VPH-06205; No of Pages 5 Vascular Pharmacology xxx (2015) xxx–xxx
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Arterial stiffness and sedentary lifestyle: Role of oxidative stress Gianfranco Lessiani a,1,2, Francesca Santilli a,1,2, Andrea Boccatonda a,2, Pierpaolo Iodice c,2, Rossella Liani a,2, Romina Tripaldi a,2, Raoul Saggini b,2, Giovanni Davì a,⁎,2 a b c
Internal Medicine and Center of Excellence on Aging, “G. d'Annunzio” University of Chieti, Italy Department of Neuroscience and Imaging, “G. d'Annunzio” University of Chieti, Italy Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
a r t i c l e
i n f o
Article history: Received 13 May 2015 Received in revised form 28 May 2015 Accepted 29 May 2015 Available online xxxx Chemical compounds: 8-iso-PGF2α Cholesterol Triglycerides Keywords: Exercise Arterial stiffness Oxidative stress Isoprostanes
a b s t r a c t Sedentary lifestyle is a risk factor for the development of cardiovascular disease, and leads to a quantifiable impairment in vascular function and arterial wall stiffening. We tested the hypothesis of oxidative stress as a determinant of arterial stiffness (AS) in physically inactive subjects, and challenged the reversibility of these processes after the completion of an eight-week, high-intensity exercise training (ET). AS was assessed before and after ET, measuring carotid to femoral pulse wave velocity (PWV) with a Vicorder device. At baseline and after ET, participants performed urine collection and underwent fasting blood sampling. Urinary 8-iso-PGF2α, an in vivo marker of lipid peroxidation, total, HDL and LDL cholesterol, and triglyceride concentrations were measured. ET was associated with significantly reduced urinary 8-iso-PGF2α(p b 0.0001) levels. PWV was significantly reduced after ET completion (p b 0.0001), and was directly related to urinary 8-iso-PGF2α(Rho = 0.383, p = 0.021). After ET, cardiovascular fitness improved [peak oxygen consumption (p b 0.0001), peak heart rate (p b 0.0001)]. However, no improvement in lipid profile was observed, apart from a significant reduction of triglycerides (p = 0.022). PWV and triglycerides were significantly related (Rho = 0.466, p = 0.005) throughout the study period. PWV levels were also related to urinary 8-iso-PGF2α in our previously sedentary subjects. We conclude that regular physical exercise may be a natural antioxidant strategy, lowering oxidant stress and thereby the AS degree. © 2015 Published by Elsevier Inc.
1. Introduction Arterial stiffness (AS) is a major factor contributing to the development of cardiovascular disease (CVD). Increased AS determines an augmentation of central aortic pressure, thus causing systolic hypertension, left ventricular hypertrophy, and potentially impaired coronary perfusion [1–3]. AS is associated with a high risk of cardiovascular morbidity and of death [1,2]. Aging increases the risk of CVD[3] and is associated with stiffening of the large elastic arteries, mainly caused by changes including functional alterations of vascular smooth muscle tone and
Abbreviations: AS, arterial stiffness; ET, exercise training; PWV, pulse wave velocity; CVD, cardiovascular disease; SBP, systolic blood pressure; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; SOD, superoxide dismutase; GSH, glutathione; MI, myocardial infarction; NSAIDs, nonsteroidal anti-inflammatory drugs. ⁎ Corresponding author at: Center of Excellence on Aging, “G. d'Annunzio” University Foundation, Via Luigi Polacchi, 13, 66013 Chieti, Italy. E-mail address: [email protected] (G. Davì). 1 Gianfranco Lessiani and Francesca Santilli equally contributed to this work. 2 Each author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
structural changes in the arterial wall. Such changes may be caused and/or sustained by the development of age-related oxidative stress and inflammation [3–6]. PWV is the “gold standard” method to estimate AS[7]. PWV establishes the time delay between pressure waves occurring at proximal and distal sites along the aorta (mainly the carotid and femoral arteries). The faster the pressure wave travels along the aorta, the greater the AS is [3,8]. Mean PWV in healthy, normotensive (systolic blood pressure [SBP] b 140 mm Hg) volunteers is 6.1 ± 1.4 m/s and significantly increases with age [9]. PWV is an independent predictor of cardiovascular events in patients with established CVD as well in healthy adults [10]. Isoprostanes are a family of bioactive compounds produced from arachidonic acid via a free radical-catalyzed mechanism of lipid peroxidation on cell membrane phospholipids or circulating low density lipoproteins (LDLs) [11]. Urinary levels of these compounds represent reliable and sensitive markers of in vivo lipid peroxidation [13]. A sedentary lifestyle has been identified as a risk factor for the development of CVD[12] and leads to quantifiable impairment in vascular function and arterial wall stiffening, as a result of increased oxidative stress, favoring endothelial dysfunction [13]. Exercise training (ET) may delay the development of arterial stiffness
http://dx.doi.org/10.1016/j.vph.2015.05.017 1537-1891/© 2015 Published by Elsevier Inc.
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
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by increasing shear stress and augmenting nitric oxide (NO) bioavailability [14]. Several studies have documented increased shear stress to upregulate endothelial nitric oxide synthase (eNOS) activity in cell culture, animal or human studies [15]. Extended periods of ET also has an impact on the generation of reactive oxygen species (ROS) [15], by lowering the expression of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase and stimulating radical scavenging systems that include copper/zinc-containing superoxide dismutase (SOD), extracellular SOD, glutathione (GSH) peroxidase and GSH levels [15]. Thus, aerobic ET decreases oxidative stress by increasing the efficiency of the antioxidant system, and finally improving endothelial dysfunction [15,16]. In a previous study in sedentary subjects [17], aimed at assessing the effects of high-amount, high-intensity exercise on in vivo platelet activation, we reported a significant reduction of the F2-isoprostane8iso-PGF2α, after completion of the exercise program. We also unraveled that modulation of oxidative stress might be a major determinant of the “antiplatelet effect” of aerobic exercise. Indeed aerobic activity is considered to be an effective component of CVD prevention [12]. While there is compelling evidence of beneficial effects of various exercise modalities on endothelial function [16] and oxidative stress [17–23], their impact on PWV is more controversial [24,25]. Therefore, the main objective of this study was to test the hypothesis of a significant association between evaluation of in vivo oxidative stress and the degree of arterial stiffness in sedentary subjects, and to challenge their parallel reversibility after 8 weeks of high-amount, high-intensity ET. As a secondary objective, we aimed at assessing ET effects on cardiovascular fitness and lipid profile. 2. Materials and methods 2.1. Patient selection Informed consent was obtained from each patient and the study protocol conformed with the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institutional Human Research Committee. After giving written, informed consent, 18 subjects (12 males), median age 54 (48–66) years, were enrolled in the study. The clinical characteristics of participating subjects are summarized in Table 1 Clinical characteristics of study subjects at baseline. Variable
Baseline⁎
n, (%) Age, years Male gender, n (%) BMI, kg/m2 Obesity, n (%) Hypertension, n (%) Diabetes, n (%) Smoking, n (%) Fasting plasma glucose, mg/dl AST, mg/dl ALT, mg/dl Smoke, n (%) Rate of adherence, % ACE-inhibitors, n (%) ARBs, n (%) Diuretics, n (%) Beta-blockers, n (%) Calcium channel blockers, n (%) Statins, n (%) PUFA, n (%) PPI, n (%)
18 54 (48–66) 12 (66.7) 25.5 (24.4–27.5) 3 (16.7) 8 (44.4) 0 (0) 3 (16.7) 89 (81–97) 18.0 (16.0–23.7) 20.5 (17.2–24.5) 3 (16.7) 95.3 (90.6–99.8) 3 (16.7) 4 (22.2) 2 (11.1) 1 (5.5) 2 (11.1) 1 (5.5) 0 (0) 1 (5.5)
AST, aspartate transaminase; ALT, alanine transaminase; ACE, angiotensin-convertingenzyme; ARBs, angiotensin receptor blockers; PUFA, polyunsaturated fatty acids; PPI, proton pump inhibitors. ⁎ Continuous variables are reported as median [interquartile range (IQR)].
