Vascular Adaptation to Exercise in Humans: Role of Hemodynamic Stimuli.

On the 400th anniversary of Harvey's Lumleian lectures, this review focuses on "hemodynamic" forces associated with the movement of blood through arteries in humans and the functional and structural adaptations that result from repeated episodic exposure to such stimuli. The late 20th century discovery that endothelial cells modify arterial tone via paracrine transduction provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the interrelationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions, and the implications for human health. Exercise modifies blood flow, luminal shear stress, arterial pressure, and tangential wall stress, all of which can transduce changes in arterial function, diameter, and wall thickness. There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute to the well-established decrease in cardiovascular risk attributed to physical activity.

Cardiac functional adaptation to resistance and endurance exercise training: a randomized crossover study.

Few training studies have assessed the impact of different modes of exercise on changes in cardiac function. This study investigated changes in left ventricular (LV) systolic and diastolic function following endurance (END) and resistance (RES) training in healthy participants. Sixty-four individuals participated in a randomized crossover design trial, involving 12 wk of END and RES training, separated by a 12-wk washout. Echocardiograms assessed systolic function [ejection fraction (EF) and global longitudinal strain (GLS)], diastolic function [mitral valve early velocity (E), tissue Doppler velocity (e'), their ratio (E/e')], and left atrial volume indexed to body surface area (LA ESVi). LV mass (LVM) increased with both RES (Δ5.3 ± 11.9, P = 0.001) and END (Δ7.5 ± 13.9, P < 0.001). Once adjusted for lean body mass (LVMi), changes remained significant following END. E/e' improved following END (Δ-0.35 ± 0.98, P = 0.011) not RES (Δ0.35 ± 1.11, P =0.157; P = 0.001 between modes). LA ESVi increased with END (Δ2.0 ± 6.1, P = 0.019) but not RES (Δ1.7 ± 5.7, P = 0.113). EF and GLS were not impacted significantly by either mode of training. Adaptation in LVM and LA volumes, as well as diastolic function, was exercise mode specific. Twelve weeks of intensive END increased LVM, LA volumes, and increased diastolic function. Following RES, LVM increased, although this was attenuated after accounting for changes in lean body mass. There were no changes in systolic function following either mode of exercise training.NEW & NOTEWORTHY Different types of exercise training induce distinct physiological adaptations however few exercise training studies have assessed the impact of different modes of exercise on cardiac function. This study investigated changes in left ventricular systolic and diastolic function following exercise training. Participants completed both endurance and resistance training separated by a 12-wk washout period so each participant is their own control. We present adaptations in cardiac structure and diastolic function are exercise mode specific.

The effects of water temperature on cerebral blood flow during aquatic exercise.

PURPOSE: Recent studies suggest that episodic increases in cerebral blood flow (CBF) may contribute to the improvement in brain health associated with exercise training. Optimising CBF during exercise may enhance this benefit. Water immersion in ~ 30-32 °C augments CBF at rest and during exercise; however, the impact of water temperature on the CBF response has not been investigated. We hypothesised that cycle ergometry in water would increase CBF compared to land-based exercise, and that warm water would attenuate the CBF benefits. METHODS: Eleven young heathy participants (nine males; 23.8 ± 3.1 yrs) completed 30 min of resistance-matched cycle exercise in three separate conditions; non-immersion (Land), 32 °C and 38 °C water immersion up to the level of the waist. Middle cerebral artery velocity (MCAv), blood pressure, and respiratory measures were assessed throughout the exercise bouts. RESULTS: Core temperature was significantly higher in the 38 °C immersion than 32 °C (+ 0.84 ± 0.24 vs + 0.04 ± 0.16, P < 0.001), whilst mean arterial pressure was lower during 38 °C exercise compared to Land (84 ± 8 vs 100 ± 14 mmHg, P < 0.001) and 32 °C (92 ± 9, P = 0.03). MCAv was higher in 32 °C immersion compared to the Land and 38 °C conditions throughout the exercise bout (68 ± 10 vs 64 ± 11 vs 62 ± 12 cm/s, P = 0.03 and P = 0.02, respectively). CONCLUSION: Our findings suggest that cycle exercise in warm water attenuates the beneficial impact of water immersion on CBF velocity due to redistribution of blood flow to subserve thermoregulatory demand. Our findings suggest that, whilst water-based exercise can have beneficial effects on cerebrovascular function, water temperature is a key determinant of this benefit.

