Daniel P. Credeur

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.

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.

Impact of prolonged sitting on lower and upper limb micro‐ and macrovascular dilator function

What is the central question of this study? The prevalence of sedentary behaviour in the workplace and increased daily sitting time have been associated with the development of cardiovascular disease; however, studies investigating the impact of sitting on vascular function remain limited. What is the main finding and its importance? We demonstrate that there is a marked vulnerability of the vasculature in the lower and upper limbs to prolonged sitting and highlight the importance of physical activity in restoring vascular function in a limb‐specific manner.

Effects of Handgrip Training With Venous Restriction on Brachial Artery Vasodilation

UNLABELLED Previous studies have shown that resistance training with restricted venous blood flow (Kaatsu) results in significant strength gains and muscle hypertrophy. However, few studies have examined the concurrent vascular responses following restrictive venous blood flow training protocols. PURPOSE The purpose of this study was to examine the effects of 4 wk of handgrip exercise training, with and without venous restriction, on handgrip strength and brachial artery flow-mediated dilation (BAFMD). METHODS Twelve participants (mean +/- SD: age = 22 +/- 1 yr, men = 5, women = 7) completed 4 wk of bilateral handgrip exercise training (duration = 20 min, intensity = 60% of the maximum voluntary contraction, cadence = 15 grips per minute, frequency = three sessions per week). During each session, venous blood flow was restricted in one arm (experimental (EXP) arm) using a pneumatic cuff placed 4 cm proximal to the antecubital fossa and inflated to 80 mm Hg for the duration of each exercise session. The EXP and the control (CON) arms were randomly selected. Handgrip strength was measured using a hydraulic hand dynamometer. Brachial diameters and blood velocity profiles were assessed, using Doppler ultrasonography, before and after 5 min of forearm occlusion (200 mm Hg) before and at the end of the 4-wk exercise. RESULTS After exercise training, handgrip strength increased 8.32% (P = 0.05) in the CON arm and 16.17% (P = 0.05) in the EXP arm. BAFMD increased 24.19% (P = 0.0001) in the CON arm and decreased 30.36% (P = 0.0001) in the EXP arm. CONCLUSIONS The data indicate handgrip training combined with venous restriction results in superior strength gains but reduced BAFMD compared with the nonrestricted arm.

The role of α-adrenergic receptors in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man

•  Sympathetic support of blood pressure demands the efficient control of vascular tone; however, little is known regarding how spontaneously occurring bursts of muscle sympathetic nerve activity (MSNA) dynamically influence forearm vascular conductance. •  This study examined the extent to which spontaneous MSNA bursts evoke changes in forearm vascular conductance and blood pressure with and without local α‐adrenergic blockade in young healthy men during supine rest. •  We observed that under resting conditions, forearm vascular conductance increases briefly and then significantly decreases in association with the total amount of the preceding MSNA; however, during α‐adrenergic blockade the decrease in vascular conductance is eliminated. •  These results indicate that normal variations in spontaneous MSNA burst activity are systematically followed by transient and robust responses of forearm vasoconstriction and that this influence is mediated via α‐adrenergic receptor mechanisms.

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

Recent work suggests that β-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.

Characterizing rapid-onset vasodilation to single muscle contractions in the human leg

Rapid-onset vasodilation (ROV) following single muscle contractions has been examined in the forearm of humans, but has not yet been characterized in the leg. Given known vascular differences between the arm and leg, we sought to characterize ROV following single muscle contractions in the leg. Sixteen healthy men performed random ordered single contractions at 5, 10, 20, 40, and 60% of their maximum voluntary contraction (MVC) using isometric knee extension made with the leg above and below heart level, and these were compared with single isometric contractions of the forearm (handgrip). Single thigh cuff compressions (300 mmHg) were utilized to estimate the mechanical contribution to leg ROV. Continuous blood flow was determined by duplex-Doppler ultrasound and blood pressure via finger photoplethysmography (Finometer). Single isometric knee extensor contractions produced intensity-dependent increases in peak leg vascular conductance that were significantly greater than the forearm in both the above- and below-heart level positions (e.g., above heart level: leg 20% MVC, +138 ± 28% vs. arm 20% MVC, +89 ± 17%; P < 0.05). Thigh cuff compressions also produced a significant hyperemic response, but these were brief and smaller in magnitude compared with single isometric contractions in the leg. Collectively, these data demonstrate the presence of a rapid and robust vasodilation to single muscle contractions in the leg that is largely independent of mechanical factors, thus establishing the leg as a viable model to study ROV in humans.