Table 1. Subjects were enrolled if they reported a sedentary lifestyle (regular aerobic exercise b 3 times/week and for b20 min (min)/session, with a sedentary occupation) and their baseline HDL cholesterol concentration was b50 mg/dL (1.0 mmol/l). All subjects were classified at low or intermediate risk by the Framingham Risk Score (FRS) at the time of study entry. Exclusion criteria included obesity (BMI N 30 kg/m2), a diagnosis of diabetes mellitus, poorly-controlled hypertension or hypercholesterolemia, pregnancy, impaired liver or renal function, previous vascular events (myocardial infarction (MI), stroke), or other medical conditions that would preclude vigorous exercise, treatment with nonsteroidalanti-inflammatory drugs (NSAIDs), anticoagulants or antiplatelet drugs, and statins.
2.2. Training program Each participant completed an eight-week standardized aerobic training program. The exercise training involved 2 sessions per week of supervised exercise on a cycle ergometer (Monark 915E, Vansbro, Sweden). The exercise prescriptions in the exercise group was highamount, high-intensity exercise for 55 min per session, the caloric equivalent of jogging approximately 20 miles (32.0 km) per week at 60% to 75% of peak oxygen consumption. During an initial period of one month the amount and intensity of exercise were gradually increased, followed by 8 weeks at the appropriate exercise prescription. Participants started at 55% of their baseline VO2 max for 45 min per session, and progressed in intensity or duration every week according to a standardized protocol, until achieving the standards scheduled for the training program (55 min at 75% of baseline VO2 max). The subjects performed a maximal incremental ramp test, consisting of 3 min at rest and 5 min of priming exercise at 50 W, followed by a continuous increase in the workload by 20 W/min until exhaustion. The accepted criteria for maximal effort were: respiratory exchange ratio N 1.1, and heart rate N90% of the predicted maximum based on age. Breath-by-breath (B-byB) VO2 and carbon dioxide output (VCO2) were measured continuously at the mouth (Quark b2, Cosmed, Rome, Italy). Peak VO2 (mL/min/kg) was defined as the average of maximum 30-s attained VO2 at the end of the exercise period. Analyzers and the respiratory flow transducer were calibrated following the manufacturer's instructions before each experimental run. All exercise sessions were verified by directly supervised by a physician under heart rate monitoring (Polar Electro, Kempele, Finland) that recorded data. Daily energy consumption was monitored with a metabolic armband (Sensewear Pro3, Pittsburgh (PA), USA). Nutrient intakes were determined at baseline and at the end of the study. To minimize the confounding effects of weight loss, participants were counseled to maintain body weight, which was ethically justified by the short time frame of the study. Thus, we suggested not to alter their health habits and to continue their usual eating pattern, physical activity outside of the study, alcohol and tobacco use. Data would be excluded from the analysis for subjects whose weight varied by more than 5% from baseline to the end of the study.
2.3. Assays At baseline (before the run-in period) and after the 8-week training program, the participants were instructed to perform an overnight urine collection, and underwent fasting blood sampling the following morning. Plasma, serum, and urine were stored in aliquots at −20 °C until used for the various analyses. Urinary 8-iso-PGF2α was measured by a previously described radioimmunoassay [26]. Measurements of urinary 8-iso-PGF2α by this radioimmunoassay has been validated using different antisera and by comparison with gas chromatography/ mass spectrometry, as detailed elsewhere [26]. Total, HDL and LDL cholesterol, and triglyceride concentrations were measured as previously described [27].
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
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Table 2 Effects of the 8-week exercise training program on cardiovascular fitness, lipid profile, U-8-iso-PGF2α and PWV. Variable
Baseline
After 8-weeks exercise program⁎
p-value⁎⁎
Peak oxygen consumption, mL/kg/min Peak oxygen consumption, ml/min Peak heart rate, bpm Respiratory exchange ratio O2 pulse, mL/beat Total cholesterol, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dL PWV, m/s U-8-iso-PGF2α, pg/mg creatinine
35.2 (30.3–40.0) 2844 (2140–3456) 171.0 (161.2–181.1) 1.11 (1.10–1.16) 16.6 (12.8–20.3) 199.5 (184.0–224.7) 132.2 (120.6–149.1) 46.0 (40.5–49.0) 107 (82–126) 6.28 (5.44–7.86) 320 (287–435)
35.5 (30.7–40.2) 2931 (2231–3555) 172.4 (161.8–181.1) 1.12 (1.10–1.16) 17.0 (13.2–20.3) 200.5 (185.0–235.5) 130.5 (113.8–160.7) 50.0 (42.8–58.5) 86 (62–111) 5.31 (4.59–6.67) 209 (154–258)
0.040 b 0.0001 b 0.0001 0.831 0.445 0.396 0.845 0.107 0.022 b 0.0001 b 0.0001
⁎ Continuous variables are reported as median [interquartile range (IQR)]. ⁎⁎ by Wilcoxon signed rank test.