Effect of low-volume combined aerobic and resistance high-intensity interval training on vascular health in people with type 2 diabetes: a randomised controlled trial.

PURPOSE: We compared the effects of low-volume combined aerobic and resistance high-intensity interval training (C-HIIT), combined moderate-intensity continuous training (C-MICT) and waitlist control (CON) on vascular health after 8-weeks of supervised training, and an additional 10-months of self-directed training, in adults with type 2 diabetes (T2D). METHODS: Sixty-nine low active adults with T2D were randomised to 8-weeks of supervised C-HIIT (3 times/week, 78-min/week), C-MICT (current exercise guidelines, 4 times/week, 210-min/week) or CON. CON underwent usual care for 8-weeks before being re-randomised to C-HIIT or C-MICT. This was followed by 10-months of self-directed training for participants in C-HIIT and C-MICT. Vascular outcomes were evaluated at baseline, 8-weeks, and 12-months. RESULTS: After 8-weeks, supervised C-HIIT significantly improved relative flow-mediated dilation (FMD) compared with CON (mean difference [MD] 0.8% [0.1, 1.4], p = 0.025). Although not significantly different from CON, the magnitude of change in relative FMD following 8-weeks of supervised C-MICT was similar (MD 0.8% [-0.1, 1.7], p = 0.080). There were no differences in haemodynamic indices, carotid-femoral pulse wave velocity (cfPWV), or aortic reservoir pressure between groups at 8-weeks. After 12-months, there was a significant reduction in haemodynamic indices (time effect, p < 0.05) for both C-HIIT and C-MICT, with no between-group difference. The reduction in cfPWV over 12-months was significantly greater in C-MICT than C-HIIT (group × time effect, p = 0.018). There was no difference in FMD over time or between groups at 12-months. CONCLUSIONS: Short-term supervised C-HIIT and C-MICT both increased brachial artery FMD compared with CON. Long-term C-HIIT and C-MICT were beneficial for improving haemodynamic indices, but not brachial artery FMD. C-MICT was superior to C-HIIT for improving cfPWV at 12-months. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier ACTRN12615000475549.

Sex differences in cardiovascular risk factor responses to resistance and endurance training in younger subjects.

This study compared differences in cardiovascular (CV) risk factor responses between males and females following endurance (END) and resistance (RES) training. We present the frequency of responders to each training modality and the magnitude of response. Using a randomized crossover design, 68 healthy adults [age: female (F): 24.5 ± 4.6; male (M): 27.3 ± 6.6] completed 3 mo of RES and END, with 3 mo washout. Peak oxygen consumption (V̇o2peak), strength, body composition, blood pressure, glucose, insulin, and lipids were measured. V̇o2peak (L/min) significantly increased in both sexes following END, but not RES. The magnitude of change was larger in males (F: +0.20 L/min; M: +0.32 L/min), although this did not achieve statistical significance (P = 0.051). Strength significantly increased in both sexes following RES (P < 0.01), with a larger increase in males (Leg press: F: +39 kg; M: +63 kg; P < 0.05). Lean mass significantly increased in both sexes (P < 0.01) following RES and fat mass decreased in females following END (P = 0.019). The change in C-reactive protein following END was significantly different between sexes (F: -0.4 mg/L; M: +0.5 mg/L; P = 0.035). There were no differences between sexes in the proportion of individuals who responded positively to any variable following RES or END; differences between sexes were due to the magnitude of change. Males had a larger increase in V̇o2peak following END and strength following RES. There were no sex differences in other CV risk factors. This suggests differences in physiological responses to strength and V̇o2peak may not translate to changes in CV risk in healthy subjects.NEW & NOTEWORTHY This study investigated sex differences in cardiovascular risk factors in response to different exercise training modalities. Males had a larger improvement in peak oxygen consumption following endurance training and strength following resistance training compared with females. These changes in peak oxygen consumption and strength did not translate to changes in other cardiovascular risk factors. Despite the greater magnitude of change in males, there were no sex differences in the proportion of individuals who responded to training.

