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EFFECTS OF REGULAR MODERATE EXERCISE ON ARTERIAL STIFFNESS, PTX3 PROTEIN AND SOME CARDIAC PARAMETERS Controlled clinical study تأثيرات التمارين الرياضية ذات الدرجة المتوسطة والمستمرة لفترة طويلة والمنتظمة على تصلب وعلى بعض متغيرات القلبPTX3 الشرايين وعلى بروتين ABSTRACT Objectives:This study intends to show some of the effects of long-term and regular moderate exercise on arterial stiffness, PTX3 protein levels and some cardiac parameters in individuals of middle and advanced age. Twenty mountaineers between the ages 35 to 68 who are interested in regular moderate exercise one day a week for 5 to 20 years (mean 10.45 years) were subjects of this study. Twenty sedentary individuals of the same age group were also included as the control group. Methods: Each mountaineer and the individuals in the control group was measured for lipid profile and complete blood count, and underwent echocardiography and exercise stress test. Central and peripheral pulse wave velocity was measured by measurement device noninvasively. The plasma Pentraxin 3 protein was assayed by ELISA. This study was conducted at Erciyes University in 2013. Results: Metabolic equivalent and plasma Pentraxin 3 protein levels were found to be significantly higher in mountaineers, compared to the sedentary group. Femoral-ankle pulse wave velocity carotid-femoral pulse wave velocity, left ventricular end-systolic diameter and the neutrophil to lymphocyte ratio were found to be significantly lower in mountaineers, compared to the sedentary group (p < 0.05). A statistically significant and inverse relationship was found between metabolic equivalent, pentraxin 3 protein levels and carotid-femoral pulse wave velocity, femoral-ankle pulse wave velocity. Conclusions: Long-term and regular, moderate exercise significantly decreases indicators of systemic inflammation and arterial stiffness. Keywords: Arterial stiffness, pulse wave velocity, pentraxin 3 protein, moderate exercise, metabolic equivalent, mountaineers. تأثيرات التمارين الرياضية ذات الدرجة المتوسطة والمستمرة لفترة طويلة والمنتظمة على تصلب الشرايين وعلى بروتين PTX3وعلى بعض متغيرات القلب الملخص األهداف :الغاية من هذه الدراسة هي مراقبة تأثيرات التمارين الرياضية ذات الدرجة المتوسطة والمستمرة لفترة طويلة والمنتظمة على تصلب الشرايين وعلى بروتين بينتراكسين 3-وعلى بعض متغيرات القلب لدى األشخاص ذات األعمار المتوسطة والمسنين .اشترك في هذه الدراسة 20شخصا ُ من متسلقي الجبال حيث تتراوح أعمارهم بين 68 – 35سنة ويجرون تمرينا ً رياضيا ً واحدا ً في األسبوع بانتظام لمدة 20-5سنة (بمعدل 10.45سنة) .وتم إشراك 20شخص (مجموعة فحص) ممن ال يمارسون الرياضة من نفس فئة األعمار من أجل مقارنة النتائج. الطرق :تم قياس معايير الدهون والتعداد الكامل للدم وتخطيط القلب واختبار شدة الرياضة لدى المشتركين في هذ الدراسة من مجموعة الفحص ومن عينة متسلقي الجبال .تم قياس سرعة موجات النبض المركزية والطرفية ) )PWVمن خالل جهاز قياس غير باضع .تم تحديد مستوى PTX3للبالزما من خالل .ELISA النتائج :وجد المكافئ االستقالبي ومستوى PTX3للبالزما لدى فئة متسلقي الجبال مرتفعا ً بشكل ملموس قياسا ً لفئة الفحص .ووجدت سرعة موجة نبض الفخذي – الكاحلي ،وسرعة موجة نبض السباتي – الفخذي وقطر نهاية االنقباض البطيني األيسر ونسبة الخاليا اللمفاوية العدلة لدى فئة متسلقي الجبال منخفضة إحصائيا ً بشكل ملموس قياسا ً لفئة الفحص ( .)p<0.05وتم العثور على عالقة عكسية ملموسة إحصائيا ً بين مستويات المكافئ االستقالبي وبروتين بينتراكسين3- من جهة وسرعة موجة النبض السباتي – الفخذي و سرعة موجة النبض الفخذي – الكاحلي من جهة أخرى. االستنتاجات :التمارين الرياضية ذات الدرجة المتوسطة والمستمرة لفترة طويلة والمنتظمة تخفض مؤشرات االلتهاب المجموعي والتصلب الشرياني بشكل ملموس. الكلمات الدليلية :تصلب للشرايين ،سرعة موجة النبض ،بروتين بينتراكسين ،3-تمارين رياضية ذات الدرجة المتوسطة، مكافئ استقالبي ،متسلقي الجبال. INTRODUCTION Cardiovascular diseases (CVD) remain the leading cause of mortality in modern societies. Approximately 80% of all CVD deaths are associated with dysfunction and disorders of arteries1. Increased arterial stiffness, determined invasively, has been shown to predict a higher risk of coronary atherosclerosis2. The serial noninvasive evaluation of the arterial stiffness allows early detection of pathologic acceleration of the aging process and may be useful for prevention of coronary artery disease, which constitutes a major atherosclerotic complication. Intensive