2.4. PWV measurement Measurement of AS was obtained noninvasively, using a volume displacement method (Vicorder system, Wuerzburg, Germany). After 15 min of rest, with participants in a supine position, a 100 mm-wide blood pressure cuff was placed around the right upper thigh to measure the femoral pulse wave and a 30 mm plethysmographic partial inflatable sensor was placed over the carotid region, able to pick up the carotid pulse wave. After preparation, both were inflated to about 60 mm Hg, and high-quality waveforms were recorded simultaneously over about 10 consecutive heartbeats. The foot-to-foot transit time was calculated using an in-builtcross-correlation algorithm that was centered around the peak of the second derivative of pressure, according to current guidelines [28]. In the present study, path length was defined by a direct measurement between the suprasternal notch to the top of the thigh cuff, as documented in a previous study [29]. 2.5. Statistical analysis Sample size calculation was based on the primary endpoint of the study, the urinary 8-iso-PGF2α excretion rate (mean ± SD, about 190 ± 90 in healthy or low-risk subjects by previous studies) [30]. It was estimated that 16 patients would be required, for a two-tailed alpha of 0.05 and a power of 90%, to detect a mean difference in urinary 8-iso-PGF2α excretion rate of at least 25% between pre- and post-intervention. Allowing for a 10% drop-out rate, we estimated that 18 patients per group would need to be enrolled. Given the baseline values of urinary 8-iso-PGF2α excretion rate actually measured [320 (287–435) pg/mg creatinine], the study had 94% power to detect a mean absolute difference in excretion rate of 140 pg/mg creatinine after the completion of the training program [U-8-iso-PGF2α excretion rate (in pg/mg creatinine) before exercise training (364 ± 142) and after training program (224 ± 92)]. The Shapiro– Wilk normality test was performed to determine whether each variable had a normal distribution. When necessary, log transformation or appropriate non-parametric tests were used. Comparisons of data before and after the intervention program were performed by the Wilcoxon signed rank test. Univariate associations between serum lipid levels and experimental measurements were assessed by the Spearman rank correlation test. Data are presented as median [interquartile range (IQR)] or n (%). p-Values lower than 0.05 were regarded as statistically significant. All tests were two-tailed, and analyses were performed using the SPSS (v. 16.0; APSS, Chicago, IL, USA), statistical package.
the effects of exercise on cardiovascular fitness is shown in Table 2. After the high-amount, high-intensity exercise program, a statistically significant increase in peak oxygen consumption (median increase 3.0%, p b 0.0001) and in peak heart rate (0.8%, p b 0.0001) was recorded (Table 2). Respiratory exchange ratio (0.9%, p = 0.831) and O2 pulse (2.4%, p = 0.445) also increased in previously sedentary subjects after the 8-week standardized aerobic training program, although this difference did not achieve statistical significance (Table 2). Lipoprotein data obtained at baseline and at the end of the study are also shown in Table 2. Exercise training led to a non-statistically significant increase in total cholesterol (0.5% vs baseline, p = 0.396), and a non-statistically significant decrease in LDL-C concentrations (1.3% vs baseline, p = 0.845). Moreover, the increase in HDL-C concentration after the high-amount, high-intensity training period was not significant (by 8.7% vs baseline, p = 0.107) (Table 2). Otherwise, we observed a statistically significant reduction in triglyceride concentration [107 (82–126) mg/dL vs 86 (62–111) mg/dL, p = 0.022; 24.4% decrease vs baseline] (Table 2). PWV was significantly reduced after the completion of the training program [6.28 (5.44–7.86) m/s vs 5.31 (4.59–6.67) m/s, p b 0.0001; 9.9% decrease vs baseline] (Fig. 1). By pooling data before and after the ET program, a significant correlation was found between PWV levels and triglyceride levels (Rho = 0.466, p = 0.005) (Fig. 2) throughout the intervention period.
3. Results Baseline characteristics of the subjects are presented in Table 1. No patient had his/her weight varied by more than 5% from baseline to the end of the study. A description of the exercise prescriptions and
Fig. 1. PWV was significantly reduced after the completion of the 8 -week high-amount, high-intensity exercise training program (p b 0.0001).
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
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Fig. 2. Correlations between triglycerides and PWV in the study subjects, before (solid circle) and after (open circle) the eight-week exercise training program.
Moreover, ET resulted in a significant reduction in urinary 8-isoPGF2α [320 (287–435) pg/mg creatinine vs 209 (154–258) pg/mg creatinine, p b 0.0001; 25.9% decrease vs baseline] (Fig. 3). Interestingly, PWV levels throughout the study were directly related to urinary excretion of urinary 8-iso-PGF2α(Rho = 0.383, p = 0.021) (Fig. 4). Finally, there was a non-significant decrease in heart rate levels after exercise training [73 (69–80) bpm vs 71 (67–76) bpm, p = 0.082; 2.8% decrease vs baseline]. 4. Discussion Sedentary lifestyle is considered a risk factor for CVD[12]. Sedentary lifestyle is directly related to increased incidence of CVD[31,32]. Physical activity is associated with lower CVD mortality and all-cause mortality in comparison with sedentary lifestyle [33]. The higher the level of physical fitness, the less likely an individual will suffer premature cardiovascular death [34]. AHA recommends physical activity for prevention of CVD (class I recommendation), with at least 30 min of moderate-intensity aerobic activity 7 days per week, with a minimum of 5 days per week [35]. Part of the risk reduction associated with physical fitness, may be attributed to effects on vascular hemodynamics: endothelial function,
Fig. 3. Urinary 8-iso-PGF2α was significantly reduced after the completion of the 8 -week high-amount, high-intensity exercise training program (p b 0.0001).
Fig. 4. Correlations between urinary 8-iso-PGF2α and PWV in the study subjects, before (solid circle) and after (open circle) the eight-week exercise training program.