The effects of water-based circuit exercise training on vascular function in people with coronary heart disease.

Impaired endothelial function in people with coronary heart disease (CHD) is associated with increased mortality. Water immersion can increase peripheral artery shear stress which may provide an additional stimulus to the endothelium during exercise. This study compared the effects of water-based circuit exercise training (WEX) and gym-based circuit exercise training (GEX) on vascular function in people with stable CHD. Participants were randomized to 12 wk of WEX (n = 20), GEX (n = 20), or a control group (usual activities; n = 12). Endothelium-dependent flow-mediated dilation (FMD) and glyceryl trinitrate-mediated dilation (GTN) of the brachial artery were assessed pre- and postintervention. FMD increased following WEX [4.0% (3.0%-5.1%) to 5.3% (4.1%-6.5%); P = 0.016], but was unchanged following GEX [4.9% (3.8%-5.9%) to 5.0% (3.8%-6.1%); P = 0.822]. There were no between-group differences in the change in FMD and no significant changes in GTN-mediated dilation percentage. Triglycerides decreased following GEX [1.2 mmol·L-1 (1.0-1.4 mmol·L-1) to 1.0 mmol·L-1 (0.8-1.3 mmol·L-1); P = 0.022], but there were no further differences in lipid profiles. WEX improved endothelial function of the brachial artery in people with stable CHD, suggesting that WEX is an effective alternative to gym-based exercise in people living with CHD, which may specifically address vascular health.NEW & NOTEWORTHY This study found that 12 wk of water-based circuit exercise training was well tolerated and improved vascular endothelial function in people with stable coronary heart disease. However, there was no effect on endothelium-independent function. Water-based exercise appears to be an effective alternative to gym-based exercise for people with coronary heart disease, which has specific benefits to vascular health and function.

Effects of exercise during water immersion on arterial function in humans.

Flow-mediated dilation (FMD) provides a valid bioassay of vascular function in humans. Although water immersion induces hemodynamic effects that modify brachial artery shear stress, it is unclear whether water-based exercise modifies FMD. We hypothesized that exercise in 32°C water would decrease brachial artery shear and FMD relative to land-based exercise, whereas exercise in 38°C would increase brachial shear and FMD. Ten healthy participants (8 males; 23.9 ± 3.3 yr) completed 30 min of resistance-matched cycle exercise in three separate conditions: on land and in 32°C and 38°C water. Brachial artery shear rate area under the curve (SRAUC) was measured throughout each condition, with FMD measured pre- and postexercise. Brachial SRAUC increased during exercise in all conditions and was highest across the 38°C condition compared with Land and 32°C conditions (38°C: 27,507 ± 8,350 vs. Land: 9,908 ± 4,738 vs. 32°C: 13,840 ± 5,861 1/s, P < 0.001). Retrograde diastolic shear was greater during 32°C than both Land and 38°C conditions (32°C:-3,869 ± 2,198 vs. Land:-1,602 ± 1,334 vs. 32°C:-1,036 ± 1,754, P < 0.01). FMD increased as a result of 38°C (6.2 ± 1.9 vs. 8.5 ± 2.7%, P = 0.03), with no change in the Land exercise (6.3 ± 2.4 vs. 7.7 ± 2.4%, P = 0.10) or 32°C condition (6.4 ± 3.2 vs. 6.7 ± 3.2%, P = 0.99). Our findings indicate that cycle exercise in hot water attenuates retrograde shear, increases antegrade shear, and FMD. Exercise in 32°C water induces central hemodynamic changes relative to land-based exercise, but these do not translate to increases in FMD in either condition, likely due to the impact of increased retrograde shear. Our findings indicate that modification of shear has direct acute impacts on endothelial function in humans.