investigations have been continued to assess the state and the function of large arteries noninvasively for early detection of atherosclerotic damage to these vessels3. Many methodologies, both invasive and noninvasive, have been applied to the assessment of arterial elasticity in vivo. Interest in and measurement of the velocity of arterial wave propagation as an index of vascular stiffness and vascular health dates back to the early part of the last century. One of the most widely used non-invasive methods is 'pulse wave velocity' measurement. Carotid-femoral PWV is considered as the ‘gold-standard’ measurement of arterial stiffness4. Habitual aerobic exercise may delay age-associated increases in central arterial stiffness5. Greater central arterial compliance may contribute to the lower incidence of cardiovascular disease observed in middle-aged and older men who exercise regularly6. The role of the immune system and inflammatory pathways in the development of atherosclerotic disease is well established, and systemic markers of inflammation appear useful for indicating elevated cardiovascular disease risk in middle-age7. Recently, pentraxin 3 protein (PTX3), which is mainly produced by endothelial cells, macrophages, and smooth muscle cells in the atherosclerotic region, has been identified as a substance playing an important role in cardioprotection and atheroprotection8. Elevated plasma levels of the pentraxin protein family member C-reactive protein (CRP) are associated with increased risk of cardiovascular disease in both healthy and high-risk subjects9. Because of the homology between PTX3 and CRP, the relevance of PTX3 measurement as diagnostic tool has been investigated in cardiovascular pathology10. PTX3 in humans, like CRP, is a marker of atherosclerosis and correlates with the risk of developing vascular events. In conclusion, the integration of the available evidence on the role of PTX3 as cardiovascular biomarker and as atheroprotective agent suggests that the increased levels of PTX3 in subjects with CVD could reflect a protective physiologic response that correlates with the severity of the disease10. It is known that regular aerobic exercise increases metabolic equivalent (MET), causes left ventricular hypertrophy, reduces arterial stiffness and consequently reduces cardiovascular diseases 6. We aimed to show some of the effects of long-term and regular moderate exercise on arterial stiffness, PTX3 levels and some cardiac parameters in middle and advanced age individuals. METHODS This study was conducted at Erciyes University in 2013. The study was performed 20 mountaineers who between the ages 35 to 68 known as the Erciyes Tigers, members of the Turkish Mountaineering Federation (TDF). Twenty sedentary individuals of the same age group were also included as the control group. Inclusion criteria: For mountaineers; interesting regular moderate exercise (tracking) one day a week for 5 to 20 years. For sedentary individuals; to be the same age group who have not exercised in the last two years for more than 2 hours a week. Exclusion criteria: Metabolic bone disease, arthritis, diabetes, liver disease, kidney failure, corticosteroid use, smoking, use of alcohol and body mass index over 24.9 kg/m2. Twenty mountaineers between the ages 35 to 68 known as the Erciyes Tigers, members of the Turkish Mountaineering Federation (TDF) who are interested in regular moderate exercise (tracking) one day a week for 5 to 20 years (mean 10.45 years), and 20 sedentary individuals of the same age group were included as the control group in this study. The control group consisted of volunteers who haven’t exercised in the last two years for more than 2 hours a week. Subjects with the presence of any of the following were excluded: metabolic bone disease, arthritis, diabetes, liver disease, kidney failure, corticosteroid use, smoking, use of alcohol and body mass index over 24.9 kg/m2. All the mountaineers and the control groups were measured for lipid profile and complete blood count, also underwent echocardiography. Exercise stress test was performed with Bruce protocol. MET values were calculated according the Bruce Protocol MET chart. Arterial stiffness was measured by PulseTrace PWV device (Micro medical PulseTrace, Rochester, 2009, UK). Distance