [3]. The more severe PAD, the greater impairment of endothelial
☆ The study was supported, in part, by grant no NN404026035 from the Ministry of Science and Higher Education, Poland. ⁎ Corresponding author at: Department of Clinical Rehabilitation, University School of Physical Education, Al. Jana Pawla II 78, 31-571 Cracow, Poland. Tel.: +48 12 6831134; fax: +48 12 6831300. E-mail address: [email protected] (P. Mika). 0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.10.003
function [2]. The endothelial dysfunction, manifested by impairment of the endothelial-dependent vasodilatation contributes to the increased peripheral resistance, decreased blood flow rate, limited tissue oxygenation and walking intolerance that occur in this disease [3]. Therefore, impaired endothelial function, besides atherosclerotic stenosis is a potential contributor to phenomenon of intermittent claudication. It has been suggested, that the interventions which improve endothelial function increase walking capacity of the affected individuals [2]. Changes in endothelial reactivity are one of the physiological responses to physical exercise. Regular exercise has been shown to enhance endothelial function in healthy individuals as well as in patients with coronary artery disease and with PAD [3–6]. Walking programs have long been considered the best option to improve walking distance in patients with claudication [7]. Based on the meta-analysis summarizing 21 exercise trials in this group of patients, Gardner et al. [8] suggested that the optimal program to improve walking distance should use intermittent walking to near-maximal leg pain.
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The recent Intersociety Consensus for the Management of PAD (TASC II) states that in optimal program exercise should be performed to the point “when claudication pain is considered moderate” [1]. It was suggested previously that repeated episodes of leg muscle pain followed by rest may lead to cumulative inflammatory response and disease progression in patients with claudication [9]. The acute inflammatory response to strenuous exercise may also exacerbate endothelial function in patients with claudication which paralleled with an increase of inflammation markers [2,3]. In light of these, the pain-free treadmill training with exercises interrupted at the onset of claudication pain seems most safe, effective option for the treatment of patients with claudication [10]. However, it has also been noticed that less optimal training response occurs when the patients stop at the onset of claudication [1,8]. To date, no direct comparison between treadmill programs applying various claudication pain intensities has been reported. Thus, identifying the most appropriate level of submaximal exercise for this group of patients is still an important issue which needs more clarification. The purpose of this randomized trial was to compare the efficacy of two treadmill training programs for patients with claudication. The training using exercises performed to moderate claudication pain vs pain-free treadmill training were compared in the context of their effects on endothelial function, walking performance, as well as plasma level of fibrinogen and CRP (the stable biochemical markers of inflammation and disease severity). 2. Methods 2.1. Study population Sixty patients with PAD and intermittent claudication, aged 50–75 years, in stage II of PAD (Fontaine classification), have been recruited from the vascular outpatient clinic. The diagnosis of PAD was confirmed by Doppler ultrasound and an ankle/brachial index (ABI) of less than 0.9 at rest. All patients had stable claudication distance and were able to walk at least 150 m without pain. None of the enrolled patients had a history of unstable angina pectoris, recent myocardial infarction, or vascular surgery within the previous year. Patients affected by impaired cardiac or lung function, cancer, kidney and liver disease, or arthritis that limited walking were excluded. Patients who were unable to walk on the treadmill at a speed of at least 3.2 km/h were also excluded. Pharmacological treatment of all patients (anti-platelet therapy, anti-hypertensive therapy, cholesterol-lowering agents) was stable within 6 months before the enrolment and remained unchanged during the study. None of the participants in the study was taking pentoxifylline, cilostazol or selective cox-2 inhibitors. The study complied with the Declaration of Helsinki. All subjects provided written informed consent before the investigation. Local ethical committee approval was obtained for this study.