Exercise breaks prevent attenuation in cerebrovascular function following an acute bout of uninterrupted sitting in healthy children.

The purpose of this study was to examine the effect of an acute bout of prolonged sitting with and without exercise breaks on cerebrovascular function in 7- to 13-year-old children. Forty-two children and adolescents were recruited to a crossover trial, with 15 girls (mean age 10.1 ± 2.5 years) and 16 boys (mean age 10.5 ± 1.3 years) completing the two trial conditions: SIT, uninterrupted sitting for 3 h and CYCLE, 3 h of sitting interrupted hourly with a 10-min moderate intensity exercise break. Cerebrovascular function was measured Pre and Post SIT and CYCLE from blood flow ( Q ̇ ${\dot{Q}}$ ), diameter, and shear rate of the internal carotid artery (ICA) at rest and in response to CO2 . Blood velocity in the middle (MCA) and posterior (PCA) cerebral arteries was assessed at rest, during a neurovascular coupling task (NVC) and in response to CO2 . We demonstrate that SIT but not CYCLE reduced ICA cerebrovascular reactivity to CO2 (%Δ ICA Q ̇ ${\dot{Q}}$ /Δ end-tidal CO2 : SIT: Pre 5.0 ± 2.4%/mmHg to Post 3.3 ± 2.8%/mmHg vs. CYCLE: Pre 4.4 ± 2.3%/mmHg to Post 5.3 ± 3.4%/mmHg, P = 0.05) and slowed the MCA blood velocity onset response time to hypercapnia (SIT: Pre 57.2 ± 32.6 s to Post 76.6 ± 55.2 s, vs. CYCLE: Pre 64.1 ± 40.4 s to Post 52.3 ± 28.8 s, P = 0.05). There were no changes in NVC. Importantly, breaking up prolonged sitting with hourly exercise breaks prevented the reductions in cerebrovascular reactivity to CO2 and the slowed intracranial blood velocity onset response time to hypercapnia apparent with uninterrupted sitting in children. NEW FINDINGS: What is the central question of this study? What are the effects of interrupting prolonged sitting on cerebrovascular function in children? What is the main finding and its importance? Prolonged sitting results in declines in cerebrovascular reactivity, a valuable index of cerebrovascular health. Breaking up prolonged sitting with hourly 10 min exercise breaks prevented these changes. These initial findings suggest excessive sedentary behaviour does impact cerebrovascular function in childhood, but taking exercise breaks prevents declines.

Association between atherogenic risk-modulating proteins and endothelium-dependent flow-mediated dilation in coronary artery disease patients.

PURPOSE: Endothelial dysfunction is an early and integral event in the development of atherosclerosis and coronary artery disease (CAD). Reduced NO bioavailability, oxidative stress, vasoconstriction, inflammation and senescence are all implicated in endothelial dysfunction. However, there are limited data examining associations between these pathways and direct in vivo bioassay measures of endothelial function in CAD patients. This study aimed to examine the relationships between in vivo measures of vascular function and the expression of atherogenic risk-modulating proteins in endothelial cells (ECs) isolated from the radial artery of CAD patients. METHODS: Fifty-six patients with established CAD underwent trans-radial catheterization. Prior to catheterization, radial artery vascular function was assessed using a) flow-mediated dilation (FMD), and b) exercise-induced dilation in response to handgrip (HE%). Freshly isolated ECs were obtained from the radial artery during catheterization and protein content of eNOS, NAD(P)H oxidase subunit NOX2, NFκB, ET-1 and the senescence markers p53, p21 and p16 were evaluated alongside nitrotyrosine abundance and eNOS Ser1177 phosphorylation. RESULTS: FMD was positively associated with eNOS Ser1177 phosphorylation (r = 0.290, P = 0.037), and protein content of p21 (r = 0.307, P = 0.027) and p16 (r = 0.426, P = 0.002). No associations were found between FMD and markers of oxidative stress, vasoconstriction or inflammation. In contrast to FMD, HE% was not associated with any of the EC proteins. CONCLUSION: These data revealed a difference in the regulation of endothelium-dependent vasodilation measured in vivo between patients with CAD compared to previously reported data in subjects without a clinical diagnosis, suggesting that eNOS Ser1177 phosphorylation may be the key to maintain vasodilation in CAD patients.

