Impaired endothelial function has been implicated as an initial step in the pathogenesis of atherosclerosis and accelerated risk of cardiovascular disease (CVD) (15,17,26). Overweight individuals commonly demonstrate impairment of endothelial function, and obesity is thus considered a strong link between impaired endothelial function and the development of atherosclerosis in men and women (1,2,12).
Increased intimamedia thickness (IMT) of the carotid artery is closely related to the severity of atherosclerotic changes associated with CVD (13). There is a significant relationship between elevated IMT and the presence of traditional risk factors for CVD, including age, body mass index (BMI), hypertension, low-density lipoprotein (LDL) cholesterol, blood pressure, diabetes, and cigarette smoking (9). Further, carotid artery IMT, a better predictor of risk for CVD than carotid artery distensibility (19), is associated with the severity of obesity and distribution of body fat, particularly in middle-aged overweight women (5).
Regular aerobic physical activity has long been associated with reduced risk of CVD morbidity and mortality (28). Numerous studies have demonstrated the positive effect of aerobic exercise on risk factors for CVD, including blood lipids (20), blood pressure and insulin resistance (6), type 2 diabetes, and obesity (29). Aerobic exercise also has proven to be effective for improving arterial endothelial function in healthy low-risk individuals (24), those with risk factors for CVD (11), and individuals with known established CVD (10). However, mixed results have been reported regarding the ability of aerobic exercise to augment elevated IMT or attenuate age-related increases in IMT (5,9). A recent study conducted by Miyachi et al. (23) examined the effect of 4 months of resistance training on central and peripheral arterial compliance and carotid artery IMT. These investigators reported that resistance training induced a reduction in central, but not peripheral, arterial compliance, with no effect on carotid artery IMT in healthy young and middle-aged men.
Although resistance training is recommended as an integral component of an overall cardiorespiratory and muscular fitness program (16), to our knowledge, no previous studies have examined the effect of resistance training alone on vascular function in women, and only one study examined its effect on carotid artery IMT specifically in young healthy men (23). It is currently understood that aerobic training significantly elevates blood flow under relatively moderate pressure for prolonged periods of time, creating significant shear stress on the endothelial cell layer of an artery (24). This elevation in flow triggers nitric oxide production and release, resulting in subsequent vasodilation. Resistance training, conversely, elevates blood flow for short periods of time under much higher pressure and thus poses an alternative type of stress stimulus on the endothelial cells. Furthermore, this combination of shear stress and perpendicular force may act to alter the structural composition of the arterial wall, which may be reflected through altered carotid artery IMT. The purpose of the present study was, therefore, to determine the effectiveness of 1 yr of resistance training on vascular structure and function in otherwise healthy overweight young and middle-aged women. We hypothesized that resistance training would improve arterial structure and function as assessed by carotid artery IMT and flow-mediated dilation of the brachial artery in this population.
Thirty overweight (BMI > 25 kg·m−2) premenopausal women aged 24-44 yr from the Minneapolis/St. Paul metropolitan area volunteered to participate in this study. Inclusion criteria included no positive responses on the physical activity readiness questionnaire; sedentary (three or fewer physical activity sessions per week of no greater intensity than brisk walking) with no history of resistance training (RT) in the past 6 months; not participating or planning to enroll in a formal weight loss program during the study period; stable body weight (<10% body weight change over the past year); no medical conditions or use of medications that could alter study results (including cholesterol-lowering medications, psychiatric medications at dosages known to alter weight, appetite suppressants, contraceptive or hormone replacement medications); not currently or recently (past 6 months) pregnant; not currently or recently (past 2 months) lactating; no history of physician-diagnosed menstrual irregularities, significant gynecological conditions or peri/postmenopausal status; blood pressure less than stage 1 hypertension (< 160/99 mm Hg) and not currently or recently (past 6 months) taking hypertensive medications;nonsmoker (past 2 yr); nonhyperlipidemic (total cholesterol < 200 and triglycerides < 174 mg·dL−1) and normoglycemic (fasting glucose < 100 mg·dL−1); and no history of cancer (past 5 yr). After enrollment, participants were randomly assigned to either a control or a RT group. Randomization was stratified and balanced by age range (25-34 and 35-44 yr) and baseline body fat percentage (balanced within recruitment waves). All participants enrolled in this study gave written informed consent after being provided a description of the study's requirements. The protocol was approved by the University of Minnesota institutional review board and was in accordance with institutional and HIPAA guidelines.
