Journal of Strength and Conditioning Research Publish Ahead of Print DOI: 10.1519/JSC.0000000000000536
Acute effect of high-intensity eccentric exercise on vascular endothelial function in young men
Youngju Choi1, Nobuhiko Akazawa1, Asako Miyaki2, Song-Gyu Ra3,
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Hitoshi Shiraki1, Ryuichi Ajisaka1, Seiji Maeda1
Department of Sports Medicine, Faculty of Health and Sport Sciences, 2Faculty of Medicine, and 3Division of Sports Medicine, Graduate School of Comprehensive
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Human Sciences, University of Tsukuba, Japan
Running title: Eccentric exercise and vascular endothelial function
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Address for correspondence: Seiji Maeda, Ph.D.
Department of Sports Medicine
Faculty of Health and Sport Sciences
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University of Tsukuba
Tsukuba, Ibaraki 305-8574 Japan
(TEL) +81 29-853-2683 (FAX) +81 29-853-2986 E-mail: [email protected]
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Abstract Increased central arterial stiffness is as an independent risk factor for cardiovascular disease. Evidence regarding the effects of high-intensity resistance exercise on vascular endothelial function and central arterial stiffness is conflicting. The purpose of this
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study was to examine the effects of acute high-intensity eccentric exercise on vascular endothelial function and central arterial stiffness. We evaluated the acute changes in
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endothelium-dependent flow-mediated dilation, low-flow-mediated constriction, and arterial stiffness following high-intensity eccentric exercise. Seven healthy, sedentary men (age, 24 ± 1 years) performed maximal eccentric elbow flexor exercise using their non-dominant arm. Before and 45 min after eccentric exercise, carotid arterial
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compliance and brachial artery flow-mediated dilation and low-flow-mediated constriction in the non-exercised arm were measured. Carotid arterial compliance was significantly decreased, and β-stiffness index significantly increased, after eccentric
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exercise. Brachial flow-mediated dilation was significantly reduced after eccentric exercise, whereas there was no significant difference in brachial low-flow-mediated constriction before and after eccentric exercise. A positive correlation was detected between change in arterial compliance and change in flow-mediated dilation (r = 0.779,
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P < 0.05), and a negative correlation was detected between change in β-stiffness index and change in flow-mediated dilation (r = -0.891, P < 0.01) with eccentric exercise. In the present study, acute high-intensity eccentric exercise increased central arterial stiffness; this increase was accompanied by a decrease in endothelial function caused by reduced
endothelium-dependent
vasodilation
but
not
by
a
change
endothelium-dependent vasoconstriction.
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Keywords: high-intensity eccentric exercise; flow-mediated dilation; low-flow mediated
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constriction; vasodilation; vasoconstriction
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INTRODUCTION Central arteries (e.g., aorta) provide buffer function to level off fluctuations in blood pressure and blood flow (39). However, increased central arterial stiffness reduces this buffer function and subsequently leads to an increase in systolic blood pressure and
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pulse pressure. (40). Increased central arterial stiffness has also been identified as an independent risk factor for future cardiovascular disease (26). High-intensity resistance
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exercise is recommended for maximizing strength and muscle hypertrophy (1). However, research has shown that both acute (14, 16, 21) and chronic (9, 12, 34, 35) high-intensity resistance exercise leads to increased central arterial stiffness in young subjects, although this is not a universal finding (6, 22, 23, 43). This possible increased
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central arterial stiffness with both acute and chronic high-intensity resistance exercise is related to upper-limb exercise (16, 41) and is not found in lower-limb exercise (22, 23).
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Previous studies have reported that high-intensity resistance training did not change vascular endothelial function (6, 28, 44). On the other hand, the effects of acute high-intensity resistance exercise on vascular endothelial function are under debate. Several studies have shown that acute high-intensity resistance exercise may decrease
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vascular endothelial function (42, 50), whereas other studies have found either no effect on (42), or even an increase in vascular endothelial function with acute high-intensity resistance exercise (10, 42, 50). Thus, it is unclear that the effects of acute high-intensity resistance exercise on vascular endothelial function.
High-intensity resistance exercise is associated with elevated oxidative stress and inflammation (3-5, 8, 17, 24, 31), both of which acutely impair endothelial function (19).
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Because increased arterial stiffness may be associated with reduced endothelial function (7, 38), one possible mechanism by which high-intensity resistance exercise induces an increase in central arterial stiffness is through a decrease in endothelial function. However, it is unclear whether high-intensity resistance exercise produces this effect.
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Endothelial function is commonly assessed by endothelium-dependent flow-mediated dilation (FMD) (11), which reflects the nitric oxide (NO) bioactivity in response to
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increased blood flow. Recently, Gori et al. (18) have described low-flow-mediated constriction (L-FMC), a novel index that evaluates the endothelium-dependent response of the artery to the low-flow state utilizing data obtained from the cuff-occlusion period of FMD assessment. L-FMC may be partly mediated by endothelin-1 (ET-1), a potent
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vasoconstrictor peptide produced by vascular endothelial cells (47), and is considered an endothelium-dependent constrictor function (13).
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The purpose of this study was to examine the effects of acute high-intensity resistance exercise using eccentric exercise protocol on vascular endothelial function and central arterial stiffness. We hypothesized that acute high-intensity eccentric exercise would decrease endothelial function and increase central arterial stiffness. The
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present study evaluated the acute changes in endothelium-dependent flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and carotid arterial stiffness following high-intensity eccentric exercise.
METHODS Experimental Approach to the Problem The present study was investigated the acute effects of high-intensity eccentric
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exercise on vascular endothelial function and central arterial stiffness, as determined by brachial artery flow-mediated dilation (FMD) and low-flow-mediated constriction (L-FMC), and carotid arterial compliance. Participants, who have no experience of resistance training in the past, performed 1 set of 50 maximal eccentric elbow flexor
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exercise using their non-dominant arm. To determine acute effect of high-intensity eccentric exercise, brachial FMD, L-FMC and carotid arterial compliance were
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measured before and at 45 minutes after the acute exercise. Thus, the independent variables were “pre-exercise (rest) ” and “post-exercise” measurement timing, and the dependent variables were brachial FMD, L-FMC and carotid arterial compliance.