Studies of Twin Responses to Understand Exercise THerapy (STRUETH): cerebrovascular function.

We studied monozygotic (MZ) and dizygotic (DZ) twin pairs following resistance (RES) and endurance (END) training to assess genetic and environmental contributions to cerebrovascular function. Cerebrovascular function (rest, autoregulation, hypercapnia, exercise) was assessed in 86 healthy same-sex MZ (30 pairs) and DZ (13 pairs) twins, who underwent 3 months of END and RES. Carbon dioxide ( PETCO2${P_{{\rm{ETC}}{{\rm{O}}_{\rm{2}}}}}$ ), mean arterial pressure (MAP) and middle cerebral artery velocity (MCAv) were measured and MCAv resistance (MCACVRi ) was calculated. Resting MCAv reduced by -2.8 cm/s following RES (P = 0.024), with no change following END (-0.3 cm/s, P = 0.758). Change in MCACVRi following RES was +0.11 mmHg/cm/s (P < 0.001), which was significantly greater than END (+0.02 mmHg/cm/s, P = 0.030). MAP also increased following RES (+4 mmHg, P = 0.010), but not END (+1 mmHg, P = 0.518). No changes were apparent in PETCO2${P_{{\rm{ETC}}{{\rm{O}}_{\rm{2}}}}}$ . At rest, positive response rates following RES ranged from 27 to 71% and from 40 to 64% following END. Intraclass correlations between twins were moderate for most variables at baseline. In response to training, only MZ pairs were significantly correlated for a change in MCAv (P = 0.005) and low frequency phase (P = 0.047) following RES.This study is the first to compare cerebrovascular function following RES and END in MZ and DZ twins. Most individuals who did not respond to one modality were able to respond by switching modality, and baseline heritability estimates were higher than training response. Exercise professionals should therefore consider modality and environmental factors when optimising interventions. KEY POINTS: Characterising individual responses to resistance and endurance exercise training can inform optimal strategies for exercise prescription. This study utilised monozygotic and dizygotic twins in a randomised cross-over study to determine individual responsiveness to different modalities of exercise training. The influence of environment vs. genetics on cerebrovascular responses to training was determined. It is apparent that individuals respond differently to distinct exercise stimuli and that switching modality may be a beneficial way to obtain positive responses in cerebrovascular function. This study has implications for improving individualised exercise prescription to maintain or improve cerebrovascular structure and function.

Visualising and quantifying microvascular structure and function in patients with heart failure using optical coherence tomography.