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2.4. Treadmill testing Walking abilities (PFWT and MWT) were assessed during morning hours according to the graded treadmill protocol [13]. Subject walked on the treadmill (Gait Trainer, Biodex, USA) at an initial workload of 3.2 km/h, 0% grade for 2 min. Subsequent stages increased 2% in grade every 2 min. The speed was set constant (3.2 km/h) throughout the test. The PFWT was determined when the patient reported first pain feeling, discomfort, or numbness in the calf (level 2 on pain scale) whereas the MWT was recorded when the patient refused to continue the test because of severe claudication pain (level 5 on pain scale) [11]. Patients were instructed not to use handrail support during the treadmill test. The treadmill was calibrated prior to each testing. The test was repeated on the next day and the best of the two measurements was used in the data analysis. 2.5. Endothelial function assessment The endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was assessed using a high resolution echo-Doppler ultrasound (Sequoia 512, Acuson, linear probe 7 MHz). The examination was performed in a quiet, temperature-controlled room (23°–24 °C) after 15 min resting period. The subjects reported to the laboratory between 7 and 8 a.m. after overnight fasting. Patients were instructed to refrain from physical exercises, caffeine beverages, and tobacco use for 12 h prior to the test. All temporary medications were withheld for 24 h before testing [12]. The subject was positioned supine with the arm fixed in a comfortable position for imaging the brachial artery 2 cm above the antecubital fossa in the longitudinal plane. A segment with clear anterior and posterior intimal interfaces between the lumen and vessel wall was selected for imaging [14]. The images were recorded for 30 s at rest. Thereafter, arterial occlusion was produced with the pneumatic sphygmomanometric cuff placed below the antecubital fossa and inflated 50 mm Hg over the systolic blood pressure. After 5 min of ischemia, the cuff was deflated. The diameter of the brachial artery was measured for 60 to 90 s after deflation. The mean of 3 maximal end-diastolic diameter measurements was assumed to calculate FMD value. The percent change in artery diameter during postocclusive reactive hyperemia was taken as the value of FMD [3]. The measurement was performed at rest and repeated 15 min after the treadmill test to maximal claudication pain. 2.6. Biochemical analyses On the next day blood samples were collected at rest, after overnight fasting. Patients were asked to refrain from smoking 12 h prior to the blood test. Blood samples for the analysis of fibrinogen, high-sensitivity C-reactive protein (hs-CRP) and lipid profile: total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides, were drawn from the forearm vein (between 9.00 and 10.00 a.m.) after a 30 min rest (sitting in a comfortable chair) and immediately sent to the laboratory. Total cholesterol, HDL-C, and triglycerides concentration were measured by photometric dry chemistry method using Vitros-350 analyzer (Johnson & Johnson, Hempstead, Hertfordshire, UK). The LDL-C was calculated by the Friedewald formula. Serum hs-CRP concentration was determined using nephelometric method on the Behring Nephelometer BN II (Simens, Marburg, Germany). Plasma fibrinogen concentration was measured using the method of Clauss [15] on Sysmex CA-500 analyzer (Sysmex, Kobe, Japan). 2.7. Other measures
2.2. Study design After initial familiarization with treadmill exercise patients were randomized to either the moderate training (MT) group, (n = 30) or the pain-free training (PFT) group (n = 30). All patients were evaluated at baseline and after 12 weeks of the study. Each time pain-free (PFWT) and maximal walking time (MWT) were measured during treadmill test. Additionally, each time endothelial function and ABI were assessed, blood analyses were performed, and smoking status of all patients was obtained. The testing and analyses were conducted by qualified medical staff blinded to the subject's group assignment.