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Subjects
A total of 7 healthy young men (age, 21–28 years) participated in this study. All subjects had led a sedentary lifestyle (no regular physical activity) for at least 1 year
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before the start of the study. To better isolate the effect of acute exercise, those who were prior resistance-trained athletes (i.e., bodybuilder) were excluded. They were normotensive and nonobese, and none of the subjects exhibited signs or symptoms, or had a history of, any chronic diseases. Furthermore, all were non-smokers, and none
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was taking any medications, anabolic steroids, or antioxidant-containing dietary supplements at the time of the study.
The present study was approved by the Ethical Committee of the University of Tsukuba. This study conformed to the principles outlined in the Helsinki Declaration, and all the subjects provided their written informed consent prior to their participation.
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Procedures Study design All subjects had refrained from alcohol and caffeine for at least 12 h, and intense physical activity (exercise) for at least 48 h, prior to the experimental session in order to
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rule out any possible acute effect. The subjects had rested in the supine position for a minimum of 15 min in a quiet, temperature-controlled room (25–26°C). With the
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subject in the supine position, resting brachial blood pressure, heart rate, carotid artery compliance, and brachial endothelial function were measured. After these measurements, blood sampling was performed to determine metabolic risk factors. Each subject then performed eccentric exercise using his non-dominant elbow (15). The pre-exercise
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measurements (brachial blood pressure, heart rate, carotid artery compliance, and brachial endothelial function) were repeated 45 min after exercise.
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Resting blood pressure and heart rate
Systolic and diastolic blood pressures and heart rate were measured in the non-exercised arm with the subject in the supine position using a semi-automated
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system (Dinamap; GE Healthcare, Salt Lake City, UT, USA).
Carotid artery compliance Carotid artery compliance was noninvasively determined using a combination of
ultrasound imaging of a common carotid artery with simultaneous applanation of tonometrically obtained arterial pressure from the contralateral carotid artery, as previously described (36). The common carotid artery diameter was measured from the images derived from an ultrasound machine (EnVisor, Koninklijke Philips Electronics,
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Eindhoven, Netherlands) equipped with a high-resolution (7.5 MHz) linear-array transducer. Cross-sectional compliance was calculated on the basis of the change in the cross-sectional area (dA), local pulse pressure (dP), arterial diameter (D), and the change in arterial diameter (dD) during the heart cycle using the formula cross-sectional
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compliance = dA/dP, and dA was calculated as dA = π × ([(D + dD]/2)2 – π × (D/2)2. The pressure waveforms of the left common carotid artery were recorded with an
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applanation tonometry device (form PWV/ABI; Colin Medical Technology, Komaki, Japan) and calibrated by equating the mean arterial and diastolic blood pressure values of the carotid artery to those of the brachial artery.
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The β-stiffness index provided an index of arterial compliance adjusted for distending pressure, as previously described (36). In brief, the β-stiffness index was calculated using the equation β = In (Ps/Pd)/[(Ds – Dd)/Dd], where Ds and Dd are the
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maximum and minimum inner arterial diameters and Ps and Pd are the highest and lowest blood pressure. All image analyses were performed by the same investigator.
Flow-mediated dilation and low-flow-mediated constriction
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Brachial artery FMD was measured according to guidelines (48) using a novel stereotactic probe-holding device equipped with an edge-tracking system for 2D imaging and pulsed Doppler flow velocimeter for automatic measurement (UNEXEF; Unex Co. Ltd., Japan) as previously described (27). A high-resolution linear artery transducer was coupled to computer-assisted analysis software that used an automated edge detection system for measurement of brachial artery diameter. In brief, the diameter of the non-exercised brachial artery at baseline was measured in place 5–10
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cm proximal to the antecubital fossa by using a 10-MHz linear-array transducer probe. The cuff distal to the measurement site was then inflated to 50 mmHg above systolic blood pressure for 5 min and deflated. The diameter at the same point of the artery was monitored continuously for 3 min following deflation of the cuff, and the maximum
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dilation after deflation was recorded. FMD was calculated as the percent change in the arterial diameter divided by the baseline value at maximal dilation after the cuff
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deflation, or FMD (%) = ([maximal diameter – baseline mean diameter]/baseline mean diameter) × 100.
Generally, L-FMC data were obtained from the cuff occlusion period of FMD
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assessment (18, 20). L-FMC can also be determined after the cuff deflation period because L-FMC persists for period immediately after deflation. Indeed, our lab’s pilot data suggest that subjects’ brachial artery diameters during the cuff occlusion period and
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immediately after cuff deflation were the same. Thus, we measured the brachial artery diameters in the first 10 s after cuff deflation instead of brachial artery diameters of the cuff occlusion period. L-FMC was expressed as the percent change in the arterial diameter over the baseline value at minimal values immediately after cuff deflation, or
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L-FMC (%) = ([minimal diameter immediately after the cuff deflation – baseline mean diameter]/baseline mean diameter) × 100.
Blood biochemical analysis Before blood sampling, the subjects had fasted for at least of 12 h overnight. Fasting serum cholesterol and plasma glucose concentrations were determined using standard enzymatic techniques.
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Eccentric exercise The high-intensity eccentric exercise was based on previous research in which elbow flexor eccentric exercise using a Biodex isokinetic dynamometer (System 3) was
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used (15). The non-dominant arm was selected for exercise to minimize the effects on daily activity. Subjects were seated on the dynamometer chair with the arm supported
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and were stabilized at the waist and chest. Starting with the elbow flexed to 50º and ending at an angle of 170º, each subject performed 1set of 50 maximal eccentric movements of the elbow flexor, at an angular velocity of 120º⋅s−1. Subjects were verbally encouraged to produce a maximal effort to resist extension of the elbow by the
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dynamometer. Subjects were given a 12-s rest between each contraction, during which time the dynamometer arm returned passively to the starting position.
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Statistical analysis
Values are expressed as mean ± SE. Mean differences between pre (rest) and post exercise were examined using a paired t-test. Associations between the change in central arterial stiffness and the change in FMD were determined by Pearson’s correlations. All
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statistical analysis was performed using SPSS Statistical Package Version 11.0 (SPSS Japan, Inc.) with statistical significance set at P < 0.05. Cohen’s d effect sizes were also
calculated to determine the magnitude of change and d ＞ 0.80 was accepted as an
large effect.