Heart failure (HF) is characterised by abnormal conduit and resistance artery function in humans. Microvascular function in HF is less well characterised, due in part to the lack of tools to image these vessels in vivo. The skin microvasculature is a surrogate for systemic microvascular function and health and plays a key role in thermoregulation, which is dysfunctional in HF. We deployed a novel optical coherence tomography (OCT) technique to visualise and quantify microvascular structure and function in 10 subjects with HF and 10 age- and sex-matched controls. OCT images were obtained from the ventral aspect of the forearm, at baseline (33°C) and after 30 min of localised skin heating. At rest, OCT-derived microvascular density (20.3 ± 8.7%, P = 0.004), diameter (35.1 ± 6.0 µm, P = 0.006) and blood flow (82.9 ± 41.1 pl/s, P = 0.021) were significantly lower in HF than CON (27.2 ± 8.0%, 40.4 ± 5.8 µm, 110.8 ± 41.9 pl/s), whilst blood speed was not significantly lower (74.3 ± 11.0 µm/s vs. 81.3 ± 9.9 µm/s, P = 0.069). After local heating, the OCT-based density, diameter, blood speed and blood flow of HF patients were similar (all P > 0.05) to CON. Although abnormalities exist at rest which may reflect microvascular disease status, patients with HF retain the capacity to dilate cutaneous microvessels in response to localised heat stress. This is a novel in vivo human observation of microvascular dysfunction in HF, illustrating the feasibility of OCT to directly visualise and quantify microvascular responses to physiological stimuli in vivo. KEY POINTS: Microvessels in the skin are critical to human thermoregulation, which is compromised in participants with heart failure (HF). We have developed a powerful new non-invasive optical coherence tomography (OCT)-based approach for the study of microvascular structure and function in vivo. Our approach enabled us to observe and quantify abnormal resting microvascular function in participants with HF. Patients with HF were able to dilate skin microvessels in response to local heat stress, arguing against an underlying structural abnormality. This suggests that microvascular functional regulation is the primary abnormality in HF. OCT can be used to directly visualise and quantify microvascular responses to physiological stimuli in vivo.

Nitric oxide contributes to cerebrovascular shear-mediated dilatation but not steady-state cerebrovascular reactivity to carbon dioxide.

Cerebrovascular CO2 reactivity (CVR) is often considered a bioassay of cerebrovascular endothelial function. We recently introduced a test of cerebral shear-mediated dilatation (cSMD) that may better reflect endothelial function. We aimed to determine the nitric oxide (NO)-dependency of CVR and cSMD. Eleven volunteers underwent a steady-state CVR test and transient CO2 test of cSMD during intravenous infusion of the NO synthase inhibitor NG -monomethyl-l-arginine (l-NMMA) or volume-matched saline (placebo; single-blinded and counter-balanced). We measured cerebral blood flow (CBF; duplex ultrasound), intra-arterial blood pressure and PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ . Paired arterial and jugular venous blood sampling allowed for the determination of trans-cerebral NO2- exchange (ozone-based chemiluminescence). l-NMMA reduced arterial NO2- by ∼25% versus saline (74.3 ± 39.9 vs. 98.1 ± 34.2 nM; P = 0.03). The steady-state CVR (20.1 ± 11.6 nM/min at baseline vs. 3.2 ± 16.7 nM/min at +9 mmHg PaCO2${P_{{\rm{aC}}{{\rm{O}}_{\rm{2}}}}}$ ; P = 0.017) and transient cSMD tests (3.4 ± 5.9 nM/min at baseline vs. -1.8 ± 8.2 nM/min at 120 s post-CO2 ; P = 0.044) shifted trans-cerebral NO2- exchange towards a greater net release (a negative value indicates release). Although this trans-cerebral NO2- release was abolished by l-NMMA, CVR did not differ between the saline and l-NMMA trials (57.2 ± 14.6 vs. 54.1 ± 12.1 ml/min/mmHg; P = 0.49), nor did l-NMMA impact peak internal carotid artery dilatation during the steady-state CVR test (6.2 ± 4.5 vs. 6.2 ± 5.0% dilatation; P = 0.960). However, l-NMMA reduced cSMD by ∼37% compared to saline (2.91 ± 1.38 vs. 4.65 ± 2.50%; P = 0.009). Our findings indicate that NO is not an obligatory regulator of steady-state CVR. Further, our novel transient CO2 test of cSMD is largely NO-dependent and provides an in vivo bioassay of NO-mediated cerebrovascular function in humans. KEY POINTS: Emerging evidence indicates that a transient CO2 stimulus elicits shear-mediated dilatation of the internal carotid artery, termed cerebral shear-mediated dilatation. Whether or not cerebrovascular reactivity to a steady-state CO2 stimulus is NO-dependent remains unclear in humans. During both a steady-state cerebrovascular reactivity test and a transient CO2 test of cerebral shear-mediated dilatation, trans-cerebral nitrite exchange shifted towards a net release indicating cerebrovascular NO production; this response was not evident following intravenous infusion of the non-selective NO synthase inhibitor NG -monomethyl-l-arginine. NO synthase blockade did not alter cerebrovascular reactivity in the steady-state CO2 test; however, cerebral shear-mediated dilatation following a transient CO2 stimulus was reduced by ∼37% following intravenous infusion of NG -monomethyl-l-arginine. NO is not obligatory for cerebrovascular reactivity to CO2 , but is a key contributor to cerebral shear-mediated dilatation.