between carotid-femoral arteries was used for central stiffness (cfPWV) and distance between femoral-tibialis posterior arteries was used for periferal stiffness (faPWV). An average of three measurements was taken. Serum levels of PTX3 was determined by BOST brand commercial kit (catalog no: EK0861) with sandwich type ELISA kit. Ethical Consent: This study approved by Erciyes University Medical Faculty Ethical Commitee (2012/704). The study was performed according to the Helsinki Charter. All subjects gave their written informed consent to participate. Statistical Analyses: Statistical analyses were made by means of IBM SPSS v22 by the Biostatistical Department of the School of Medicine of Erciyes University. The distribution of the data was found to comply with parametric tests and the mean ± standard deviation values were obtained. The independent students’s test was conducted to compare the groups by taking into consideration the homogeneity of the variation coefficients. The pearson’s correlation coefficients were used in the correlation analysis. The statistical significance level was p < 0.05. RESULTS There were no statistically significant differences at the demographic characteristics (Table 1), and haematologic and biochemical parameters (Table 2) between the two groups. MET (Table 1) and plasma PTX3 levels were found to be significantly higher in mountaineers, compared to the sedentary group (p < 0.05) (Figure 3). Femoral-ankle pulse wave velocity (faPWV), carotid-femoral pulse wave velocity (cfPWV), left ventricular endsystolic diameter and the neutrophil to lymphocyte (N/L) ratio were found to be significantly lower in mountaineers, compared to the sedentary group (p < 0.05) (Figure 1, 2). A statistically significant and inverse relationship was found between MET, PTX3 levels and cfPWV, faPWV (p < 0.05) (Table 3). Table 1: Age, body mass index (BMI), exercise and cardiovascular parameters Mountaineers (n=20) p Sedentary controls (n=20) Age (year) 52.75± 8.24 51.80± 5.99 0.68 BMI 27.85± 2,55 27.47± 1.31 0.55 Maximal heart rate 166.50 ± 9.58 163.95 ± 7.02 0.34 MET 12,95 ± 2.91 11.31 ± 1.46 < 0.03 Ejection fraction 64.00± 1.63 61.00± 1.63 0.21 Left ventricular end-systolic diameter (mm) 2.98 ±0.11 3.32 ±0.13 < 0.05 Left ventricular end-diastolic diameter (mm) 4.59± 0.16 4.60± 0.15 0.97 Mountaineers (n=20) Sedentary controls (n=20) p Hb (g/dl) 14.9 ± 1.64 15.3 ± 0.39 0.3 Hematocrit (%) 44.89 ± 0.74 45.82 ± 1.21 0.4 Triglycerides (mg/dL) 161.08 ± 16.39 152.42 ± 24.33 0.7 Cholesterol (mg/dL) 201.60 ± 6.32 211.07 ± 11.29 0.4 LDL (mg/dL) 121.51 ± 6.12 145.11 ± 17.90 0.5 HDL (mg/dL) 48.50 ± 3.61 50.64 ± 2.95 0.6 Table 2: Haematological, biochemical parameters Table 3: Correlation between PT3, MET and PVW MET carotid-femoral PWV femoral-ankle PWV 1 .943** -.820** -477** femoral-ankle PWV (m/s) .943** 1 -.832** -502** PTX3 (ng/ml) -.820** -.832** 1 323* MET -.477** -.502** .323* 1 carotid-femoral PWV (m/s) PTX3 * Correlation is significant at the 0.05 level (2-tailed). ** Correlation is significant at the 0.01 level (2-tailed). DISCUSSION Arterial stiffness is an indication of atherosclerosis and is caused by thickening of the arterial wall and loss of elasticity. It especially effects large arteries. Histopathological studies of these arteries show increased collagen and alteration of elastin structures11. Increased arterial stiffness is not only an indication of vascular aging, but is also a predictor of target organ damage and increased cardiovascular events12. There are 3 different mechanisms affecting arterial stiffness. Injury of the elastic structure (elastic fibres) of the arterial wall, distortion of the endolthelium / smooth muscle mechanism, and increased mean arterial pressure. Age, gender, cardiovascular diseases and risk factors (hypertension, coronary artery disease, peripheral artery disease, cardiac failure, cardiac syndrome X, endothelial dysfunction), endocrinological and metabolic disorders (diabetes mellitus, impaired glucose tolerance, dislipidemia, metabolic syndrome, hypothyroidism, hyperhomocisteinemia), dietary and lifestyle habits (obesity, smoking, coffein, high sodium intake) are structural effects of arterial stiffness. The collagen-elastin balance in the arterial wall with increased stiffness has been