RESULTS Subject characteristics are presented in Table 1. Subjects’ mean age was 24 ± 1
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years; height was 171 ± 1 cm; weight was 64 ± 2 kg and body mass index (BMI) was 22.1 ± 0.8. All subjects’ serum lipid and plasma glucose levels were within a clinically normal range. Haemodynamic values before and after exercise are presented in Table 2. There were no changes in systolic blood pressure, diastolic blood pressure, or heart rate
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before and 45 min after eccentric exercise. Figure 1 shows the changes in central arterial stiffness before and 45 min after exercise. Carotid arterial compliance was significantly
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decreased (P < 0.01, effect size = 0.87) and β-stiffness index was significantly increased (P < 0.05, effect size = 0.85) after eccentric exercise (Fig. 1). Brachial FMD was significantly reduced 45 min after eccentric exercise (P < 0.05, effect size = 1.58, Fig. 2). There was no significant difference between brachial L-FMC before and 45 min
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after eccentric exercise (P = 0.295, Table 3). Baseline arterial diameter and minimal diameter immediately after cuff deflation was not altered by eccentric exercise; nor was time to peak (Table 3). However, maximal diameter after cuff deflation was
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significantly reduced after eccentric exercise (P < 0.05, effect size = 0.56, Table 3).
A positive correlation was detected for change in arterial compliance and change in FMD with eccentric exercise (r = 0.779, P < 0.05, Fig. 3A). Similarly, a negative
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correlation was detected for change in β-stiffness index and change in FMD with eccentric exercise (r = -0.891, P < 0.01, Fig. 3B).
DISCUSSION The main finding of this study was a decrease in endothelium-dependent vasodilator function (reduced FMD) with increase in central arterial stiffness after high-intensity eccentric exercise. Furthermore, the decrease in endothelium-dependent
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vasodilator function was associated with an increase in central arterial stiffness. These data suggest that acute high-intensity eccentric exercise increases central arterial stiffness and that this increase is accompanied by a reduction in endothelium-dependent
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vasodilator function.
Previous research has found increased central arterial stiffness with acute
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high-intensity whole-body resistance exercise and resistance exercise training (12, 14, 21, 35). In particular, the increased arterial stiffness following the exercise is associated with upper-limb exercise but not lower-limb exercise (41). Several studies have examined the acute effects of high-intensity upper-limb resistance exercise on arterial
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stiffness (2, 16). DeVan et al. (14) has suggested that the effects of acute resistance exercise on the arterial adaptations appear to be transient, lasting no longer than 1h. Because measurements in previous studies were taken at 15 min or 90 min (these time
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point still have been influenced by elevated blood pressure or an exceeded peak vascular response) (2, 16), the results may have been inappropriate to measure the acute effects of exercise on vascular function. Furthermore, Hellsten et al. (24) have reported that inflammation was significantly increased 45 min after resistance exercise using
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eccentric exercise protocol. Inflammation is associated decrease in endothelial function (19), which is affecting the regulation of arterial stiffness. Therefore, we measured arterial function 45 min after eccentric exercise in the present study, showing that high-intensity upper limb eccentric exercise increases central arterial stiffness without the influence of other factors (elevated blood pressure or an exceeded peak vascular response).
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Endothelial function affects the regulation of arterial stiffness (33, 52). Indeed, it has been reported that NO and ET-1, potent vasodilator and vasoconstrictor substances released from the endothelium, participate in the regulation of arterial stiffness (29, 33, 51). In the present study, we assessed endothelium-dependent vasodilator function by
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concurrently measuring FMD and vasoconstrictor function by measuring brachial L-FMC. There were greater reductions in FMD responses with no changes in L-FMC
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responses after high-intensity eccentric exercise. Moreover, there were strong associations between the change in brachial artery FMD and change in carotid artery stiffness. These results indicate that the decrease in endothelial function caused by decreased endothelium-dependent vasodilator function, not by a change in
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endothelium-dependent vasoconstrictor function, increases arterial stiffness following high-intensity eccentric exercise.
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Previous studies have shown that high-intensity resistance training did not change vascular endothelial function (6, 28, 44). On the other hand, the effects of acute high-intensity resistance exercise on vascular endothelial function are conflicting. Several studies have shown that acute high-intensity resistance exercise in sedentary
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individuals may decrease vascular endothelial function (42, 50). On the one hand, other studies have found acute high-intensity resistance exercise did not alter vascular endothelial function in athletes (42), or increased vascular endothelial function in sedentary individuals or athletes (10, 42, 50). In present study, we demonstrated that acute high-intensity upper-limb eccentric exercise in sedentary men decreases vascular endothelial function. This discrepancy in the current and previous studies may be related to the subject population (e.g., untrained vs. trained), exercise method (upper
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body exercise vs. lower body exercise), and/or exercise muscle contraction (eccentric vs. concentric).
To our knowledge, this is the first study to investigate the responses of both
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endothelial function and central arterial stiffness after high-intensity eccentric exercise. Few studies have reported that acute resistance exercise reduced endothelial function
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(42, 50). However, these studies did not measure endothelial function and arterial stiffness at the same time. In present study, we found that endothelial function decreases after high-intensity upper-limb eccentric exercise and that this reduction was associated with an increase in central arterial stiffness. Thus, it is possible that changes in
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endothelial function could account for the mechanism underlying eccentric exercise-induced increase in arterial stiffness.
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It is not clear why endothelial function is decreased acutely after high-intensity eccentric exercise. Many previous studies have reported that high-intensity eccentric exercise increases blood oxidative stress (8, 17, 31). Eccentric exercise increases free radical production through various pathways, including mitochondrial electron transport,
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ischemia-reperfusion injury, and inflammation (24, 32, 46, 49). In particular, superoxide anions (O2-) can be normally dismutated by superoxide dismutase (SOD) in endothelial cells (37); they also scavenge NO, resulting in the formation of peroxynitrite (45). This reduces considerably the bioavailability of NO (30). Thus, it is possible that increases in oxidative stress and inflammation following eccentric exercise are associated with reduced endothelium-dependent vasodilation.