Near infrared spectroscopy in peripheral artery disease and the diabetic foot: A systematic review.

With the need for tools that assess microvascular status in diabetic foot disease (DFD) being clear, near infrared spectroscopy (NIRS) is a putative method for noninvasive testing of the diabetic foot. The use of NIRS in patients with peripheral arterial disease (PAD) has extended to its role in studying the pathophysiology of DFD. NIRS generates metrics such as recovery time, deoxygenation, oxygen consumption (VO2 ), tissue oxygen saturation (StO2 ), total haemoglobin (HbT), and oxyhaemoglobin area under the curve (O2 HbAUC ). NIRS may potentially help the multidisciplinary team stratify limbs as high-risk, especially in diabetic patients with symptoms masked by peripheral neuropathy. NIRS may be useful for assessing treatment effectiveness and preventing deterioration of patients with PAD.

Comparison of high intensity interval training with standard cardiac rehabilitation on vascular function.

OBJECTIVES: To compare the short- and long-term effects of high-intensity interval training (HIIT) with usual care moderate intensity continuous training (MICT) on systemic vascular function and stiffness in patients with coronary artery disease undergoing a cardiac rehabilitation program. DESIGN: Randomized controlled trial. METHODS: Fifty-four patients (age = 63 ± 8 years, 93% male) were randomized to complete 3 sessions/week (2 supervised, 1 home-based) of either (1) 4 × 4-min HIIT or (2) 40-min MICT, for 4 weeks. Patients then continued 3 unsupervised home-based sessions/week of their allocated training for 11 months. Brachial artery flow-mediated dilation, pulse wave velocity, and blood pressure were measured at baseline, 4 weeks, 3 months, 6 months, and 12 months. Data were analyzed using linear mixed modeling and are presented as mean change from baseline (95% CI). RESULTS: HIIT showed a greater improvement in flow-mediated dilation compared to MICT after 4 weeks [1.5% (0.9, 2.1) vs 0.1% (-0.5, 0.8); p = 0.004) but not 12 months [1.2% (-0.2, 2.5) vs 0.4% (-0.8, 1.7); p = 0.153). There were no short- or long-term group differences for changes in pulse wave velocity, peripheral or central blood pressure between HIIT and MICT after 4 weeks, or over 12 months. CONCLUSIONS: A 4-week HIIT program was superior to MICT for improving vascular function, but not arterial stiffness or blood pressure. Over 12 months, changes in vascular function, blood pressure, and arterial stiffness were similar for HIIT and MICT.

Sitting less and moving more for improved metabolic and brain health in type 2 diabetes: 'OPTIMISE your health' trial protocol.