arterial remodeling and compliance [36]. In fact, augmentation of AS increases the risk of coronary artery calcification [37] and cardiovascular events [38]. PWV provides a simple, non-invasive and reproducible estimate of arterial stiffness [28]. Epidemiological studies demonstrate the predictive value of aortic stiffness (carotid-femoral PWV) for CV events [28]. AS is lower in those who performed aerobic exercise on a regular basis, compared with sedentary peers [39]. Consistently, our results show a significant reduction in PWV levels in sedentary subjects, after 8 week of high-amount, high-intensity exercise (median from 6.28 m/s to 5.31 m/s) (p b 0.0001). The term AS does not only refer to a diminished vessel compliance, but is also related to endothelial dysfunction [40]. Oxidative stress may play a major role in the pathogenesis of endothelial dysfunction [14], and is generated by an imbalance between pro- and anti-oxidant molecules. In this study, we tried to correlate oxidative stress and AS in sedentary people, before and after high-amount, high-intensity exercise, previously proved to be beneficial on HDL levels [19]. As an integrated biomarker of systemic oxidative stress, we analyzed urinary 8iso-PGF2α levels, generated in vivo by lipid peroxidation [41]. In our sedentary people, urinary 8-iso-PGF2α excretion before exercise training was higher (364 ± 142 pg/mg creatinine) than that reported in healthy or low-risk subjects [30]. This result is in agreement with the notion that sedentary lifestyle is characterized by an imbalance between pro- and anti-oxidant molecules [14,42–44]. After 8 weeks of training program, urinary 8-iso-PGF2α excretion rate decreased to 224 ± 92 pg/mg creatinine (−25.9% vs baseline), reinforcing the idea that physical activity exerts its favorable effects on endothelial function through a reduction of oxidative stress. Enhanced generation of ROS within the vascular wall may be responsible for vascular remodeling, favoring the proliferation of smooth muscle cells, thus inducing endothelial dysfunction [45]. This concept is supported, in our study, by the direct correlation between PWV and urinary 8-iso-PGF2α throughout the training period (Rho = 0.383, p = 0.021) (Fig. 4). Thus, oxidative stress may be the link connecting sedentary lifestyle with increased arterial stiffness. Obesity has been associated with increased oxidative stress [46] and augmented arterial stiffness [47]. Thus, in our study design, no dietary intervention was included and no patient had his/her weight varied by more than 5% from baseline to the end of ET. This study setting should have minimized the dietary contribution in modulating oxidative stress levels, thus emphasizing the role of physical activity. The weight loss achieved after 8 weeks of ET was not significant, and is unlikely to be responsible for the observed modulation of PWV levels or oxidative stress. Finally, unlike previously reported data [37], we obtained only a slight and non-significant(p = 0.107) increase in HDL-C concentrations after high-amount, high-intensity exercise (Table 2). The small sample size of our study, as well as the clinical characteristics of study patients, may explain such a discrepancy of results. Instead, and consistent with
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
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previous studies [19], we observed a statistically significant reduction in triglyceride concentrations, after the 8-week exercise training program (p = 0.022) (Table 2), as previously shown. Interestingly, we found a significant correlation between PWV and triglyceride levels (Rho = 0.466, p = 0.005). Thus, in sedentary people, triglycerides seem to represent a further risk factor for endothelial dysfunction and arterial stiffness, whereas ET was able to improve vascular stiffness, at least in part by lowering triglyceride levels. Consistently, acute resistance exercise attenuates triglyceride increase following a high fat meal, with simultaneous improvement of peripheral AS[48]. Therefore, our results are consistent with the findings of the Malmö Diet and Cancer study, reporting that triglyceride levels were among the stronger predictors of arterial stiffness after 17 years of follow-up[49]. 5. Conclusions This study indicates that sedentary lifestyle is characterized by increased oxidative stress. In fact, urinary levels of 8-iso-PGF2α, an in vivo biomarker of lipid peroxidation, are higher in sedentary subjects and directly related to increased PWV. Thus, oxidative stress-induced endothelial dysfunction seems to be responsible for AS in this setting. High-amount, high-intensity exercise training improves the cardiovascular risk profile in these subjects, lowering oxidative stress and thereby the degree of AS. Therefore, regular physical exercise may be a natural antioxidant strategy for preventing diseases such as diabetes and CVD in sedentary people. Funding sources Partially supported by grants from the University of Chieti (ex-60%) to GD and from the Italian Ministry of University and Research (PRIN n. 2010JS3PMZ to FS). References [1] S.J. Zieman, V. Melenovsky, D.A. Kass, Mechanism, pathophysiology, and therapy of arterial stiffness, Arterioscler. Thromb. Vasc. Biol. 25 (2005) 932–943. [2] M. Cecelja, P. Chowienczyk, Role of arterial stiffness in cardiovascular disease, JRSM Cardiovasc Dis. 1 (4) (2012). [3] E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease, Circulation 107 (2003) 139–146. [4] E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease, Circulation 107 (2003) 346–354. [5] C. Vlachopoulos, I. Dima, K. Aznaouridis, et al., Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals, Circulation 112 (2005) 2193–2200. [6] M. Wang, J. Zhang, L.Q. Jiang, et al., Proinflammatory profile within the grossly normal aged human aortic wall, Hypertension 50 (2007) 219–227. [7] G.F. Mitchell, H. Parise, E.J. Benjamin, et al., Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study, Hypertension 43 (2004) 1239–1245. [8] K.S. Heffernan, A. Chale, C. Hau, et al., Systemic vascular function is associated with muscular power in older adults, J. Aging Res. 2012 (2012) 386–387. [9] J. Muller, R. Oberhoffer, C. Barta, et al., Oscillometric carotid to femoral pulse wave velocity estimated with the Vicorder device, J. Clin. Hypertens. 15 (2013) 176–179. [10] F.U. Mattace-Raso, T.J. van der Cammen, A. Hofman, et al., Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study, Circulation 113 (2006) 657–663. [11] F. Santilli, N. Vazzana, G. Davì, et al., Oxidative stress drivers and modulators in obesity and cardiovascular disease: from biomarkers to therapeutic approach, Curr. Med. Chem. 22 (2015) 582–595. [12] G.F. Mitchell, S.J. Hwang, R.S. Vasan, et al., Arterial stiffness and cardiovascular events: the Framingham Heart Study, Circulation 121 (2010) 505–511. [13] E.V. Nosova, P. Yen, K.C. Chong, et al., Short-term physical inactivity impairs vascular function, J. Surg. Res. 190 (2014) 672–682. [14] S.S. Thosar, B.D. Johnson, J.D. Johnston, et al., Sitting and endothelial dysfunction: the role of shear stress, Med. Sci. Monit. 18 (2012) 173–180. [15] G. Schuler, V. Adams, Y. Goto, Role of exercise in the prevention of cardiovascular disease: results, mechanisms, and new perspectives, Eur. Heart J. 34 (2013) 1790–1799. [16] F.R. Roque, R. Hernanz, M. Salaices, et al., Exercise training and cardiometabolic diseases: focus on the vascular system, Curr. Hypertens. Rep. 15 (2013) 204–214. [17] F. Santilli, R. Saggini, G. Davì, et al., Effects of high-amount-high-intensity exercise on in vivo platelet activation: modulation by lipid peroxidation and AGE/RAGE axis, Thromb. Haemost. 110 (2013) 1232–1240.