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The present study had several important limitations. First, L-FMC was assessed immediately after cuff deflation period of FMD assessment. However, our pilot study has confirmed that brachial artery diameters during the cuff occlusion period and immediately after cuff deflation were the same. Thus, we measured the brachial artery
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diameters in the first 10 s after cuff deflation instead of brachial artery diameters of the cuff occlusion period. Second, this study was conducted with a small sample size. Effect
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size was calculated using Cohen’s d for significant results (i.e., central arterial stiffness and FMD) to determine the magnitude for change. We observed large effect sizes for the changes in arterial compliance, β-stiffness index and FMD after eccentric exercise (0.87, 0.85, and 1.58, respectively). Third, we did not include a non-exercising control group.
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Finally, the physiological or clinical significance of our finding is unclear in present study. Furthermore, it is unclear the link between acute and chronic effects of resistance exercise on vascular endothelial function. Further studies as to whether changes in
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vascular endothelial function following eccentric exercise participate in the physiological regulation and/or adaptation after exercise are needed.
In conclusion, in the present study has shown for the first time a significant
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reduction in endothelium-dependent vasodilator function after high-intensity eccentric exercise but no change in endothelium-dependent vasoconstrictor function after the exercise. In addition, central arterial stiffness was increased following high-intensity eccentric exercise, and the decrease in endothelium-dependent vasodilator function was associated with an increase in central arterial stiffness. These results suggest that acute high-intensity eccentric exercise increases central arterial stiffness and that this increase is accompanied by a decrease in endothelial function caused by the reduction of
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endothelium-dependent vasodilation but not by a change in endothelium-dependent vasoconstriction.
PRACTICAL APPLICATIONS
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Resistance exercise has favorable effects on the musculoskeletal system, and recommended by the major national health organizations (e.g., American College of
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Sports Medicine and American Heart Association). Resistance exercise typically incorporates a mixture of concentric, eccentric, and isometric muscle contraction. In particular, eccentric exercise is more effective than concentric exercise to improve muscle strength (25), and often used by athletes and other individuals. This is the first
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study to demonstrate the acute high-intensity eccentric exercise decreases in vascular endothelial function with increasing central arterial stiffness. Although these findings are limited to elbow flexor eccentric exercise, our results indicate that high-intensity
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eccentric exercise may have acute unfavourable cardiovascular effect in young men.
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ACKNOWLEDGEMENTS This work was supported by Grants-in-Aid for Scientific Research 21300234 from Japan Society for the Promotion of Science.
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CONFLICT OF INTEREST The authors have no financial, consultant, institutional, or other relationships that
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might lead to bias or a conflict of interest.
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35. Miyachi, M, Kawano, H, Sugawara, J, Takahashi, K, Hayashi, K, Yamazaki, K, Tabata, I, and Tanaka, H. Unfavorable effects of resistance training on central arterial
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compliance: a randomized intervention study. Circulation 110: 2858-2863, 2004. 36. Miyaki, A, Maeda, S, Yoshizawa, M, Misono, M, Saito, Y, Sasai, H, Kim, MK, Nakata, Y, Tanaka, K, and Ajisaka, R. Effect of habitual aerobic exercise on body weight and arterial function in overweight and obese men. Am J Cardiol 104: 823-828, 2009.
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37. Morikawa, K, Shimokawa, H, Matoba, T, Kubota, H, Akaike, T, Talukder, MA, Hatanaka, M, Fujiki, T, Maeda, H, Takahashi, S, and Takeshita, A. Pivotal role of Cu, Zn-superoxide dismutase in endothelium-dependent hyperpolarization. J Clin Invest 112: 1871-1879, 2003.
38. Nakamura, M, Sugawara, S, Arakawa, N, Nagano, M, Shizuka, T, Shimoda, Y, Sakai,
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T, and Hiramori, K. Reduced vascular compliance is associated with impaired endothelium-dependent dilatation in the brachial artery of patients with congestive heart failure. J Card Fail 10: 36-42, 2004.
39. Nichols WW and O’Rourke MF. McDonald’s blood flow in arteries. Theoretical, experimental and clinical principles. 4th ed, London, Arnold. 1998.
40. O'Rourke M. Arterial stiffness, systolic blood pressure, and logical treatment of arterial hypertension. Hypertension 15: 339-347, 1990. 41. Okamoto, T, Masuhara, M, and Ikuta, K. Upper but not lower limb resistance training increases arterial stiffness in humans. Eur J Appl Physiol 107: 127-134,
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2009. 42. Phillips, SA, Das, E, Wang, J, Pritchard, K, and Gutterman, DD. Resistance and aerobic exercise protects against acute endothelial impairment induced by a single exposure to hypertension during exertion. J Appl Physiol 110:1013-1020, 2011. 43. Rakobowchuk, M, McGowan, CL, de Groot, PC, Bruinsma, D, Hartman, JW, Phillips, SM, and MacDonald, MJ. Effect of whole body resistance training on
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arterial compliance in young men. Exp Physiol 90: 645-651, 2005. 44. Rakobowchuk, M, McGowan, CL, de Groot, PC, Hartman, JW, Phillips, SM, and MacDonald, MJ. Endothelial function of young healthy males following whole body
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resistance training J Appl Physiol 98 :2185-2190, 2005.
45. Rubanyi, GM, and Vanhoutte, PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 250: H822-827, 1986.
46. Sahlin, K, Cizinsky, S, and Warholm, M. Repetitive static muscle contractions in
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humans: a trigger of metabolic and oxidative stress? Eur J Appl Physiol Occup Physiol 64: 228-236, 1992.
47. Spieker, LE, Lüscher, TF, and Noll, G. ETA receptors mediate vasoconstriction of large conduit arteries during reduced flow in humans. J Cardiovasc Pharmacol 42: 315-318, 2003.
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48. Thijssen, DH, Black, MA, Pyke, KE, Padilla, J, Atkinson, G, Harris, RA, Parker, B, Widlansky, ME, Tschakovsky, ME, and Green, DJ. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol 300: H2-12, 2011. 49. Urso, ML, and Clarkson, PM. Oxidative stress, exercise, and antioxidant
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supplementation. Toxicology 189: 41-54, 2003. 50. Varady, KA, Bhutani, S, Church, EC, and Phillips, SA. Adipokine responses to acute resistance exercise in trained and untrained men. Med Sci Sports Exerc. 42:456-462, 2010.