2.3. Treadmill training Both exercise programs consisted of 12 weeks of supervised, intermittent treadmill walking. Exercise sessions were conducted three times a week. During each exercise session, treadmill walking was at the speed of 3.2 km/h and the grade was individually determined for each patient that will induce claudication within 3 to 5 min [1]. The exercise was interrupted when claudication pain was considered moderate (MT group) or the patient stopped at the onset of claudication (PFT group). The severity of claudication pain experienced by the patient was determined on a scale, where 1 = no pain, 2 = onset of claudication pain, 3 = mild pain, 4 = moderate pain, and 5 = maximal pain [11]. After exercise, the patient was resting until claudication has abated and then walking was resumed. This cycle of intermittent walking exercise was applied for 35 min at the start of the program with progressive increase of session time by 5 min per 2 weeks until a total of 60 min was accomplished. At subsequent visits, the grade of the treadmill was increased (for the new session), if the patient was able to walk for 8 min or longer at the previous workload [12].
ABI was measured at rest according to the standard procedure [1]. Smoking status was determined as the daily amount of smoked cigarettes reported by the patient, height and weight were measured before and after the program, and BMI (body mass index) was calculated. 2.8. Statistical analysis Changes in variables over 12 weeks of the program were analyzed by repeated measures ANOVA (within subjects, between groups). One-way ANOVA was used to determine initial between-group differences. Stepwise multiple regression analysis was performed to identify the variables independently related to the changes in FMD and walking ability. The statistical analyses were performed using Statistica 10.0 software. The data are expressed as means and SD. Statistical significance was accepted at 0.05 level of probability.
3. Results Of the 60 patients who entered the program, 3 were withdrawn from the moderate training group and 5 from the pain-free training group. One patient was excluded because of gastric ulcer surgery, one developed diabetic foot ulceration, one was disinterested in the final examination, five patients refused to continue for unspecified, but not health-related, reasons. The clinical characteristics of the 52 patients completing the 12-week program are shown in Table 1.
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Table 1 Subjects' characteristics and baseline clinical data.
Male:female Age, years Weight, kg BMI, kg/m2 ABI Smoking history Never, n (%) Former, n (%) Current, n (%) Smoking, years Cigarettes/d Claudication, years Diabetes, n (%) Treatment, n ACEi ASA Statins
Table 3 The rest and post-exercise changes in FMD after 12 weeks of the treadmill training.
Moderate training Group (n = 27)
Pain-free training Group (n = 25)
16:11 64.8 ± 7.2 75.8 ± 13.8 26.9 ± 3.7 0.52 ± 0.15
16:9 65.2 ± 8.0 72.2 ± 8.5 25.1 ± 2.8 0.47 ± 0.16
1 (3.7) 13 (48.1) 13 (48.1) 34 ± 12.1 6.7 ± 7.8 8.3 ± 6.7 5 (18.5)
1 (4) 10 (40) 14 (56) 35 ± 12.0 5.4 ± 7.7 9 ± 5.5 3 (12)
21 26 27
17 25 24
Table 2 Changes in pain-free walking time (PFWT) and maximal walking time (MWT) in moderate and pain-free training groups (mean ± SD). Baseline
PFWT (s)
MT PFT MT PFT MT PFT
140 ± 72 169 ± 62 441 ± 178 489 ± 147 0.52 ± 0.15 0.47 ± 0.16
MWT (s) ABI
p1 0.12 0.29 0.22
Week 12
p2
Change
307 ± 182 327 ± 155 881 ± 326 969 ± 376 0.58 ± 0.18 0.48 ± 0.20
b0.001 b0.001 b0.001 b0.001 0.02 0.70
167 ± 158 157 ± 117 440 ± 262 479 ± 333 0.06 ± 0.12 0.01 ± 0.16
p1 — value between PFT group and MT group at baseline. p2 — value between 12-week and baseline. p3 — value between change in PFT group and change in MT group. MT — moderate training, PFT — pain-free training. Change — difference between 12-week and baseline.
p1
Baseline Rest Post-exercise p Rest Post-exercise p
Week 12
3.98 ± 1.90 6.22 ± 2.0 4.58 ± 2.09 6.65 ± 2.56 0.22 0.41 4.59 ± 2.14 0.29 6.27 ± 2.80 4.24 ± 2.01 0.56 5.69 ± 2.43 0.42 0.29
p2
Change
p3
b0.001 2.24 ± 2.09 b0.001 2.06 ± 2.34 b0.01 b0.01
1.68 ± 2.84 0.42 1.44 ± 2.42 0.36
p — value between rest and post-exercise (baseline or 12-week). p1 — value between PFT group and MT group at baseline (rest or post-exercise). p2 — value between 12-week and baseline (rest or post-exercise). p3 — value between change in PFT group and change in MT group (rest or post-exercise). MT — moderate training, PFT — pain-free training. Change — difference between 12-week and baseline.