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Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph
Arterial stiffness and sedentary lifestyle: Role of oxidative stress Gianfranco Lessiani a,1,2, Francesca Santilli a,1,2, Andrea Boccatonda a,2, Pierpaolo Iodice c,2, Rossella Liani a,2, Romina Tripaldi a,2, Raoul Saggini b,2, Giovanni Davì a,⁎,2 a b c
Internal Medicine and Center of Excellence on Aging, “G. d'Annunzio” University of Chieti, Italy Department of Neuroscience and Imaging, “G. d'Annunzio” University of Chieti, Italy Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy
a r t i c l e
i n f o
Article history: Received 13 May 2015 Received in revised form 28 May 2015 Accepted 29 May 2015 Available online xxxx Chemical compounds: 8-iso-PGF2α Cholesterol Triglycerides Keywords: Exercise Arterial stiffness Oxidative stress Isoprostanes
a b s t r a c t Sedentary lifestyle is a risk factor for the development of cardiovascular disease, and leads to a quantifiable impairment in vascular function and arterial wall stiffening. We tested the hypothesis of oxidative stress as a determinant of arterial stiffness (AS) in physically inactive subjects, and challenged the reversibility of these processes after the completion of an eight-week, high-intensity exercise training (ET). AS was assessed before and after ET, measuring carotid to femoral pulse wave velocity (PWV) with a Vicorder device. At baseline and after ET, participants performed urine collection and underwent fasting blood sampling. Urinary 8-iso-PGF2α, an in vivo marker of lipid peroxidation, total, HDL and LDL cholesterol, and triglyceride concentrations were measured. ET was associated with significantly reduced urinary 8-iso-PGF2α(p b 0.0001) levels. PWV was significantly reduced after ET completion (p b 0.0001), and was directly related to urinary 8-iso-PGF2α(Rho = 0.383, p = 0.021). After ET, cardiovascular fitness improved [peak oxygen consumption (p b 0.0001), peak heart rate (p b 0.0001)]. However, no improvement in lipid profile was observed, apart from a significant reduction of triglycerides (p = 0.022). PWV and triglycerides were significantly related (Rho = 0.466, p = 0.005) throughout the study period. PWV levels were also related to urinary 8-iso-PGF2α in our previously sedentary subjects. We conclude that regular physical exercise may be a natural antioxidant strategy, lowering oxidant stress and thereby the AS degree. © 2015 Published by Elsevier Inc.
1. Introduction Arterial stiffness (AS) is a major factor contributing to the development of cardiovascular disease (CVD). Increased AS determines an augmentation of central aortic pressure, thus causing systolic hypertension, left ventricular hypertrophy, and potentially impaired coronary perfusion [1–3]. AS is associated with a high risk of cardiovascular morbidity and of death [1,2]. Aging increases the risk of CVD[3] and is associated with stiffening of the large elastic arteries, mainly caused by changes including functional alterations of vascular smooth muscle tone and
Abbreviations: AS, arterial stiffness; ET, exercise training; PWV, pulse wave velocity; CVD, cardiovascular disease; SBP, systolic blood pressure; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; NADPH, nicotinamide adenine dinucleotide phosphate; SOD, superoxide dismutase; GSH, glutathione; MI, myocardial infarction; NSAIDs, nonsteroidal anti-inflammatory drugs. ⁎ Corresponding author at: Center of Excellence on Aging, “G. d'Annunzio” University Foundation, Via Luigi Polacchi, 13, 66013 Chieti, Italy. E-mail address: [email protected] (G. Davì). 1 Gianfranco Lessiani and Francesca Santilli equally contributed to this work. 2 Each author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
structural changes in the arterial wall. Such changes may be caused and/or sustained by the development of age-related oxidative stress and inflammation [3–6]. PWV is the “gold standard” method to estimate AS[7]. PWV establishes the time delay between pressure waves occurring at proximal and distal sites along the aorta (mainly the carotid and femoral arteries). The faster the pressure wave travels along the aorta, the greater the AS is [3,8]. Mean PWV in healthy, normotensive (systolic blood pressure [SBP] b 140 mm Hg) volunteers is 6.1 ± 1.4 m/s and significantly increases with age [9]. PWV is an independent predictor of cardiovascular events in patients with established CVD as well in healthy adults [10]. Isoprostanes are a family of bioactive compounds produced from arachidonic acid via a free radical-catalyzed mechanism of lipid peroxidation on cell membrane phospholipids or circulating low density lipoproteins (LDLs) [11]. Urinary levels of these compounds represent reliable and sensitive markers of in vivo lipid peroxidation [13]. A sedentary lifestyle has been identified as a risk factor for the development of CVD[12] and leads to quantifiable impairment in vascular function and arterial wall stiffening, as a result of increased oxidative stress, favoring endothelial dysfunction [13]. Exercise training (ET) may delay the development of arterial stiffness
http://dx.doi.org/10.1016/j.vph.2015.05.017 1537-1891/© 2015 Published by Elsevier Inc.
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
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by increasing shear stress and augmenting nitric oxide (NO) bioavailability [14]. Several studies have documented increased shear stress to upregulate endothelial nitric oxide synthase (eNOS) activity in cell culture, animal or human studies [15]. Extended periods of ET also has an impact on the generation of reactive oxygen species (ROS) [15], by lowering the expression of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase and stimulating radical scavenging systems that include copper/zinc-containing superoxide dismutase (SOD), extracellular SOD, glutathione (GSH) peroxidase and GSH levels [15]. Thus, aerobic ET decreases oxidative stress by increasing the efficiency of the antioxidant system, and finally improving endothelial dysfunction [15,16]. In a previous study in sedentary subjects [17], aimed at assessing the effects of high-amount, high-intensity exercise on in vivo platelet activation, we reported a significant reduction of the F2-isoprostane8iso-PGF2α, after completion of the exercise program. We also unraveled that modulation of oxidative stress might be a major determinant of the “antiplatelet effect” of aerobic exercise. Indeed aerobic activity is considered to be an effective component of CVD prevention [12]. While there is compelling evidence of beneficial effects of various exercise modalities on endothelial function [16] and oxidative stress [17–23], their impact on PWV is more controversial [24,25]. Therefore, the main objective of this study was to test the hypothesis of a significant association between evaluation of in vivo oxidative stress and the degree of arterial stiffness in sedentary subjects, and to challenge their parallel reversibility after 8 weeks of high-amount, high-intensity ET. As a secondary objective, we aimed at assessing ET effects on cardiovascular fitness and lipid profile. 2. Materials and methods 2.1. Patient selection Informed consent was obtained from each patient and the study protocol conformed with the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institutional Human Research Committee. After giving written, informed consent, 18 subjects (12 males), median age 54 (48–66) years, were enrolled in the study. The clinical characteristics of participating subjects are summarized in Table 1 Clinical characteristics of study subjects at baseline. Variable
Baseline⁎
n, (%) Age, years Male gender, n (%) BMI, kg/m2 Obesity, n (%) Hypertension, n (%) Diabetes, n (%) Smoking, n (%) Fasting plasma glucose, mg/dl AST, mg/dl ALT, mg/dl Smoke, n (%) Rate of adherence, % ACE-inhibitors, n (%) ARBs, n (%) Diuretics, n (%) Beta-blockers, n (%) Calcium channel blockers, n (%) Statins, n (%) PUFA, n (%) PPI, n (%)
18 54 (48–66) 12 (66.7) 25.5 (24.4–27.5) 3 (16.7) 8 (44.4) 0 (0) 3 (16.7) 89 (81–97) 18.0 (16.0–23.7) 20.5 (17.2–24.5) 3 (16.7) 95.3 (90.6–99.8) 3 (16.7) 4 (22.2) 2 (11.1) 1 (5.5) 2 (11.1) 1 (5.5) 0 (0) 1 (5.5)
AST, aspartate transaminase; ALT, alanine transaminase; ACE, angiotensin-convertingenzyme; ARBs, angiotensin receptor blockers; PUFA, polyunsaturated fatty acids; PPI, proton pump inhibitors. ⁎ Continuous variables are reported as median [interquartile range (IQR)].