51. Vuurmans, TJ, Boer, P, and Koomans, HA. Effects of endothelin-1 and endothelin-1 receptor blockade on cardiac output, aortic pressure, and pulse wave velocity in humans. Hypertension 41: 1253-1258, 2003. 52. Wilkinson, IB, MacCallum, H, Cockcroft, JR, and Webb, DJ. Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in
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vivo. Br J Clin Pharmacol 53: 189-192, 2002.
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Figure legends Figure 1. Carotid arterial compliance and β-stiffness index before and after eccentric exercise. **P < 0.01, *P < 0.05. Values are means ± SE.
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Figure 2. Flow-mediated dilation (FMD) before and after eccentric exercise. *P < 0.05.
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Values are means ± SE.
Figure 3. Relationship between endothelium-dependent flow-mediated dilation (FMD)
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and carotid arterial compliance (A), and β-stiffness index (B) from pre to post exercise.
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Subjects characteristics
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Table 1.
n=7
Age, years
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Variable
24 ± 1
Height, cm
171 ± 1
Weight, kg
64 ± 2
22.1 ± 0.8
Total cholesterol, mg/dl
151 ± 11
HDL cholesterol, mg/dl
49 ± 2
LDL cholesterol, mg/dl
90 ± 10
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Body mass index, kg/m2
Triglyceride, mg/dl
84 ± 13
Glucose, mg/dl
90 ± 2
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Values are means ± SE.
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pre
Systolic blood pressure, mmHg
Heart rate, beats/min
108 ± 1
59 ± 1
59 ± 1
55 ± 1
56 ± 1
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Values are means ± SE.
post
105 ± 1
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Diastolic blood pressure, mmHg
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Variable
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Table 2. Hemodynamic parameters before and after eccentric exercise
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pre
Baseline diameter, mm Maximal diameter after cuff deflation, mm low-flow mediated constriction, % Time to peak, sec
post
3.82
±
0.06
3.82 ± 0.06
4.09
±
0.07
3.99 ± 0.06 *
3.72
±
0.07
3.67 ± 0.04
-2.6
±
0.9
-4.1 ± 1.1
42
±
3
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Minimal diameter immediately after cuff deflation, mm
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Variable
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Table 3. Brachial artery structure and function before and after eccentric exercise
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Values are means ± SE. *P < 0.05 vs. pre.
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39 ± 3
Acute effect of high-intensity eccentric exercise on vascular endothelial function in young men
Youngju Choi1, Nobuhiko Akazawa1, Asako Miyaki2, Song-Gyu Ra3,
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Hitoshi Shiraki1, Ryuichi Ajisaka1, Seiji Maeda1
Department of Sports Medicine, Faculty of Health and Sport Sciences, 2Faculty of Medicine, and 3Division of Sports Medicine, Graduate School of Comprehensive
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Human Sciences, University of Tsukuba, Japan
Running title: Eccentric exercise and vascular endothelial function
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Address for correspondence: Seiji Maeda, Ph.D.
Department of Sports Medicine
Faculty of Health and Sport Sciences
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University of Tsukuba
Tsukuba, Ibaraki 305-8574 Japan
(TEL) +81 29-853-2683 (FAX) +81 29-853-2986 E-mail: [email protected]
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Abstract Increased central arterial stiffness is as an independent risk factor for cardiovascular disease. Evidence regarding the effects of high-intensity resistance exercise on vascular endothelial function and central arterial stiffness is conflicting. The purpose of this
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study was to examine the effects of acute high-intensity eccentric exercise on vascular endothelial function and central arterial stiffness. We evaluated the acute changes in
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endothelium-dependent flow-mediated dilation, low-flow-mediated constriction, and arterial stiffness following high-intensity eccentric exercise. Seven healthy, sedentary men (age, 24 ± 1 years) performed maximal eccentric elbow flexor exercise using their non-dominant arm. Before and 45 min after eccentric exercise, carotid arterial
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compliance and brachial artery flow-mediated dilation and low-flow-mediated constriction in the non-exercised arm were measured. Carotid arterial compliance was significantly decreased, and β-stiffness index significantly increased, after eccentric
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exercise. Brachial flow-mediated dilation was significantly reduced after eccentric exercise, whereas there was no significant difference in brachial low-flow-mediated constriction before and after eccentric exercise. A positive correlation was detected between change in arterial compliance and change in flow-mediated dilation (r = 0.779,
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P < 0.05), and a negative correlation was detected between change in β-stiffness index and change in flow-mediated dilation (r = -0.891, P < 0.01) with eccentric exercise. In the present study, acute high-intensity eccentric exercise increased central arterial stiffness; this increase was accompanied by a decrease in endothelial function caused by reduced
endothelium-dependent
vasodilation
but
not
by
a
change
endothelium-dependent vasoconstriction.
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in
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Keywords: high-intensity eccentric exercise; flow-mediated dilation; low-flow mediated
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constriction; vasodilation; vasoconstriction
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INTRODUCTION Central arteries (e.g., aorta) provide buffer function to level off fluctuations in blood pressure and blood flow (39). However, increased central arterial stiffness reduces this buffer function and subsequently leads to an increase in systolic blood pressure and
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pulse pressure. (40). Increased central arterial stiffness has also been identified as an independent risk factor for future cardiovascular disease (26). High-intensity resistance
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exercise is recommended for maximizing strength and muscle hypertrophy (1). However, research has shown that both acute (14, 16, 21) and chronic (9, 12, 34, 35) high-intensity resistance exercise leads to increased central arterial stiffness in young subjects, although this is not a universal finding (6, 22, 23, 43). This possible increased
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central arterial stiffness with both acute and chronic high-intensity resistance exercise is related to upper-limb exercise (16, 41) and is not found in lower-limb exercise (22, 23).
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Previous studies have reported that high-intensity resistance training did not change vascular endothelial function (6, 28, 44). On the other hand, the effects of acute high-intensity resistance exercise on vascular endothelial function are under debate. Several studies have shown that acute high-intensity resistance exercise may decrease
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vascular endothelial function (42, 50), whereas other studies have found either no effect on (42), or even an increase in vascular endothelial function with acute high-intensity resistance exercise (10, 42, 50). Thus, it is unclear that the effects of acute high-intensity resistance exercise on vascular endothelial function.
High-intensity resistance exercise is associated with elevated oxidative stress and inflammation (3-5, 8, 17, 24, 31), both of which acutely impair endothelial function (19).
