The effects of improved metabolic risk factors on bone turnover markers after 12 weeks of simvastatin treatment with or without exercise.

OBJECTIVE: Emerging evidence supports an association between metabolic risk factors and bone turnover. Statins and exercise independently improve metabolic risk factors; however whether improvements in metabolic risk factor affects bone turnover is unknown. The purpose of the present study was to: 1) evaluate the relationship between metabolic risk factors and bone turnover; and 2) determine if improvements in metabolic risk factors after 12 weeks of statin treatment, exercise or the combination affect bone turnover. METHODS: Fifty participants with ≥2 metabolic syndrome defining characteristics were randomly assigned to one of three groups: statin (STAT: simvastatin, 40 mg/day), exercise (EX: brisk walking and/or slow jogging, 45 minutes/day, 5 days/week), or the combination (STAT+EX). Body composition and whole body bone mineral density were measured with dual energy X-ray absorptiometry. Serum markers of bone formation (bone specific alkaline phosphatase, BAP; osteocalcin, OC), resorption (C-terminal peptide of type I collagen, CTX) and metabolic risk factors were determined. Two-factor (time, group) repeated-measures ANCOVA was used to examine changes of metabolic risk factors and bone turnover. General linear models were used to determine the effect of pre-treatment metabolic risk factors on post-treatment bone turnover marker outcomes. RESULTS: Participants with ≥4 metabolic syndrome defining characteristics had lower pre-treatment OC than those with 3 or fewer. OC was negatively correlated with glucose, and CTX was positively correlated with cholesterol. STAT or STAT+EX lowered total and LDL cholesterol. The OC to CTX ratio decreased in all groups with no other significant changes in bone turnover. Higher pre-treatment insulin or body fat predicted a greater CTX reduction and a greater BAP/CTX increase. CONCLUSION: Metabolic risk factors were negatively associated with bone turnover markers. Short-term statin treatment with or without exercise lowered cholesterol and all treatments had a small effect on bone turnover.

Effect of aging on carotid baroreflex control of blood pressure and leg vascular conductance in women.

Recent work suggests that ß-adrenergic vasodilation offsets α-adrenergic vasoconstriction in young women, but this effect is lost after menopause. Given these age-related vascular changes, we tested the hypothesis that older women would exhibit a greater change in vascular conductance following baroreflex perturbation compared with young women. In 10 young (21 ± 1 yr) and 10 older (62 ± 2 yr) women, mean arterial pressure (MAP; Finometer), heart rate (HR), cardiac output (CO; Modelflow), total vascular conductance (TVC), and leg vascular conductance (LVC, duplex-Doppler ultrasound) were continuously measured in response to 5-s pulses of neck suction (NS; -60 Torr) and neck pressure (NP; +40 Torr) to simulate carotid hypertension and hypotension, respectively. Following NS, decreases in MAP were similar between groups; however, MAP peak response latency was slower in older women (P < 0.05). Moreover, at the time of peak MAP, increases in LVC (young, -11.5 ± 3.9%LVC vs. older, +19.1 ± 7.0%LVC; P < 0.05) and TVC were greater in older women, whereas young women exhibited larger decreases in HR and CO (young, -10 ± 3% CO vs. older, +0.8 ± 2% CO; P < 0.05). Following NP, increases in MAP were blunted (young, +14 ± 1 mmHg vs. older, +8 ± 1 mmHg; P < 0.05) in older women, whereas MAP response latencies were similar. Interestingly, decreases in LVC and TVC were similar between groups, but HR and CO (young, +7.0 ± 2% CO vs. older, -4.0 ± 2% CO; P < 0.05) responses were attenuated in older women. These findings suggest that older women have greater reliance on vascular conductance to modulate MAP via carotid baroreflex, whereas young women rely more on cardiac responsiveness. Furthermore, older women demonstrate a blunted ability to increase MAP to hypotensive stimuli.

Impact of reduced daily physical activity on conduit artery flow-mediated dilation and circulating endothelial microparticles.