shown to increase histopathologically in favour of collagen13. Hypertension or increased intraluminal pressure induces collagen formation and facilitates increased stiffness14. Arterial stiffness represents the cumulative effect of cardiovascular risk factors, including aging, on the arterial wall. The arterial pulse wave velocity is determined to a large extent by the arterial elastic modulus. The gold-standard measure of arterial stiffness, pulse wave velocity (PWV), reflects the speed of pressure pulse transmission along the arterial wall15. Aortic PWV was used as a measure of the stiffness of the central arteries, whereas leg and arm PWV were used as measures of peripheral arterial stiffness5. As the propagation of the pressure wave in elastic tubes occurs at a definite velocity, it is possible to measure arterial stiffness through the pulse wave velocity (PWV). Aortic stiffness is approximated by the carotid to femoral pulse wave velocity (typical value: 8 m/s)16. Higher levels of physical activity and cardiorespiratory fitness have been found to be associated with a decreased incidence of and mortality from coronary heart disease17. However, effects of physical activity on the functional properties of arteries have contradictory results. Some researchers have demonstrated that regular aerobic exercise is efficacious in preventing and reversing arterial stiffening in healthy adults5,6,18. They report that through regular aerobic exercise cardiorespiratory fitness develops, arterial stiffness and cardiovascular risk factors and cardiovascular mortality are reduced1. With daily brisk walking, previously sedentary middle-age/older adults show reduced stiffness and improved EDD (endothelium-dependent dilatation). The mechanisms underlying the effects of regular aerobic exercise on large elastic artery stiffness with ageing are largely unknown, but are likely to include changes to the composition of the arterial wall1. Furthermore, studies report that decreased arterial stiffness may be associated with factors related to vasodilatation, increased gene expression and decreased oxidative stress19. Regular aerobic exercise is associated with a reduced risk of CVD in middle-aged and older adults20. Regular aerobic exercise benefits the reversal of arterial stiffness in middle aged and older individuals and decrease of age-associated cardiovagal baroreflex sensitivity6,21. Several long-term studies provide evidence of reductions in central and peripheral arterial stiffness with endurance exercise training in both young22 and older23 individuals. A few months of resistance training significantly reduces central arterial compliance in healthy men21 but effects of resistance training on the compliance of the peripheral muscular artery (ie, femoral artery) were not apparent. Adults who regularly perform aerobic exercise have less large elastic artery stiffness and largely preserved vascular endothelial function with aging1. It has been speculated that rather than structural characteristics in the arterial wall that take a long time to change, the alterations in the contractile states of the smooth muscle cells may be a potential mechanism underlying improvements in arterial stiffness with regular exercise19. In contrast, Schmidt-Trucksuss et al. indicated that femoral arterial lumen diameter and compliance (via an ultrasound imaging device and simultaneous applanation tonometry) in endurance-trained males were significantly higher than those in age-matched sedentary counterparts24. Dinneno et al. observed an expansion of the femoral arterial lumen diameter in previously sedentary middle-aged and elderly men after a 3-month aerobic exercise intervention (primarily walking). The expansion of arteries seems to relate to structural remodeling or reduced vascular smooth muscular tone and leads to decreasing peripheral arterial stiffness25. In endurance trained male athletes, 54 to 75 years old (V02max = 44±3 ml. kg/min), the arterial stiffness indexes were significantly reduced relative to their sedentary age peers (AGI, 36% lower, APWV, 26% lower) despite similar blood pressures. Higher physical conditioning status, indexed by V02max was associated with reduced arterial stiffness, both within this predominantly sedentary population and in endurance trained