Table 1. Subjects were enrolled if they reported a sedentary lifestyle (regular aerobic exercise b 3 times/week and for b20 min (min)/session, with a sedentary occupation) and their baseline HDL cholesterol concentration was b50 mg/dL (1.0 mmol/l). All subjects were classified at low or intermediate risk by the Framingham Risk Score (FRS) at the time of study entry. Exclusion criteria included obesity (BMI N 30 kg/m2), a diagnosis of diabetes mellitus, poorly-controlled hypertension or hypercholesterolemia, pregnancy, impaired liver or renal function, previous vascular events (myocardial infarction (MI), stroke), or other medical conditions that would preclude vigorous exercise, treatment with nonsteroidalanti-inflammatory drugs (NSAIDs), anticoagulants or antiplatelet drugs, and statins.
2.2. Training program Each participant completed an eight-week standardized aerobic training program. The exercise training involved 2 sessions per week of supervised exercise on a cycle ergometer (Monark 915E, Vansbro, Sweden). The exercise prescriptions in the exercise group was highamount, high-intensity exercise for 55 min per session, the caloric equivalent of jogging approximately 20 miles (32.0 km) per week at 60% to 75% of peak oxygen consumption. During an initial period of one month the amount and intensity of exercise were gradually increased, followed by 8 weeks at the appropriate exercise prescription. Participants started at 55% of their baseline VO2 max for 45 min per session, and progressed in intensity or duration every week according to a standardized protocol, until achieving the standards scheduled for the training program (55 min at 75% of baseline VO2 max). The subjects performed a maximal incremental ramp test, consisting of 3 min at rest and 5 min of priming exercise at 50 W, followed by a continuous increase in the workload by 20 W/min until exhaustion. The accepted criteria for maximal effort were: respiratory exchange ratio N 1.1, and heart rate N90% of the predicted maximum based on age. Breath-by-breath (B-byB) VO2 and carbon dioxide output (VCO2) were measured continuously at the mouth (Quark b2, Cosmed, Rome, Italy). Peak VO2 (mL/min/kg) was defined as the average of maximum 30-s attained VO2 at the end of the exercise period. Analyzers and the respiratory flow transducer were calibrated following the manufacturer's instructions before each experimental run. All exercise sessions were verified by directly supervised by a physician under heart rate monitoring (Polar Electro, Kempele, Finland) that recorded data. Daily energy consumption was monitored with a metabolic armband (Sensewear Pro3, Pittsburgh (PA), USA). Nutrient intakes were determined at baseline and at the end of the study. To minimize the confounding effects of weight loss, participants were counseled to maintain body weight, which was ethically justified by the short time frame of the study. Thus, we suggested not to alter their health habits and to continue their usual eating pattern, physical activity outside of the study, alcohol and tobacco use. Data would be excluded from the analysis for subjects whose weight varied by more than 5% from baseline to the end of the study.
2.3. Assays At baseline (before the run-in period) and after the 8-week training program, the participants were instructed to perform an overnight urine collection, and underwent fasting blood sampling the following morning. Plasma, serum, and urine were stored in aliquots at −20 °C until used for the various analyses. Urinary 8-iso-PGF2α was measured by a previously described radioimmunoassay [26]. Measurements of urinary 8-iso-PGF2α by this radioimmunoassay has been validated using different antisera and by comparison with gas chromatography/ mass spectrometry, as detailed elsewhere [26]. Total, HDL and LDL cholesterol, and triglyceride concentrations were measured as previously described [27].
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
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Table 2 Effects of the 8-week exercise training program on cardiovascular fitness, lipid profile, U-8-iso-PGF2α and PWV. Variable
Baseline
After 8-weeks exercise program⁎
p-value⁎⁎
Peak oxygen consumption, mL/kg/min Peak oxygen consumption, ml/min Peak heart rate, bpm Respiratory exchange ratio O2 pulse, mL/beat Total cholesterol, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dL PWV, m/s U-8-iso-PGF2α, pg/mg creatinine
35.2 (30.3–40.0) 2844 (2140–3456) 171.0 (161.2–181.1) 1.11 (1.10–1.16) 16.6 (12.8–20.3) 199.5 (184.0–224.7) 132.2 (120.6–149.1) 46.0 (40.5–49.0) 107 (82–126) 6.28 (5.44–7.86) 320 (287–435)
35.5 (30.7–40.2) 2931 (2231–3555) 172.4 (161.8–181.1) 1.12 (1.10–1.16) 17.0 (13.2–20.3) 200.5 (185.0–235.5) 130.5 (113.8–160.7) 50.0 (42.8–58.5) 86 (62–111) 5.31 (4.59–6.67) 209 (154–258)
0.040 b 0.0001 b 0.0001 0.831 0.445 0.396 0.845 0.107 0.022 b 0.0001 b 0.0001
⁎ Continuous variables are reported as median [interquartile range (IQR)]. ⁎⁎ by Wilcoxon signed rank test.