Physical inactivity promotes the development of cardiovascular diseases. However, few data exist examining the vascular consequences of short-term reductions in daily physical activity. Thus we tested the hypothesis that popliteal and brachial artery flow-mediated dilation (FMD) would be reduced and concentrations of endothelial microparticles (EMPs) would be elevated following reduced daily physical activity. To examine this, popliteal and brachial artery FMD and plasma levels of EMPs suggestive of apoptotic and activated endothelial cells (CD31(+)/CD42b(-) and CD62E(+) EMPs, respectively) were measured at baseline and during days 1, 3, and 5 of reduced daily physical activity in 11 recreationally active men (25 ± 2 yr). Subjects were instructed to reduce daily physical activity by taking <5,000 steps/day and refraining from planned exercise. Popliteal artery FMD decreased with reduced activity (baseline: 4.7 ± 0.98%, reduced activity day 5: 1.72 ± 0.68%, P < 0.05), whereas brachial artery FMD was unchanged. In contrast, baseline (pre-FMD) popliteal artery diameter did not change, whereas brachial artery diameter decreased (baseline: 4.35 ± 0.12, reduced activity day 5: 4.12 ± 0.11 P < 0.05) following 5 days of reduced daily physical activity. CD31(+)/CD42b(-) EMPs were significantly elevated with reduced activity (baseline: 17.6 ± 9.4, reduced activity day 5: 104.1 ± 43.1 per µl plasma, P < 0.05), whereas CD62E(+) EMPs were unaltered. Collectively, our results provide evidence for the early and robust deleterious impact of reduced daily activity on vascular function and highlight the vulnerability of the vasculature to a sedentary lifestyle.

Simvastatin impairs exercise training adaptations.

OBJECTIVES: This study sought to determine if simvastatin impairs exercise training adaptations. BACKGROUND: Statins are commonly prescribed in combination with therapeutic lifestyle changes, including exercise, to reduce cardiovascular disease risk in patients with metabolic syndrome. Statin use has been linked to skeletal muscle myopathy and impaired mitochondrial function, but it is unclear whether statin use alters adaptations to exercise training. METHODS: This study examined the effects of simvastatin on changes in cardiorespiratory fitness and skeletal muscle mitochondrial content in response to aerobic exercise training. Sedentary overweight or obese adults with at least 2 metabolic syndrome risk factors (defined according to National Cholesterol Education Panel Adult Treatment Panel III criteria) were randomized to 12 weeks of aerobic exercise training or to exercise in combination with simvastatin (40 mg/day). The primary outcomes were cardiorespiratory fitness and skeletal muscle (vastus lateralis) mitochondrial content (citrate synthase enzyme activity). RESULTS: Thirty-seven participants (exercise plus statins: n = 18; exercise only: n = 19) completed the study. Cardiorespiratory fitness increased by 10% (p < 0.05) in response to exercise training alone, but was blunted by the addition of simvastatin resulting in only a 1.5% increase (p < 0.005 for group by time interaction). Similarly, skeletal muscle citrate synthase activity increased by 13% in the exercise-only group (p < 0.05), but decreased by 4.5% in the simvastatin-plus-exercise group (p < 0.05 for group-by-time interaction). CONCLUSIONS: Simvastatin attenuates increases in cardiorespiratory fitness and skeletal muscle mitochondrial content when combined with exercise training in overweight or obese patients at risk of the metabolic syndrome. (Exercise, Statins, and the Metabolic Syndrome; NCT01700530).

Disturbed blood flow acutely induces activation and apoptosis of the human vascular endothelium.

There is strong and consistent evidence from in vitro studies that disturbed blood flow produces a proatherogenic vascular endothelial phenotype. However, data from human studies are lacking. To address this, a 220 mm Hg occlusion cuff was placed on the distal forearm of 10 young, healthy men to induce a localized region of disturbed blood flow in the proximal vasculature for 20 minutes. We hypothesized that disturbed blood flow would induce endothelial activation and apoptosis as indicated by increases in local concentrations of CD62E(+) and CD31(+)/CD42b(-) endothelial microparticles, respectively. Distal cuff occlusion induced reductions in mean blood flow, mean shear, and antegrade shear, and increases in retrograde flow, retrograde shear, and oscillatory shear stress, confirming that our protocol produced a disturbed blood flow stimulus in the experimental arm. Relative to baseline (0 minutes), CD62E(+) endothelial microparticles increased by ≈3-fold at 10 minutes and ≈4-fold at 20 minutes in the experimental arm (P<0.05). CD31(+)/CD42b(-) endothelial microparticles were elevated by ≈9-fold at the 20 minutes time point (P<0.05). There were no changes in the concentrations of either endothelial microparticle population throughout the experiment in the contralateral arm, exposed to normal resting blood flow (no cuffs). These findings indicate that disturbed blood flow acutely induces endothelial activation and apoptosis in humans, as reflected by release of microparticles from activated (CD62E(+)) and apoptotic (CD31(+)/CD42b(-)) endothelial cells. These data provide the first in vivo experimental evidence of disturbed blood flow-induced endothelial injury in humans.