older men relative to their less active age peers19. If long-term aerobic exercise or training has a lasting effect on arterial stiffness is uncertain. If the answer of the latter is yes, when the effect starts is also uncertain. Collier et al. found that central pulse wave velocity decreased 8% after aerobic exercise and remained depressed at this level through 60 minutes of observation, whereas resistance exercise increased central pulse wave velocity by 9.8% from pre to 40 and 60 minutes postexercise26. Kingwell et al. reported that a single 30 min cycling bout at 65% VO2max increased arterial compliance by 40% at 30 min postexercise, but values returned to resting levels by 60min postexercise27. Cameron at al. found that after training three times/week for 4 weeks using the same protocol, resting arterial compliance (24 h after the last exercise bout) was elevated by approximately 30%28. In another study, Kingwell et al. Wistar-Kyoto rats were allowed to train spontaneously in exercise wheels from 4 to 20 weeks of age and aortic cross-sectional compliance was examined in organ baths29. They concluded that the slope of the diameter–tension curve was higher in trained rats, which indicated training induced structural aortic adaptations. They also underlined that while arterial elasticity and fitness increased in parallel in both human and rat studies, it was not possible to determine whether a causative relationship existed. Hayashi et al. studied 17 healthy and sedentary middle-aged men, aged 31–64 years (mean age: 50 ± 3 yr) similar to the age group in our study. The subjects performed open-air aerobic exercise training (brisk walk- ing/jogging) for 16 weeks30. Hayashi et al. observed a reduced PWV as a result of a 16-week long aerobic training however peripheral PWV did not change significantly and the stiffness of the peripheral artery was difficult to change in short- term and moderate-intensity aerobic exercise training. Even moderate-intensity aerobic exercise training could increase femoral arterial diameter25. However peripheral vessels are able to respond to central artery enlargement in a longer time period. The duration, intensity and frequency of exercise required to decrease stiffness of the peripheral arteries is not known yet however we believe that continuous exercises such as endurance training are indicated/are required. Hayashi et al.21 explained that this was related to the increased elastin content in the central arteries versus the peripheral vessels and the improved enlargement response of central arteries to training. It was shown that 16 weeks of aerobic exercise training reduced the calcium content of elastin and increased the elastin content in the aortic wall in rats31. There is an inverse and statistically significantly correlation between of MET and peripheral PWV. In other words, central and peripheral PWV decreases when MET increases. We speculate that long-term protection/maintenance of the MET value facilitated a lower peripheral PWV which is an important subject for future investigations. N/L ratio reflects the balance between the neutrophil and lymphocyte levels in the body and is an indicator of systemic inflammation32. N/L ratio is an inexpensive, easy to obtain, widely available marker of inflammation, which can aid in the risk stratification of patients with various cardiovascular diseases. N/L ratio is reported as an independent predictor of outcome in stable coronary artery disease, as well as a predictor of short-and long term mortality in patients with acute coronary syndromes. In patients admitted with advanced heart failure, high N/L ratio was reported with higher inpatient mortality33. In the present study, we observed that the N/L ratio was lower in mountaineers. So, this measurement showed us that prolonged moderate exercise might decrease the risk of long-term mortality. Chronic low-grade inflammation accompanies aging as well as some chronic medical disorders34. Chronic inflammation that occurs with aging is one of the risk factors for cardiovascular disease. Systemic inflammatory factors increase with age, which lead to an increased risk of cardiovascular disease in middle-age and elderly individuals8. Physical inactivity, as well as aging, may induce systemic inflammation. It has been