All measurements were performed in the morning after a 12-h overnight fast and at least 48 h after the last exercise session. Body composition was measured by dual energy x-ray absorptiometry (DXA) (Prodigy, 3M, Madison, WI; software version 6.7). The total body scans were performed using a fast transverse speed mode for a duration of approximately 10-15 min. The scanner was calibrated monthly with known phantoms, and no machine drift was noted during the period of the study. Height and weight were measured by a standard wall stadiometer and medical beam scale, respectively. BMI was calculated as weight in kilograms divided by the square of height in meters. Venous blood was drawn from an antecubital vein into chilled tubes containing EDTA. Plasma was separated by centrifugation at 4°C for measurement of glucose, triglycerides (TG), total cholesterol (total-C), low-density lipoproteins (LDL-C), and high-density lipoproteins (HDL-C) by standard colorimetric reflectance spectrophotometry. Insulin sensitivity was calculated using the homeostasis model of assessment for insulin resistance (HOMA-IR) equation of Mathews et al. (22). All blood assays were conducted at Fairview Diagnostics Laboratories, Fairview-University Medical Center (Minneapolis, Minnesota) a U.S. Centers for Disease Control and Prevention-certified laboratory. Systolic blood pressure (SBP) and diastolic blood (DBP) pressure were measured in the morning at baseline and at follow-up by a standard manual sphygmomanometer and cuff method: in a seated position three times, after 5 min of rest, with 1 min between measurements; these measurements were reported as the mean of the last two measurements. Mean arterial blood pressure (MABP) was calculated as mean DBP plus one third of the difference between mean SBP and mean DBP.
Vascular structure and function measurements were conducted in a quiet, temperature-controlled environment in the general clinical research center at least 72 h prior to or after completion of menstruation to avoid confounding by menstrual cycle hormonal fluctuations (12). Vascular images were obtained using a conventional ultrasound scanner (Image Point Hx, Philips Medical, Andover, MA) with a 7.5-MHz linear array transducer held in place by a stereotactic device. This system is interfaced with a standard personal computer equipped with a data acquisition card for attainment of radio frequency ultrasound signals from the scanner. All arterial images were triggered and captured at the R wave of the electrocardiogram (end-diastolic diameter), then digitized and stored on a personal computer for later offline analysis using electronic wall-tracking software (CVI, Information Integrity, Boston, MA). Digital image analysis was performed by the same trained reader, who was blinded to group assignments.
The diameter and intimamedia thickness (IMT) of the carotid artery was measured approximately 5-11 cm proximal to the carotid bulb over a period of 10 s while the subject rested in the supine position with the head rotated 45° from neutral. Individual differences in carotid artery lumen diameter were accounted for by calculating the IMT/lumen ratio. Cross-sectional area of the carotid artery wall (WCSA) was calculated using the formula of Linhart et al. (19).
Assessment of flow-mediated endothelial-dependent dilation (FMD) was performed by imaging the left brachial artery at the distal third of the upper arm using techniques previously described in our laboratory and by others (3,14). After measuring resting artery diameter, a blood pressure cuff was inflated below the elbow (distal to imaged artery segment) to a pressure of 200 mm Hg maintained for 5 min to induce muscle ischemia. Brachial artery diameter was measured continuously for a 3-min period immediately after cuff release during reactive hyperemia to determine peak percent dilation (peak FMD) and FMD area under the curve (FMD AUC) in relation to initial artery diameter.
After a 15-min rest, 0.4 mg of sublingual nitroglycerin was administered, and the diameter of the brachial artery was remeasured (three times) at 3 min postadministration. Nitroglycerine-mediated endothelial-independent dilation (EID) was defined as the percent change from resting baseline to the average of the three post-NTG brachial artery diameters. Interindividual transducer placement matching between baseline and follow-up measurements for the carotid artery was assured through measurement between the transducer and specific external anatomical landmarks as well as the image relationship with the carotid bulb. The interindividual transducer placement matching between the baseline and follow-up measurements for the brachial artery was assured through measurement between the transducer and specific external anatomical landmarks as well as comparison of resting arterial diameters. Reproducibility of the IMT and FMD techniques in our laboratory have shown mean differences of 0.02 ± 0.03 and 0.39 ± 0.65%, respectively, for analysis separated by 1 wk in healthy young adults.