Differences in baseline variables between groups were insignificant (p > 0.05). The ANOVA analyses showed significant main effect for time but group effect and group-by-time interactions were insignificant for both walking abilities and FMD which means that the groups were changing over 12 weeks in similar ways. Both groups demonstrated significant (p b 0.001) improvement in walking abilities (PFWT and MWT) after treadmill program (Table 2). The change in each measure was similar between two groups (p > 0.05). Between-group differences in PFWT and MWT were insignificant at baseline (p > 0.05). The training program resulted in significant increases in resting FMD from 4.59 ± 2.14% to 6.27 ± 2.8% (p b 0.01) in the PFT group, and from 3.98 ± 1.9% to 6.22 ± 2% (p b 0.001) in the MT group (Table 3). A significant improvement of FMD was also observed after the program in the post-exercise values (after treadmill test to the maximal claudication pain). The post-exercise FMD increased from 4.24 ± 2.01% to 5.69 ± 2.43% (p b 0.01) in the PFT group and from 4.58 ± 2.09 to 6.65 ± 2.56 (p b 0.001) in the MT group. The change in each measure was similar between two groups (p > 0.05). Between-group differences in both rest and post-exercise FMD were insignificant (p > 0.05) at baseline. The treadmill test to maximal claudication pain did not induce significant (p > 0.05) FMD changes in MT and PFT groups both at the beginning and at the end of the study. ABI values were similar (p > 0.05) at baseline in both MT and PFT groups. The significant ABI change (p b 0.05) from 0.52 ± 0.15 to 0.58 ± 0.18 was observed after exercise program in the MT group
Group
MT
PFT
Values are mean ± SD and percentages (in parentheses) when appropriate. Differences between groups for all parameters are not significant. BMI, body mass index; ABI, ankle–brachial index; ACEi, angiotensin enzyme converter inhibitors; ASA, acetylsalicylic acid.
Variables
Group
p3
only (Table 2). However, group effect and group-by-time interaction were insignificant (p > 0.05). The groups did not differ significantly (p > 0.05) in biochemical parameters at baseline (Table 4). Neither group had a significant change (p > 0.05) in hs-CRP, fibrinogen and lipid profile after treadmill training. The smoking status and BMI did not change significantly after the program in both groups (p > 0.05). No significant correlation between baseline FMD, ABI, walking abilities, smoking status, BMI or biochemical measurements and the improvement in FMD, ABI and walking abilities was observed after exercise training. The changes in FMD, ABI and walking abilities observed after the program did not correlate with each other. 4. Discussion This randomized controlled trial of the two types of exercise program demonstrates similar improvement of endothelial function and walking ability regardless of the training method. To our knowledge, this is the first direct comparison of treadmill training programs which applied claudication pain level as an end point of treadmill exercise. Coronary and cerebral events are considered the main causes of death in patients with claudication [16]. Impaired endothelial function, measured as reduced brachial artery FMD, associated with high levels of CRP and fibrinogen, has been demonstrated in PAD [17,18]. Preliminary studies suggest that restoration of normal endothelial function is coupled with reduction of cardiovascular events, as well as the improvement in walking abilities in patients with claudication [2,19]. The present study shows significant improvement of 120% PFWT and 100% MWT in the MT group as well as 93% PFWT and 98% MWT in the PFT group. This improvement of walking abilities did not statistically differ between groups and was comparable to that reported by the Cochrane Collaboration in the rigorous systematic review of 22 Table 4 Changes in biochemical variables in the moderate training (MT) and pain-free training (PFT) groups (mean ± SD). Variables
Group
Baseline
Week 12
p
total-cholesterol (mmol/l)
MT PFT MT PFT MT PFT MT PFT MT PFT MT PFT
4.87 ± 0.98 4.52 ± 0.88 2.76 ± 0.91 2.33 ± 0.97 1.33 ± 0.25 1.40 ± 0.34 1.70 ± 0.72 1.73 ± 0.90 2.45 ± 1.69 2.40 ± 2.02 4.22 ± 1.80 4.48 ± 1.18
4.64 ± 0.90 4.88 ± 1.06 2.54 ± 0.85 2.63 ± 1.02 1.31 ± 0.24 1.46 ± 0.29 1.71 ± 0.76 1.72 ± 0.77 2.41 ± 2.70 2.57 ± 2.73 4.24 ± 1.38 4.30 ± 1.12
0.14 0.08 0.10 0.11 0.65 0.14 0.80 0.90 0.94 0.78 0.90 0.46