suggested that regular physical activity may contribute to lower levels of pro-inflammatory and higher levels of anti-inflammatory factors. Regular exercise protects against diseases associated with chronic low-grade systemic inflammation35. This long-term effect of exercise may be ascribed to the anti inflammatory response elicited by an acute bout of exercise, which is partly mediated by muscle-derived IL-6. Physiological concentrations of IL-6 stimulate the appearance in the circulation of the anti-inflammatory cytokines IL-1ra and IL-10 and inhibit the production of the proinflammatory cytokine CRP and TNFα34. Given that the atherosclerotic process is characterized by inflammation, one alternative explanation would be that regular exercise, which offers protection against atherosclerosis, indirectly offers protection against vascular inflammation and hence systemic low-grade inflammation35. Although these observations point to a cardiovascular protective effect of PTX3, they also suggest the possibility that the increased levels of PTX3 in subjects with cardiovascular disease (CVD) may reflect a protective physiologic response that correlates with the severity of the disease. Recently, PTX3 has been established as an anti-inflammatory protein in atherosclerosis10. Measurement of levels of circulating inflammatory factors, in determining the state of cardiovascular disease may be a useful diagnostic tool34. In previous studies using PTX3-deficient or PTX3-over expressing mice, it has been shown that PTX3 has an antiinflammatory and/or anti-atherosclerotic role36. Daily regular exercise is known to induce anti-inflammatory effects and protect against the risk of cardiovascular diseases associated with chronic low-grade systemic inflammation such as atherosclerosis34, resulting in a decrease in serum CRP37. 8 weeks of moderate aerobic exercise training (walking and cycling, 30-45min, 3-5 days/wk) increased plasma PTX3 concentration in healthy postmenopausal middle-aged and elderly women, and this may partly participate in the mechanism underlying aerobic exercise training-induced anti-inflammatory effect and cardiovascular protection38. On the other hand, it has been reported that plasma PTX3 concentrations decreased with exercise training in patients undergoing cardiac rehabilitation39. In another study Miyaki et al. demonstrated that plasma PTX3 concentrations in young endurance-trained men were higher than age-matched sedentary controls8. Circulating PTX3 and hsCRP significantly increased immediately after 70% RE and peak EX, while they did not increase after 70% AT exercise. Habitual aerobic exercise is thought to have an anti-inflammatory effect. High-intensity exercises significantly increase circulatory PTX3 as well as CRP. The release from peripheral neutrophils is suggested to be involved in the exercise-induced plasma PTX3 increase40. However, it is unclear whether aerobic exercise training affects circulating PTX3 concentrations in healthy middle aged and elderly individuals. Our results indicate that PTX3 levels in mountaineers who trek for moderate and long periods were significantly higher than sedentary group. Although the exact mecahnism is not known, this can be explained by the fact that MET of mountaineers is significantly higher than the sedentary group. Analysis of the statistically significant inverse correlation between cfPWV, faPWV and PTX3 supports that long term exercise reduces arterial stiffness and increases PTX3. CONCLUSION Consequently, long-term and regular moderate exercise (tracking) significantly decreases indicators of systemic inflammation and arterial stiffness, and reduces the risk of cardiovascular disease with advanced age. This is the first study for investigating the effects of chronic (5-20 years) moderate exercise on new cardiac disease indicators such as stiffness and PTX3. Measurement of PWV can be used to detect increase in cardiovascular risk with old age . ACKNOWLEDGEMENT This study was supported by Erciyes University Scientific Research Project Commission (TTU-2013-4408). References 1. Seals DR, Walker AE, Pierce GL, Lesniewski LA. Habitual exercise and vascular ageing. J Physiol 2009; 1(23):5541-5549. 2. Weber T, Auer J, O’Rourke MF, et al. 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