At baseline, each participant underwent a maximal strength test for the bench and leg press to assess the maximum amount of weight that can be lifted one time (1RM) (8). After a 4- to 8-min warm-up by treadmill walking and familiarization with the bench and leg press equipment and techniques, participants rated the difficulty (on a scale of 1-10, with 10 being the most difficult) of a warm-up set of four to six repetitions (reps) of 30 and 40 lb, respectively. The difficulty rating was used to determine the initial weight at which the 1RM test was attempted and weight was added until the perceived difficulty rating reached 10. At least 48 h later, following the same warm-up, the participants performed repeated single lifts (separated by 90 s of rest), beginning with the maximum weight achieved at the prior visit and continuing until a 1RM weight was achieved. Percentages of the 1RM were used to determine the weight used for initiating each individual's training program. All measurements and strength assessments were repeated after 1 yr of RT.
Participants in both groups were asked not to intentionally alter their dietary habits for the purpose of weight change. Participants who reported current participation in some regular physical activity at baseline were asked to continue their usual activities for the duration of the intervention period, regardless of group assignment. For ethical considerations, control participants were offered "Walking for a Healthy Heart-Our Guide to Help you Start a Regular Walking Program" and "Exercise and Your Heart-A Guide to Physical Activity," brochures from the American Heart Association that reflected current standard clinical practice recommendations, but they were not given further instruction.
The 1-yr RT program consisted of at least two training sessions per week with at least 48 h between sessions. Each training session began with a warm-up on a treadmill, cycle ergometer, elliptical trainer, stepper, or by walking on a track for approximately 5 min, followed by deep abdominal and lower-back exercises for core stability and injury prevention. Following the warm-up, three sets of 8-10 repetitions were performed using isotonic variable-resistance machines and free weights targeting the following major muscle groups: quadriceps, hamstrings, gluteals, pectorals, latissimus dorsi, rhomboids, deltoids, biceps, and triceps.
The protocol for progression of weight on each exercise was as follows: after two sessions in which a participant lifted the same weight for two sets of 10 reps and a third set of 12 reps, the weight was increased by the smallest increment. During the next training session, if the higher weight could be lifted at least eight times on the first set and six times on the second set, the weight was maintained, and an additional set was attempted. If at least eight and six repetitions were not accomplished on the first and second sets, respectively, the training weight was reduced to the amount lifted at the previous session. For the first 16 wk, the resistance training sessions were supervised by a certified fitness specialist in small groups of five participants. Thereafter, participants completed the RT protocol on their own while meeting twice every 12 wk with the fitness trainer. Participants were provided recording logs and taught to record the exercise type, weight lifted, and number of repetitions and sets completed. Exercise logs were reviewed twice monthly by study staff to ensure participant compliance to the protocol.
All statistical analysis and graphic presentation was accomplished using Graphpad Prism® (v 4.0, San Diego, CA). The number needed to treat for 95% power to detect statistical significance at an alpha level of 0.05 was calculated to be 12 participants in the RT group. Analysis of variance (ANOVA) with repeated measures was used to compare groups before and after the 1-yr intervention. Bonferroni's post hoc analysis was applied when the ANOVA interaction term was significant. All data are presented as mean ± standard error of the mean (SEM). Statistical significance was set at an alpha level of 0.05 for all analyses.
The RT group completed an average of 93 ± 3 out of 104 (90%) resistance training sessions. There were no significant differences between the two groups at baseline for 1RM bench press or 1RM leg press. Following 1 yr of resistance training, there was a significant difference in the RT group time trend for 1RM bench press compared with the control group (P = 0.04), with a significant increase in weight lifted in the RT group and no significant change in the control group (RT group = 37.9 ± 1.5 vs 41.2 ± 1.7 kg, P = 0.01; control group = 37.9 ± 2.2 vs 37.1 ± 1.9 kg). The time by group interaction for 1RM leg press (RT group = 123.9 ± 4.9 vs 142.7 ± 7.4 kg; control group = 121.3 ± 7.7 vs 137.6 ± 8.4 kg, P = 0.72) was not statistically significant.