2.4. PWV measurement Measurement of AS was obtained noninvasively, using a volume displacement method (Vicorder system, Wuerzburg, Germany). After 15 min of rest, with participants in a supine position, a 100 mm-wide blood pressure cuff was placed around the right upper thigh to measure the femoral pulse wave and a 30 mm plethysmographic partial inflatable sensor was placed over the carotid region, able to pick up the carotid pulse wave. After preparation, both were inflated to about 60 mm Hg, and high-quality waveforms were recorded simultaneously over about 10 consecutive heartbeats. The foot-to-foot transit time was calculated using an in-builtcross-correlation algorithm that was centered around the peak of the second derivative of pressure, according to current guidelines [28]. In the present study, path length was defined by a direct measurement between the suprasternal notch to the top of the thigh cuff, as documented in a previous study [29]. 2.5. Statistical analysis Sample size calculation was based on the primary endpoint of the study, the urinary 8-iso-PGF2α excretion rate (mean ± SD, about 190 ± 90 in healthy or low-risk subjects by previous studies) [30]. It was estimated that 16 patients would be required, for a two-tailed alpha of 0.05 and a power of 90%, to detect a mean difference in urinary 8-iso-PGF2α excretion rate of at least 25% between pre- and post-intervention. Allowing for a 10% drop-out rate, we estimated that 18 patients per group would need to be enrolled. Given the baseline values of urinary 8-iso-PGF2α excretion rate actually measured [320 (287–435) pg/mg creatinine], the study had 94% power to detect a mean absolute difference in excretion rate of 140 pg/mg creatinine after the completion of the training program [U-8-iso-PGF2α excretion rate (in pg/mg creatinine) before exercise training (364 ± 142) and after training program (224 ± 92)]. The Shapiro– Wilk normality test was performed to determine whether each variable had a normal distribution. When necessary, log transformation or appropriate non-parametric tests were used. Comparisons of data before and after the intervention program were performed by the Wilcoxon signed rank test. Univariate associations between serum lipid levels and experimental measurements were assessed by the Spearman rank correlation test. Data are presented as median [interquartile range (IQR)] or n (%). p-Values lower than 0.05 were regarded as statistically significant. All tests were two-tailed, and analyses were performed using the SPSS (v. 16.0; APSS, Chicago, IL, USA), statistical package.
the effects of exercise on cardiovascular fitness is shown in Table 2. After the high-amount, high-intensity exercise program, a statistically significant increase in peak oxygen consumption (median increase 3.0%, p b 0.0001) and in peak heart rate (0.8%, p b 0.0001) was recorded (Table 2). Respiratory exchange ratio (0.9%, p = 0.831) and O2 pulse (2.4%, p = 0.445) also increased in previously sedentary subjects after the 8-week standardized aerobic training program, although this difference did not achieve statistical significance (Table 2). Lipoprotein data obtained at baseline and at the end of the study are also shown in Table 2. Exercise training led to a non-statistically significant increase in total cholesterol (0.5% vs baseline, p = 0.396), and a non-statistically significant decrease in LDL-C concentrations (1.3% vs baseline, p = 0.845). Moreover, the increase in HDL-C concentration after the high-amount, high-intensity training period was not significant (by 8.7% vs baseline, p = 0.107) (Table 2). Otherwise, we observed a statistically significant reduction in triglyceride concentration [107 (82–126) mg/dL vs 86 (62–111) mg/dL, p = 0.022; 24.4% decrease vs baseline] (Table 2). PWV was significantly reduced after the completion of the training program [6.28 (5.44–7.86) m/s vs 5.31 (4.59–6.67) m/s, p b 0.0001; 9.9% decrease vs baseline] (Fig. 1). By pooling data before and after the ET program, a significant correlation was found between PWV levels and triglyceride levels (Rho = 0.466, p = 0.005) (Fig. 2) throughout the intervention period.
3. Results Baseline characteristics of the subjects are presented in Table 1. No patient had his/her weight varied by more than 5% from baseline to the end of the study. A description of the exercise prescriptions and
Fig. 1. PWV was significantly reduced after the completion of the 8 -week high-amount, high-intensity exercise training program (p b 0.0001).
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
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Fig. 2. Correlations between triglycerides and PWV in the study subjects, before (solid circle) and after (open circle) the eight-week exercise training program.
Moreover, ET resulted in a significant reduction in urinary 8-isoPGF2α [320 (287–435) pg/mg creatinine vs 209 (154–258) pg/mg creatinine, p b 0.0001; 25.9% decrease vs baseline] (Fig. 3). Interestingly, PWV levels throughout the study were directly related to urinary excretion of urinary 8-iso-PGF2α(Rho = 0.383, p = 0.021) (Fig. 4). Finally, there was a non-significant decrease in heart rate levels after exercise training [73 (69–80) bpm vs 71 (67–76) bpm, p = 0.082; 2.8% decrease vs baseline]. 4. Discussion Sedentary lifestyle is considered a risk factor for CVD[12]. Sedentary lifestyle is directly related to increased incidence of CVD[31,32]. Physical activity is associated with lower CVD mortality and all-cause mortality in comparison with sedentary lifestyle [33]. The higher the level of physical fitness, the less likely an individual will suffer premature cardiovascular death [34]. AHA recommends physical activity for prevention of CVD (class I recommendation), with at least 30 min of moderate-intensity aerobic activity 7 days per week, with a minimum of 5 days per week [35]. Part of the risk reduction associated with physical fitness, may be attributed to effects on vascular hemodynamics: endothelial function,
Fig. 3. Urinary 8-iso-PGF2α was significantly reduced after the completion of the 8 -week high-amount, high-intensity exercise training program (p b 0.0001).
Fig. 4. Correlations between urinary 8-iso-PGF2α and PWV in the study subjects, before (solid circle) and after (open circle) the eight-week exercise training program.