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Because increased arterial stiffness may be associated with reduced endothelial function (7, 38), one possible mechanism by which high-intensity resistance exercise induces an increase in central arterial stiffness is through a decrease in endothelial function. However, it is unclear whether high-intensity resistance exercise produces this effect.
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Endothelial function is commonly assessed by endothelium-dependent flow-mediated dilation (FMD) (11), which reflects the nitric oxide (NO) bioactivity in response to
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increased blood flow. Recently, Gori et al. (18) have described low-flow-mediated constriction (L-FMC), a novel index that evaluates the endothelium-dependent response of the artery to the low-flow state utilizing data obtained from the cuff-occlusion period of FMD assessment. L-FMC may be partly mediated by endothelin-1 (ET-1), a potent
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vasoconstrictor peptide produced by vascular endothelial cells (47), and is considered an endothelium-dependent constrictor function (13).
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The purpose of this study was to examine the effects of acute high-intensity resistance exercise using eccentric exercise protocol on vascular endothelial function and central arterial stiffness. We hypothesized that acute high-intensity eccentric exercise would decrease endothelial function and increase central arterial stiffness. The
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present study evaluated the acute changes in endothelium-dependent flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and carotid arterial stiffness following high-intensity eccentric exercise.
METHODS Experimental Approach to the Problem The present study was investigated the acute effects of high-intensity eccentric
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exercise on vascular endothelial function and central arterial stiffness, as determined by brachial artery flow-mediated dilation (FMD) and low-flow-mediated constriction (L-FMC), and carotid arterial compliance. Participants, who have no experience of resistance training in the past, performed 1 set of 50 maximal eccentric elbow flexor
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exercise using their non-dominant arm. To determine acute effect of high-intensity eccentric exercise, brachial FMD, L-FMC and carotid arterial compliance were
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measured before and at 45 minutes after the acute exercise. Thus, the independent variables were “pre-exercise (rest) ” and “post-exercise” measurement timing, and the dependent variables were brachial FMD, L-FMC and carotid arterial compliance.
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Subjects
A total of 7 healthy young men (age, 21–28 years) participated in this study. All subjects had led a sedentary lifestyle (no regular physical activity) for at least 1 year
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before the start of the study. To better isolate the effect of acute exercise, those who were prior resistance-trained athletes (i.e., bodybuilder) were excluded. They were normotensive and nonobese, and none of the subjects exhibited signs or symptoms, or had a history of, any chronic diseases. Furthermore, all were non-smokers, and none
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was taking any medications, anabolic steroids, or antioxidant-containing dietary supplements at the time of the study.
The present study was approved by the Ethical Committee of the University of Tsukuba. This study conformed to the principles outlined in the Helsinki Declaration, and all the subjects provided their written informed consent prior to their participation.
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Procedures Study design All subjects had refrained from alcohol and caffeine for at least 12 h, and intense physical activity (exercise) for at least 48 h, prior to the experimental session in order to
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rule out any possible acute effect. The subjects had rested in the supine position for a minimum of 15 min in a quiet, temperature-controlled room (25–26°C). With the
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subject in the supine position, resting brachial blood pressure, heart rate, carotid artery compliance, and brachial endothelial function were measured. After these measurements, blood sampling was performed to determine metabolic risk factors. Each subject then performed eccentric exercise using his non-dominant elbow (15). The pre-exercise
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measurements (brachial blood pressure, heart rate, carotid artery compliance, and brachial endothelial function) were repeated 45 min after exercise.
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Resting blood pressure and heart rate
Systolic and diastolic blood pressures and heart rate were measured in the non-exercised arm with the subject in the supine position using a semi-automated
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system (Dinamap; GE Healthcare, Salt Lake City, UT, USA).
Carotid artery compliance Carotid artery compliance was noninvasively determined using a combination of
ultrasound imaging of a common carotid artery with simultaneous applanation of tonometrically obtained arterial pressure from the contralateral carotid artery, as previously described (36). The common carotid artery diameter was measured from the images derived from an ultrasound machine (EnVisor, Koninklijke Philips Electronics,
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Eindhoven, Netherlands) equipped with a high-resolution (7.5 MHz) linear-array transducer. Cross-sectional compliance was calculated on the basis of the change in the cross-sectional area (dA), local pulse pressure (dP), arterial diameter (D), and the change in arterial diameter (dD) during the heart cycle using the formula cross-sectional
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compliance = dA/dP, and dA was calculated as dA = π × ([(D + dD]/2)2 – π × (D/2)2. The pressure waveforms of the left common carotid artery were recorded with an
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applanation tonometry device (form PWV/ABI; Colin Medical Technology, Komaki, Japan) and calibrated by equating the mean arterial and diastolic blood pressure values of the carotid artery to those of the brachial artery.
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The β-stiffness index provided an index of arterial compliance adjusted for distending pressure, as previously described (36). In brief, the β-stiffness index was calculated using the equation β = In (Ps/Pd)/[(Ds – Dd)/Dd], where Ds and Dd are the
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maximum and minimum inner arterial diameters and Ps and Pd are the highest and lowest blood pressure. All image analyses were performed by the same investigator.
Flow-mediated dilation and low-flow-mediated constriction
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Brachial artery FMD was measured according to guidelines (48) using a novel stereotactic probe-holding device equipped with an edge-tracking system for 2D imaging and pulsed Doppler flow velocimeter for automatic measurement (UNEXEF; Unex Co. Ltd., Japan) as previously described (27). A high-resolution linear artery transducer was coupled to computer-assisted analysis software that used an automated edge detection system for measurement of brachial artery diameter. In brief, the diameter of the non-exercised brachial artery at baseline was measured in place 5–10
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cm proximal to the antecubital fossa by using a 10-MHz linear-array transducer probe. The cuff distal to the measurement site was then inflated to 50 mmHg above systolic blood pressure for 5 min and deflated. The diameter at the same point of the artery was monitored continuously for 3 min following deflation of the cuff, and the maximum
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dilation after deflation was recorded. FMD was calculated as the percent change in the arterial diameter divided by the baseline value at maximal dilation after the cuff
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deflation, or FMD (%) = ([maximal diameter – baseline mean diameter]/baseline mean diameter) × 100.