At baseline, there were no significant differences between the two groups for any measure of body weight and composition or resting blood pressure levels (Table 1). Also, there were no significant differences between the groups observed over the 1-yr RT period for changes in weight, BMI, fat mass, percent body fat, SBP, DBP, or MABP. However, there was a significant improvement in LBM for the RT group compared with the control group (P = 0.04) (Table 1).
There were no significant differences between the two groups at baseline for fasting blood lipids, glucose, or insulin levels (Table 2), and there were no significant changes over the 1-yr RT period in plasma total-C, LDL-C, HDL-C, triglycerides, glucose, or insulin in either group (Table 2). There was no significant difference between the two groups at baseline for HOMA-IR, nor was there a training effect on HOMA-IR.
Between-group analysis demonstrated no significant difference at baseline for the measures of carotid artery structure and brachial artery endothelial function (Table 3). There were no time by group effects for resting brachial artery diameter or EID (Table 3, Figs. 1A and 1B). There also were no significant changes for IMT, IMT/lumen ratio, or WCSA (Table 3). However, there was a significant time by group interaction was observed for increase in mean peak FMD with post hoc analysis, demonstrating a significant increase in the intervention group (Table 3, Fig. 1C). Also, there was a trend towards change for the FMD AUC, with a slight decrease in the control group and an increase in the intervention group (Table 3).
To our knowledge, this is the first randomized controlled study examining the impact of resistance training alone on vascular structure and function in overweight women. The results of this study indicate that 1 yr of resistance training improves brachial artery endothelial function in our study population. These results suggest that resistance training improves FMD of the brachial artery in otherwise healthy but sedentary, overweight, young and middle-aged women. Improved arterial endothelial function was observed independent of changes in major CVD risk factors, including BMI, body composition, blood pressure, fasting blood lipids, and fasting blood glucose or insulin.
It has been previously demonstrated that endothelial function is impaired in overweight and obese men and women (1,2) independent of other risk factors for CVD. For example, Arcaro et al. (1) examined the relationship between FMD-determined endothelial function of the femoral artery and degree of adiposity and reported that the extent of impaired endothelial function could be predicted by the severity of obesity independent of body weight and other metabolic and hemodynamic indices. Further, Brook et al. (2) demonstrated that the body fat distribution measure of waist-to-hip ratio was a powerful predictor of brachial artery endothelial dysfunction assessed by FMD in both obese men and women.
Investigators also have shown that aerobic exercise, including circuit training, is an effective intervention to improve endothelial function in a variety of populations atincreased risk for CVD or with documented CVD (10,11,18,21). The present study involved participants who were overweight but who did not have other traditional major risk factors for CVD, which limited potential confounding of the results by changes in the risk factor profile. Complementary to this, Green et al. (10) examined whether improvements in vascular function with aerobic-based circuit training were associated with the reduction of risk factors affecting endothelial dysfunction in a wide range of populations at risk for CVD. These investigators failed to observe a relationship between changes in risk factors for CVD and improvement in either conduit artery or resistance artery function as measured by FMD or strain-gauge plethysmography, respectively (10). Their findings are consistent with the hypothesis that aerobic training may improve vascular function and potentially reduce CVD risk independently through the direct effects of recurrent hemodynamic changes associated with increased arterial wall laminar shear stress (24). The results of the present study are consistent with those of Green et al. (10) in that we found a significant improvement in FMD as a result of resistance training without significant changes in other risk factors for CVD that have been shown to potentially affect vascular function (i.e., body composition, blood lipids, glucose, and blood pressure levels). In contrast, Cortez-Cooper et al. (4) have recently demonstrated that 11 wk of high-intensity resistance training in young healthy women results in a significant increase of arterial stiffness. Interestingly, although the authors report a significant increase in the augmentation index of the carotid artery, both the resistance training and controls groups demonstrated a significant increase in the carotid-femoral pulse-wave velocity, with a greater increase in the control group compared with the resistance training participants. With this, there was no change in the heart-femoral pulse-wave velocity, and a slight but nonsignificant reduction in the femoral-ankle pulse-wave velocity. These results suggest primary differences in the arterial segments under investigation, with a negative impact of resistance training on the more centralized segments and a potential (although not statistically significant) benefit to the peripheral segments. The disparate results of Cortez-Cooper and colleagues and those of the present study may be a consequence of the structural or functional physiologic differences of the arterial segments under investigation, or they may simply represent differences between the populations being studied and interventions used; thus, the specific mechanisms underlying these differences remain unclear, and further investigation is warranted.