Seven days of aerobic exercise training improves conduit artery blood flow following glucose ingestion in patients with type 2 diabetes.

The vasodilatory effects of insulin account for up to 40% of insulin-mediated glucose disposal; however, insulin-stimulated vasodilation is impaired in individuals with type 2 diabetes, limiting perfusion and delivery of glucose and insulin to target tissues. To determine whether exercise training improves conduit artery blood flow following glucose ingestion, a stimulus for increasing circulating insulin, we assessed femoral blood flow (FBF; Doppler ultrasound) during an oral glucose tolerance test (OGTT; 75 g glucose) in 11 overweight or obese (body mass index, 34 ± 1 kg/m²), sedentary (peak oxygen consumption, 23 ± 1 ml·kg⁻¹·min⁻¹) individuals (53 ± 2 yr) with non-insulin-dependent type 2 diabetes (HbA1c, 6.63 ± 0.18%) before and after 7 days of supervised treadmill and cycling exercise (60 min/day, 60-75% heart rate reserve). Fasting glucose, insulin, and FBF were not significantly different after 7 days of exercise, nor were glucose or insulin responses to the OGTT. However, estimates of whole body insulin sensitivity (Matsuda insulin sensitivity index) increased (P < 0.05). Before exercise training, FBF did not change significantly during the OGTT (1 ± 7, -7 ± 5, 0 ± 6, and 0 ± 5% of fasting FBF at 75, 90, 105, and 120 min, respectively). In contrast, after exercise training, FBF increased by 33 ± 9, 39 ± 14, 34 ± 7, and 48 ± 18% above fasting levels at 75, 90, 105, and 120 min, respectively (P < 0.05 vs. corresponding preexercise time points). Additionally, postprandial glucose responses to a standardized breakfast meal consumed under "free-living" conditions decreased during the final 3 days of exercise (P < 0.05). In conclusion, 7 days of aerobic exercise training improves conduit artery blood flow during an OGTT in individuals with type 2 diabetes.

The effects of whole body vibration and exercise on fibrinolysis in men.

Whole body vibration (WBV) is a novel modality that has been demonstrated to enhance muscular and cardiovascular functions reported to increase fibrinolytic activity. The purpose of this study was to examine the fibrinolytic response to WBV and exercise in men. Twenty healthy males (23.8 ± 0.9 years, 25.6 ± 0.2 kg m(-2)) participated in the study. Each subject performed three trials in randomized order separated by 1 week: exercise (X), vibration (V) and vibration + exercise (VX). Exercise sessions consisted of 15 min of unloaded squatting at a rate of 20 per minute. Vibration sessions were conducted on a WBV platform vibrating for 15 min. Tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) were assessed at baseline and immediately after each condition. The increase in tPA activity was significantly greater in VX (0.87 ± 0.35 to 3.21 ± 1.06 IU ml(-1)) compared to X (0.71 ± 0.36 to 2.4 ± 1.13 IU ml(-1)) or V (0.83 ± 0.25 to 1.00 ± 0.37 IU ml(-1)) conditions, and greater in the X condition compared to the V condition. PAI-1 activity decreased significantly more in the VX (6.54 ± 5.53 to 4.89 ± 4.13 IU ml(-1)) and X (9.76 ± 8.19 to 7.48 ± 7.11 IU ml(-1)) conditions compared to the V (5.68 ± 3.53 to 5.84 ± 3.52 IU ml(-1)) condition. WBV does not augment fibrinolytic activity in healthy men. However, WBV combined with squatting exercise increases fibrinolytic activity more than exercise alone.