LDL-cholesterol (mmol/l) 0.80 HDL-cholesterol (mmol/l) 0.64 Triglycerides (mmol/l) 0.26 hs-CRP (mg/l) Fibrinogen (g/l)
p — value between 12-week and baseline.
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controlled exercise trials [7]. The significant improvement of endothelial function after treadmill training has been reported previously [3,6]. Brendle et al. [6] demonstrated increase in FMD value from 4.81 to 7.97 after a 6-month training program and concluded that the improvement of FMD measured in the upper extremity after treadmill walking training confirms systemic (not only local) effects of such program on endothelial function. Similar results were obtained in our study. The mechanism of such improvement was generally attributed to enhanced endothelial synthesis of nitric oxide (NO). The release of NO may be induced by physiological stimulus such as increase in blood flow. Physical exercise augments peak limb blood flow and laminar shear stress, resulting in increased NO production and enhanced FMD [2,5,20]. Although these mechanisms were not measured in the present study, however our previous findings support this notion [21]. The improvement in walking abilities (PFWT, MWT) observed after treadmill training in both groups may then be related to positive changes in endothelial function that resulted in blood flow increase via reduction of peripheral resistance. The small but significant increase of ABI from 0.52 to 0.58, observed only in moderate training group, in which more pronounced improvement of FMD was noted, may support this thesis. However, the lack of correlation between changes in FMD, ABI and walking times (which were similar in both groups) indicates that enhanced FMD is only one among other potential factors [22,23] leading to observed changes in walking abilities in patients with claudication. Kingwell et al. [4] suggested that improved endothelium-dependent dilator reserve associated long-term endurance training is due to altered lipoprotein levels. They found that the lower total cholesterol level may contribute to better endothelium-dependent vasodilatation. Our results do not seem to confirm these findings. Almost all of our patients were treated with statins and their lipid profile had been initially modified [24]. Furthermore, we did not observed any significant changes in lipid profile after 3 months of the program in both groups. Turton et al. [25] hypothesized that exercise training confers benefit on the one hand but has a potential to enhance endothelial injury on the other. It is therefore worth to underline that both these treadmill training programs are safe therapeutic modes, since none of them escalates the inflammation in patients with claudication. The elevated level of hs-CRP and fibrinogen, observed in both groups at the beginning of the program did not change significantly after 3 months of rehabilitation. It was shown that CRP has a potential use as a measure of repeated inflammatory events in claudication as well as both CRP and fibrinogen are the prognostic indicators for future cardiovascular events in person with and without clinically established atherosclerosis disease [8,26]. Additionally, the progressive rise in CRP according to disease severity has already been demonstrated [27]. It has been suggested that single exercise in patients with claudication may result in an inflammatory response [9]. However, extending these results to the regular exercise training seems, in view of our observations, too far outstretched. Moreover, it was suggested that moderate hemodynamic stress may reduce the level of inflammatory markers and increase flow-mediated vasodilatation through an ischemic preconditioning [3,22]. Based on our findings we can confirm the increase of FMD following 3 months of treadmill training, however potential changes of inflammatory markers are questionable. Tisi et al. [28] observed a significant decrease in CRP from 5.3 mg/l to 4.4 mg/l following 3 months of home-based exercise program performed every day to the limit of claudication and a mild rise to 6.6 mg/l after additional 3 months of such training. Saxton et al. [29] also reported only tendency, without statistical significance, to lowering hs-CRP level after 24 weeks of upper and lower limb exercise trainings. The influence of exercise training on fibrinogen level in patients with claudication is unclear. A significant rise in fibrinogen level (14.5%) has been observed after one month of physical training [30] however in the study of Tisi et al. [28] where exercise was performed to the limit of claudication pain fibrinogen changes were insignificant. Our results as well as those of previous researches [12]