Generally, L-FMC data were obtained from the cuff occlusion period of FMD
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assessment (18, 20). L-FMC can also be determined after the cuff deflation period because L-FMC persists for period immediately after deflation. Indeed, our lab’s pilot data suggest that subjects’ brachial artery diameters during the cuff occlusion period and
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immediately after cuff deflation were the same. Thus, we measured the brachial artery diameters in the first 10 s after cuff deflation instead of brachial artery diameters of the cuff occlusion period. L-FMC was expressed as the percent change in the arterial diameter over the baseline value at minimal values immediately after cuff deflation, or
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L-FMC (%) = ([minimal diameter immediately after the cuff deflation – baseline mean diameter]/baseline mean diameter) × 100.
Blood biochemical analysis Before blood sampling, the subjects had fasted for at least of 12 h overnight. Fasting serum cholesterol and plasma glucose concentrations were determined using standard enzymatic techniques.
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Eccentric exercise The high-intensity eccentric exercise was based on previous research in which elbow flexor eccentric exercise using a Biodex isokinetic dynamometer (System 3) was
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used (15). The non-dominant arm was selected for exercise to minimize the effects on daily activity. Subjects were seated on the dynamometer chair with the arm supported
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and were stabilized at the waist and chest. Starting with the elbow flexed to 50º and ending at an angle of 170º, each subject performed 1set of 50 maximal eccentric movements of the elbow flexor, at an angular velocity of 120º⋅s−1. Subjects were verbally encouraged to produce a maximal effort to resist extension of the elbow by the
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dynamometer. Subjects were given a 12-s rest between each contraction, during which time the dynamometer arm returned passively to the starting position.
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Statistical analysis
Values are expressed as mean ± SE. Mean differences between pre (rest) and post exercise were examined using a paired t-test. Associations between the change in central arterial stiffness and the change in FMD were determined by Pearson’s correlations. All
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statistical analysis was performed using SPSS Statistical Package Version 11.0 (SPSS Japan, Inc.) with statistical significance set at P < 0.05. Cohen’s d effect sizes were also
calculated to determine the magnitude of change and d ＞ 0.80 was accepted as an
large effect.
RESULTS Subject characteristics are presented in Table 1. Subjects’ mean age was 24 ± 1
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years; height was 171 ± 1 cm; weight was 64 ± 2 kg and body mass index (BMI) was 22.1 ± 0.8. All subjects’ serum lipid and plasma glucose levels were within a clinically normal range. Haemodynamic values before and after exercise are presented in Table 2. There were no changes in systolic blood pressure, diastolic blood pressure, or heart rate
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before and 45 min after eccentric exercise. Figure 1 shows the changes in central arterial stiffness before and 45 min after exercise. Carotid arterial compliance was significantly
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decreased (P < 0.01, effect size = 0.87) and β-stiffness index was significantly increased (P < 0.05, effect size = 0.85) after eccentric exercise (Fig. 1). Brachial FMD was significantly reduced 45 min after eccentric exercise (P < 0.05, effect size = 1.58, Fig. 2). There was no significant difference between brachial L-FMC before and 45 min
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after eccentric exercise (P = 0.295, Table 3). Baseline arterial diameter and minimal diameter immediately after cuff deflation was not altered by eccentric exercise; nor was time to peak (Table 3). However, maximal diameter after cuff deflation was
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significantly reduced after eccentric exercise (P < 0.05, effect size = 0.56, Table 3).
A positive correlation was detected for change in arterial compliance and change in FMD with eccentric exercise (r = 0.779, P < 0.05, Fig. 3A). Similarly, a negative
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correlation was detected for change in β-stiffness index and change in FMD with eccentric exercise (r = -0.891, P < 0.01, Fig. 3B).
DISCUSSION The main finding of this study was a decrease in endothelium-dependent vasodilator function (reduced FMD) with increase in central arterial stiffness after high-intensity eccentric exercise. Furthermore, the decrease in endothelium-dependent
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vasodilator function was associated with an increase in central arterial stiffness. These data suggest that acute high-intensity eccentric exercise increases central arterial stiffness and that this increase is accompanied by a reduction in endothelium-dependent
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vasodilator function.
Previous research has found increased central arterial stiffness with acute
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high-intensity whole-body resistance exercise and resistance exercise training (12, 14, 21, 35). In particular, the increased arterial stiffness following the exercise is associated with upper-limb exercise but not lower-limb exercise (41). Several studies have examined the acute effects of high-intensity upper-limb resistance exercise on arterial
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stiffness (2, 16). DeVan et al. (14) has suggested that the effects of acute resistance exercise on the arterial adaptations appear to be transient, lasting no longer than 1h. Because measurements in previous studies were taken at 15 min or 90 min (these time
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point still have been influenced by elevated blood pressure or an exceeded peak vascular response) (2, 16), the results may have been inappropriate to measure the acute effects of exercise on vascular function. Furthermore, Hellsten et al. (24) have reported that inflammation was significantly increased 45 min after resistance exercise using
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eccentric exercise protocol. Inflammation is associated decrease in endothelial function (19), which is affecting the regulation of arterial stiffness. Therefore, we measured arterial function 45 min after eccentric exercise in the present study, showing that high-intensity upper limb eccentric exercise increases central arterial stiffness without the influence of other factors (elevated blood pressure or an exceeded peak vascular response).
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Endothelial function affects the regulation of arterial stiffness (33, 52). Indeed, it has been reported that NO and ET-1, potent vasodilator and vasoconstrictor substances released from the endothelium, participate in the regulation of arterial stiffness (29, 33, 51). In the present study, we assessed endothelium-dependent vasodilator function by
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concurrently measuring FMD and vasoconstrictor function by measuring brachial L-FMC. There were greater reductions in FMD responses with no changes in L-FMC
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responses after high-intensity eccentric exercise. Moreover, there were strong associations between the change in brachial artery FMD and change in carotid artery stiffness. These results indicate that the decrease in endothelial function caused by decreased endothelium-dependent vasodilator function, not by a change in
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endothelium-dependent vasoconstrictor function, increases arterial stiffness following high-intensity eccentric exercise.