Acute inactivity impairs glycemic control but not blood flow to glucose ingestion.

PURPOSE Insulin-stimulated increases in skeletal muscle blood flow play a role in glucose disposal. Indeed, 7 d of aerobic exercise in patients with Type 2 diabetes increased blood flow responses to an oral glucose tolerance test (OGTT) and improved insulin sensitivity. More recent work suggests that reduced daily physical activity impairs glycemic control (GC) in healthy individuals. Herein, we sought to determine whether an acute reduction in daily activity (from >10,000 to <5000 steps per day) for 5 d (RA5) in healthy individuals reduced insulin-stimulated blood flow and GC in parallel and if a 1-d return to activity (RTA1) improved these outcomes. METHODS OGTT were performed as a stimulus to increase insulin in 14 healthy, recreationally active men (24 ± 1.1 yr) at baseline, RA5, and RTA1. Measures of insulin sensitivity (Matsuda index) and femoral and brachial artery blood flow were made during the OGTT. Free-living measures of GC including peak postprandial glucose (peak PPG) were also made via continuous glucose monitoring. RESULTS Femoral and brachial artery blood flow increased during the OGTT but neither was significantly impacted by changes in physical activity (P > 0.05). However, insulin sensitivity was decreased by RA5 (11.3 ± 1.5 to 8.0 ± 1.0, P < 0.05). Likewise, free-living GC measures of peak PPG (113 ± 3 to 123 ± 5 mg·dL(-1), P < 0.05) was significantly increased at RA5. Interestingly, insulin sensitivity and GC as assessed by peak PPG were not restored after RTA1 (P > 0.05). CONCLUSIONS Thus, acute reductions in physical activity impaired GC and insulin sensitivity; however, blood flow responses to an OGTT were not affected. Further, a 1-d return to activity was not sufficient to normalize GC after 5 d of reduced daily physical activity.

Vascular health toolbox for spinal cord injury: Recommendations for clinical practice

Over the last half century, the life expectancy for persons with spinal cord injury has increased drastically. Associated with the increased life expectancy, renal, metabolic and respiratory complications have given way to cardiovascular disease as the leading cause of death. Therefore, it is imperative that clinicians have at their disposal non-invasive and practical techniques for tracking cardiovascular disease risk amongst individual patients. This review provides an overview of non-invasive, widely available, and relatively inexpensive technologies for assessing cardiovascular health in persons with spinal cord injury. These technologies include ultrasound, pulse wave velocity and pulse wave analysis. A number of assessments can be conducted using these technologies, which confer acceptable reliability and validity, and are relatively simple to administer. Assessment recommendations for use in clinical practice are provided, and there is sufficient evidence to encourage the use of these techniques as a component of routine serial assessments.

Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1

Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)-1·min-1] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM-1·min-1) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P < 0.05). peNOS/eNOS content was higher in Lean under basal conditions and, although not increased by insulin, remained higher in Lean during the insulin clamp than in obese T2D (P < 0.05). ET-1 mRNA and peptide were 2.25 ± 0.50- and 1.52 ± 0.11-fold higher in obese T2D compared with Lean at baseline, and ET-1 peptide remained 2.02 ± 1.9-fold elevated in obese T2D after insulin infusion (P < 0.05) but did not increase with insulin in either group (P > 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 (P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients. NEW & NOTEWORTHY Although impairments in endothelial signaling are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), human studies examining these links are limited. We provide the first measures of nitric oxide synthase and endothelin-1 expression from skeletal muscle tissue containing native microvessels in individuals with and without T2D before and during insulin stimulation. Higher basal skeletal muscle expression of endothelin-1 and reduced endothelial nitric oxide phosphorylation (peNOS)/eNOS may contribute to reduced insulin-stimulated blood flow in obese T2D patients.