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indicate that regardless of pain level (onset or moderate) used as an end point of treadmill exercise, there is no increase in inflammation markers (fibrinogen, hs-CRP) after treadmill program. Andreozzi et al. [3] suggested possible worsening of FMD after exercise performed to the maximal claudication pain. They concluded that physical activity in intermittent claudication should not utilize the maximal working load, in order to avoid the high inflammatory activation and the acute complication of atherosclerotic plaque. In our research, changes of post-exercise FMD were insignificant in both groups at baseline as well as at the end of our training program. The post-exercise decrease of FMD in a total group of 52 patients was observed in 26 cases at baseline and in 25 cases at the end of the program. All remaining patients presented increase of FMD value. The same type of reaction (increase or decrease of FMD) on maximal exercises before and after treadmill program was observed in almost 52% of all patients. We didn't find any predictors of the changes in FMD after exercise to the maximal claudication pain. Similarly, in the study of Andreozzi et al. [3] in 6 cases out of total of 22 examined patients no decrease (or even increase) in FMD values were observed after exercise to the maximal claudication pain irrespectively of measurement (before or after treadmill program). It seems that the single episode of low-grade ischemia related to claudication pain does not always result in worsening of endothelial function. Perhaps it depends on individual pain tolerance and the degree of ischemia at the point when the patient refuses to continue the test because of severity of claudication pain. Therefore, the effect of exercise performed to the maximal claudication pain as well as treadmill training based on such exercises, on endothelial function needs additional investigations including sensitive markers of the endothelial oxidative stress response. 4.1. Study limitation The limitation of this trial is the lack of no-training control group and potential confounding effects of patients' medication on endothelial reactivity and walking ability. Statins improve endothelial function measured by FMD and walking ability in patients with claudication in a limited range [24,31]. We believe that our results are not due to statin treatment, since there was no difference between groups in statin use. Some bias in the study may exist because of the use of angiotensin enzyme converter inhibitors (ACEi), however pharmacological treatment of all patients was stable within at least 6 months before enrolment and remained unchanged during the study. The significant changes of ABI observed in the moderate training group besides suggested improvement of the endothelial function may also be a result of better collateralization due to the ischemic stimulus during this type of treadmill training, however the data of this study are not sufficient to verify this thesis. It is possible that a few additional months of training as well as analysis of growth factors and additional inflammatory markers would provide important data to answer this question. 4.2. Conclusion In conclusion, based on the improvement of both endothelial function and walking ability the efficacy of pain-free training and moderate exercise training is similar. Moreover, both programs appear safe, since none of them escalates the inflammation in patients with claudication. The post-training FMD improvement indicates systemic effects of the programs on endothelial function. The amelioration of endothelial function may be among the potential factors leading to the increase in walking ability in patients with claudication. The program with exercise interrupted at onset of claudication should be considered an effective therapeutic option. The question whether the ischemic stimulus during a training beyond the ischemic threshold would lead to a better
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