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Previous studies have shown that high-intensity resistance training did not change vascular endothelial function (6, 28, 44). On the other hand, the effects of acute high-intensity resistance exercise on vascular endothelial function are conflicting. Several studies have shown that acute high-intensity resistance exercise in sedentary
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individuals may decrease vascular endothelial function (42, 50). On the one hand, other studies have found acute high-intensity resistance exercise did not alter vascular endothelial function in athletes (42), or increased vascular endothelial function in sedentary individuals or athletes (10, 42, 50). In present study, we demonstrated that acute high-intensity upper-limb eccentric exercise in sedentary men decreases vascular endothelial function. This discrepancy in the current and previous studies may be related to the subject population (e.g., untrained vs. trained), exercise method (upper
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body exercise vs. lower body exercise), and/or exercise muscle contraction (eccentric vs. concentric).
To our knowledge, this is the first study to investigate the responses of both
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endothelial function and central arterial stiffness after high-intensity eccentric exercise. Few studies have reported that acute resistance exercise reduced endothelial function
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(42, 50). However, these studies did not measure endothelial function and arterial stiffness at the same time. In present study, we found that endothelial function decreases after high-intensity upper-limb eccentric exercise and that this reduction was associated with an increase in central arterial stiffness. Thus, it is possible that changes in
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endothelial function could account for the mechanism underlying eccentric exercise-induced increase in arterial stiffness.
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It is not clear why endothelial function is decreased acutely after high-intensity eccentric exercise. Many previous studies have reported that high-intensity eccentric exercise increases blood oxidative stress (8, 17, 31). Eccentric exercise increases free radical production through various pathways, including mitochondrial electron transport,
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ischemia-reperfusion injury, and inflammation (24, 32, 46, 49). In particular, superoxide anions (O2-) can be normally dismutated by superoxide dismutase (SOD) in endothelial cells (37); they also scavenge NO, resulting in the formation of peroxynitrite (45). This reduces considerably the bioavailability of NO (30). Thus, it is possible that increases in oxidative stress and inflammation following eccentric exercise are associated with reduced endothelium-dependent vasodilation.
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The present study had several important limitations. First, L-FMC was assessed immediately after cuff deflation period of FMD assessment. However, our pilot study has confirmed that brachial artery diameters during the cuff occlusion period and immediately after cuff deflation were the same. Thus, we measured the brachial artery
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diameters in the first 10 s after cuff deflation instead of brachial artery diameters of the cuff occlusion period. Second, this study was conducted with a small sample size. Effect
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size was calculated using Cohen’s d for significant results (i.e., central arterial stiffness and FMD) to determine the magnitude for change. We observed large effect sizes for the changes in arterial compliance, β-stiffness index and FMD after eccentric exercise (0.87, 0.85, and 1.58, respectively). Third, we did not include a non-exercising control group.
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Finally, the physiological or clinical significance of our finding is unclear in present study. Furthermore, it is unclear the link between acute and chronic effects of resistance exercise on vascular endothelial function. Further studies as to whether changes in
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vascular endothelial function following eccentric exercise participate in the physiological regulation and/or adaptation after exercise are needed.
In conclusion, in the present study has shown for the first time a significant
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reduction in endothelium-dependent vasodilator function after high-intensity eccentric exercise but no change in endothelium-dependent vasoconstrictor function after the exercise. In addition, central arterial stiffness was increased following high-intensity eccentric exercise, and the decrease in endothelium-dependent vasodilator function was associated with an increase in central arterial stiffness. These results suggest that acute high-intensity eccentric exercise increases central arterial stiffness and that this increase is accompanied by a decrease in endothelial function caused by the reduction of
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endothelium-dependent vasodilation but not by a change in endothelium-dependent vasoconstriction.
PRACTICAL APPLICATIONS
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Resistance exercise has favorable effects on the musculoskeletal system, and recommended by the major national health organizations (e.g., American College of
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Sports Medicine and American Heart Association). Resistance exercise typically incorporates a mixture of concentric, eccentric, and isometric muscle contraction. In particular, eccentric exercise is more effective than concentric exercise to improve muscle strength (25), and often used by athletes and other individuals. This is the first
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study to demonstrate the acute high-intensity eccentric exercise decreases in vascular endothelial function with increasing central arterial stiffness. Although these findings are limited to elbow flexor eccentric exercise, our results indicate that high-intensity
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eccentric exercise may have acute unfavourable cardiovascular effect in young men.
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ACKNOWLEDGEMENTS This work was supported by Grants-in-Aid for Scientific Research 21300234 from Japan Society for the Promotion of Science.
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CONFLICT OF INTEREST The authors have no financial, consultant, institutional, or other relationships that
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might lead to bias or a conflict of interest.
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vivo. Br J Clin Pharmacol 53: 189-192, 2002.
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Figure legends Figure 1. Carotid arterial compliance and β-stiffness index before and after eccentric exercise. **P < 0.01, *P < 0.05. Values are means ± SE.
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Figure 2. Flow-mediated dilation (FMD) before and after eccentric exercise. *P < 0.05.
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Values are means ± SE.
Figure 3. Relationship between endothelium-dependent flow-mediated dilation (FMD)
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and carotid arterial compliance (A), and β-stiffness index (B) from pre to post exercise.
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Subjects characteristics
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Table 1.
n=7
Age, years
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Variable
24 ± 1
Height, cm
171 ± 1
Weight, kg
64 ± 2
22.1 ± 0.8
Total cholesterol, mg/dl
151 ± 11
HDL cholesterol, mg/dl
49 ± 2
LDL cholesterol, mg/dl
90 ± 10
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Body mass index, kg/m2
Triglyceride, mg/dl
84 ± 13
Glucose, mg/dl
90 ± 2
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Values are means ± SE.
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pre
Systolic blood pressure, mmHg
Heart rate, beats/min
108 ± 1
59 ± 1
59 ± 1
55 ± 1
56 ± 1
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Values are means ± SE.
post
105 ± 1
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Diastolic blood pressure, mmHg
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Variable
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Table 2. Hemodynamic parameters before and after eccentric exercise
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pre
Baseline diameter, mm Maximal diameter after cuff deflation, mm low-flow mediated constriction, % Time to peak, sec
post
3.82
±
0.06
3.82 ± 0.06
4.09
±
0.07
3.99 ± 0.06 *
3.72
±
0.07
3.67 ± 0.04
-2.6
±
0.9
-4.1 ± 1.1
42
±
3
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Minimal diameter immediately after cuff deflation, mm
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Variable
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Table 3. Brachial artery structure and function before and after eccentric exercise
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Values are means ± SE. *P < 0.05 vs. pre.
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39 ± 3