arterial remodeling and compliance [36]. In fact, augmentation of AS increases the risk of coronary artery calcification [37] and cardiovascular events [38]. PWV provides a simple, non-invasive and reproducible estimate of arterial stiffness [28]. Epidemiological studies demonstrate the predictive value of aortic stiffness (carotid-femoral PWV) for CV events [28]. AS is lower in those who performed aerobic exercise on a regular basis, compared with sedentary peers [39]. Consistently, our results show a significant reduction in PWV levels in sedentary subjects, after 8 week of high-amount, high-intensity exercise (median from 6.28 m/s to 5.31 m/s) (p b 0.0001). The term AS does not only refer to a diminished vessel compliance, but is also related to endothelial dysfunction [40]. Oxidative stress may play a major role in the pathogenesis of endothelial dysfunction [14], and is generated by an imbalance between pro- and anti-oxidant molecules. In this study, we tried to correlate oxidative stress and AS in sedentary people, before and after high-amount, high-intensity exercise, previously proved to be beneficial on HDL levels [19]. As an integrated biomarker of systemic oxidative stress, we analyzed urinary 8iso-PGF2α levels, generated in vivo by lipid peroxidation [41]. In our sedentary people, urinary 8-iso-PGF2α excretion before exercise training was higher (364 ± 142 pg/mg creatinine) than that reported in healthy or low-risk subjects [30]. This result is in agreement with the notion that sedentary lifestyle is characterized by an imbalance between pro- and anti-oxidant molecules [14,42–44]. After 8 weeks of training program, urinary 8-iso-PGF2α excretion rate decreased to 224 ± 92 pg/mg creatinine (−25.9% vs baseline), reinforcing the idea that physical activity exerts its favorable effects on endothelial function through a reduction of oxidative stress. Enhanced generation of ROS within the vascular wall may be responsible for vascular remodeling, favoring the proliferation of smooth muscle cells, thus inducing endothelial dysfunction [45]. This concept is supported, in our study, by the direct correlation between PWV and urinary 8-iso-PGF2α throughout the training period (Rho = 0.383, p = 0.021) (Fig. 4). Thus, oxidative stress may be the link connecting sedentary lifestyle with increased arterial stiffness. Obesity has been associated with increased oxidative stress [46] and augmented arterial stiffness [47]. Thus, in our study design, no dietary intervention was included and no patient had his/her weight varied by more than 5% from baseline to the end of ET. This study setting should have minimized the dietary contribution in modulating oxidative stress levels, thus emphasizing the role of physical activity. The weight loss achieved after 8 weeks of ET was not significant, and is unlikely to be responsible for the observed modulation of PWV levels or oxidative stress. Finally, unlike previously reported data [37], we obtained only a slight and non-significant(p = 0.107) increase in HDL-C concentrations after high-amount, high-intensity exercise (Table 2). The small sample size of our study, as well as the clinical characteristics of study patients, may explain such a discrepancy of results. Instead, and consistent with
Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
G. Lessiani et al. / Vascular Pharmacology xxx (2015) xxx–xxx
previous studies [19], we observed a statistically significant reduction in triglyceride concentrations, after the 8-week exercise training program (p = 0.022) (Table 2), as previously shown. Interestingly, we found a significant correlation between PWV and triglyceride levels (Rho = 0.466, p = 0.005). Thus, in sedentary people, triglycerides seem to represent a further risk factor for endothelial dysfunction and arterial stiffness, whereas ET was able to improve vascular stiffness, at least in part by lowering triglyceride levels. Consistently, acute resistance exercise attenuates triglyceride increase following a high fat meal, with simultaneous improvement of peripheral AS[48]. Therefore, our results are consistent with the findings of the Malmö Diet and Cancer study, reporting that triglyceride levels were among the stronger predictors of arterial stiffness after 17 years of follow-up[49]. 5. Conclusions This study indicates that sedentary lifestyle is characterized by increased oxidative stress. In fact, urinary levels of 8-iso-PGF2α, an in vivo biomarker of lipid peroxidation, are higher in sedentary subjects and directly related to increased PWV. Thus, oxidative stress-induced endothelial dysfunction seems to be responsible for AS in this setting. High-amount, high-intensity exercise training improves the cardiovascular risk profile in these subjects, lowering oxidative stress and thereby the degree of AS. Therefore, regular physical exercise may be a natural antioxidant strategy for preventing diseases such as diabetes and CVD in sedentary people. Funding sources Partially supported by grants from the University of Chieti (ex-60%) to GD and from the Italian Ministry of University and Research (PRIN n. 2010JS3PMZ to FS). References [1] S.J. Zieman, V. Melenovsky, D.A. Kass, Mechanism, pathophysiology, and therapy of arterial stiffness, Arterioscler. Thromb. Vasc. Biol. 25 (2005) 932–943. [2] M. Cecelja, P. Chowienczyk, Role of arterial stiffness in cardiovascular disease, JRSM Cardiovasc Dis. 1 (4) (2012). [3] E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease, Circulation 107 (2003) 139–146. [4] E.G. Lakatta, D. Levy, Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease, Circulation 107 (2003) 346–354. [5] C. Vlachopoulos, I. Dima, K. Aznaouridis, et al., Acute systemic inflammation increases arterial stiffness and decreases wave reflections in healthy individuals, Circulation 112 (2005) 2193–2200. [6] M. Wang, J. Zhang, L.Q. Jiang, et al., Proinflammatory profile within the grossly normal aged human aortic wall, Hypertension 50 (2007) 219–227. [7] G.F. Mitchell, H. Parise, E.J. Benjamin, et al., Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study, Hypertension 43 (2004) 1239–1245. [8] K.S. Heffernan, A. Chale, C. Hau, et al., Systemic vascular function is associated with muscular power in older adults, J. Aging Res. 2012 (2012) 386–387. [9] J. Muller, R. Oberhoffer, C. Barta, et al., Oscillometric carotid to femoral pulse wave velocity estimated with the Vicorder device, J. Clin. Hypertens. 15 (2013) 176–179. [10] F.U. Mattace-Raso, T.J. van der Cammen, A. Hofman, et al., Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study, Circulation 113 (2006) 657–663. [11] F. Santilli, N. Vazzana, G. Davì, et al., Oxidative stress drivers and modulators in obesity and cardiovascular disease: from biomarkers to therapeutic approach, Curr. Med. Chem. 22 (2015) 582–595. [12] G.F. Mitchell, S.J. Hwang, R.S. Vasan, et al., Arterial stiffness and cardiovascular events: the Framingham Heart Study, Circulation 121 (2010) 505–511. [13] E.V. Nosova, P. Yen, K.C. Chong, et al., Short-term physical inactivity impairs vascular function, J. Surg. Res. 190 (2014) 672–682. [14] S.S. Thosar, B.D. Johnson, J.D. Johnston, et al., Sitting and endothelial dysfunction: the role of shear stress, Med. Sci. Monit. 18 (2012) 173–180. [15] G. Schuler, V. Adams, Y. Goto, Role of exercise in the prevention of cardiovascular disease: results, mechanisms, and new perspectives, Eur. Heart J. 34 (2013) 1790–1799. [16] F.R. Roque, R. Hernanz, M. Salaices, et al., Exercise training and cardiometabolic diseases: focus on the vascular system, Curr. Hypertens. Rep. 15 (2013) 204–214. [17] F. Santilli, R. Saggini, G. Davì, et al., Effects of high-amount-high-intensity exercise on in vivo platelet activation: modulation by lipid peroxidation and AGE/RAGE axis, Thromb. Haemost. 110 (2013) 1232–1240.
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Please cite this article as: G. Lessiani, et al., Arterial stiffness and sedentary lifestyle: Role of oxidative stress, Vascul. Pharmacol. (2015), http:// dx.doi.org/10.1016/j.vph.2015.05.017