Obesity is associated with increased carotid IMT, specifically in middle-aged women (5). A number of cross-sectional studies have examined the association between varying levels of physical activity and fitness with femoral and carotid artery IMT. These studies have demonstrated mixed results, indicating either an increase (25), no change (7,27), or a decrease in femoral and carotid artery IMT (7,9) in association with various types of regular physical activity. However, only a limited number of studies (7,27) have examined the ability of exercise to attenuate the development of increased IMT of the carotid artery. In a cross-sectional study in men, Tanaka et al. (27) found no apparent reduction of the age-related increase in IMT associated with self-reported previous training experience. The authors followed this observational study with a 3-month aerobic training intervention in middle-aged and older sedentary men and found no training-induced change in carotid artery IMT. These findings are in agreement with those of Dinenno et al. (7), who demonstrated no change in carotid artery IMT after a 3-month aerobic training program in healthy middle-aged and older men despite a significant reduction in femoral artery IMT. Thus, it has been postulated that the age-associated structural alterations in the walls of central arteries represent developmentally advanced atherosclerosis such that the more rigid arteries are less amenable to exercise-induced alterations in shear stress.
To date, only one previous study has examined the effect of resistance training on carotid artery IMT. Miyachi et al. (23) reported that 4 months of resistance training in young and middle-aged men significantly reduced central arterial compliance without affecting peripheral femoral artery compliance or carotid artery IMT. These authors ruled out the possibility of structural remodeling and elevated sympathetic adrenergic vasoconstrictive tone as potential mechanisms for the reduction in arterial compliance, noting that there was no change in carotid artery IMT or IMT/lumen ratio and no change in the compliance of the highly muscular peripheral femoral artery, respectively. Although the present study was not designed to delineate the specific mechanisms of change, our findings do indicate that the endothelial response to reactive hyperemia is enhanced by 1 yr of resistance training with no change in the carotid artery IMT or IMT/lumen ratio. The differences in our findings from those of Miyachi et al. (23) may be indicative of complex interactions of mechanical (pressure or shear stress induced), neurohormonal (sympathetic-parasympathetic balance), or other humoral (oxidative stress, inflammation, and adhesion) pathways, or they may represent a difference in functional properties of large elastic central and medium-sized muscular peripheral arteries and their response to exercise and/or exercisen modality. Further, without a lean control group as a comparison, it remains a possibility that the women in our cohort demonstrated relatively normal levels of IMT prior to beginning the RT program and, as such, would not have had reason for improvement. Importantly, however, although this RT program does not significantly improve IMT, our data also do not suggest a negative influence of this training program on IMT. In summation, our results confirm those of others and suggest that in sedentary, overweight, but otherwise healthy young and middle-aged eumenorrheic women, resistance training does not significantly alter carotid artery IMT.
Importantly, a potential limitation to this study is the lack of intermediate follow-up testing during the course of our RT program. Follow-up testing at specific intervals (e.g., bimonthly or quarterly) would have provided valuable information regarding the acute versus chronic effects of RT on vascular structure and function. Further, the use of self-reported training logs is also a potential limitation. This limitation could partially explain the relatively minor changes in leg press strength. However, it is currently understood that a primary barrier to physical activity training programs in this population appears to be the motivation of participants to go to an exercise facility. Because the training logs were kept at the exercise facility, the participants met with fitness specialists regularly during the first 16 wk and every 6 wk thereafter to review the training logs; given the result of a significant increase in bench press strength, we have no reason to believe that the information provided in the training logs was inaccurate.
To our knowledge, this is the first investigation to examine the relationship between resistance training and vascular structure and function in overweight women. The results of this study suggest that 1 yr of resistance training, although not affecting carotid artery IMT, can improve peripheral artery endothelial function, measured by flow-mediated dilation of the brachial artery, in overweight women. These data provide insight and further the rational for inclusion of resistance training as a nonpharmacologic modality to enhance endothelial function in overweight women. Because of the narrow population and relatively small sample size of this study, additional research using resistance training is warranted to confirm our results.
This study was supported financially in part by the National Institutes of Health grant #: 5R01DK060743-03, American Heart Association grant #: 0410034Z and General Clinical Research Center Program, NCRR/NIH #: M01-RR00400.
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