BACKGROUND: Clinical practice guidelines recommend that adults with type 2 diabetes (T2D) sit less and move more throughout the day. The 18-month OPTIMISE Your Health Clinical Trial was developed to support desk-based workers with T2D achieve these recommendations. The two-arm protocol consists of an intervention and control arms. The intervention arm receives 6 months health coaching, a sit-stand desktop workstation and an activity tracker, followed by 6 months of text message support, then 6 months maintenance. The control arm receives a delayed modified intervention after 12 months of usual care. This paper describes the methods of a randomised controlled trial (RCT) evaluating the effectiveness and cost-effectiveness of the intervention, compared to a delayed intervention control. METHODS: This is a two-arm RCT being conducted in Melbourne, Australia. Desk-based workers (≥0.8 full-time equivalent) aged 35-65 years, ambulatory, and with T2D and managed glycaemic control (6.5-10.0% HbA1c), are randomised to the multicomponent intervention (target n = 125) or delayed-intervention control (target n = 125) conditions. All intervention participants receive 6 months of tailored health coaching assisting them to "sit less" and "move more" at work and throughout the day, supported by a sit-stand desktop workstation and an activity tracker (Fitbit). Participants receive text message-based extended care for a further 6-months (6-12 months) followed by 6-months of non-contact (12-18 months: maintenance). Delayed intervention occurs at 12-18 months for the control arm. Assessments are undertaken at baseline, 3, 6, 12, 15 and 18-months. Primary outcomes are activPAL-measured sitting time (h/16 h day), glycosylated haemoglobin (HbA1c; %, mmol/mol) and, cognitive function measures (visual learning and new memory; Paired Associates Learning Total Errors [adjusted]). Secondary, exploratory, and process outcomes will also be collected throughout the trial. DISCUSSION: The OPTIMISE Your Health trial will provide unique insights into the benefits of an intervention aimed at sitting less and moving more in desk-bound office workers with T2D, with outcomes relevant to glycaemic control, and to cardiometabolic and brain health. Findings will contribute new insights to add to the evidence base on initiating and maintaining behaviour change with clinical populations and inform practice in diabetes management. TRIAL REGISTRATION: ANZCTRN12618001159246 .

Cerebrovascular function and its association with systemic artery function and stiffness in older adults with and without mild cognitive impairment.

PURPOSE: Our aim was to compare cerebrovascular and systemic vascular function between older adults with and without mild cognitive impairment (MCI), and to determine which measures of vascular function best predict the presence of MCI. METHODS: In 41 adults with MCI and 33 adults without MCI (control) we compared middle cerebral artery velocity (MCAv) and cerebrovascular pulsatility index (PI) at rest, cerebrovascular reactivity to CO2, and responsiveness to changes in blood pressure (%∆MCAv/%∆MAP). Systemic vascular function was assessed by flow-mediated dilation (FMD) and stiffness by pulse wave velocity (PWV). RESULTS: Cerebrovascular PI was higher in MCI compared with control (mean ± SD: 1.17 ± 0.27 vs. 1.04 ± 0.21), and MCI exhibited a lower %∆MCAv/%∆MAP (1.26 ± 0.44 vs. 1.50 ± 0.55%). Absolute (p = 0.76) and relative cerebrovascular reactivity to CO2 (p = 0.34) was similar between MCI and control. When age was included as a covariate the significant difference in cerebral PI between groups was lost. PWV was higher (13.2 ± 2.2 vs. 11.3 ± 2.5 m s-1) and FMD% (4.41 ± 1.70 vs. 5.43 ± 2.15%) was lower in MCI compared with control. FMD% was positively associated with PI across the cohort. Logistic regression analysis indicated that FMD and PWV significantly discriminated between MCI and controls, independent of age, whereas the inclusion of cerebrovascular measures did not improve the predictive accuracy of the model. CONCLUSION: These findings raise the possibility that early changes in systemic vascular stiffness and endothelial function may contribute to altered cerebrovascular haemodynamics and impaired cognitive function, and present potential targets for prevention and treatment strategies in people with MCI.

Mimicking exercise: what matters most and where to next?

The past decade has witnessed growing scientific and commercial interest in the identification of bioactive oral compounds that mimic or potentiate the effects of exercise, so-called 'exercise pills' or 'exercise mimetics.' These compounds have, to date, typically targeted skeletal muscle in an attempt to stimulate some of the adaptations to exercise induced by endurance training. Accordingly, they fail to impart many of the broad health protecting effects of exercise that are seen in tissues and organs other than skeletal muscle. In the context that multiple integrative regulatory and often redundant pathways have evolved to detect and respond to human movement, here we consider the complex challenges of designing a pill that might mimic the extensive range of exercise benefits. In particular, we consider the limits of the current 'myocentric' paradigm given the wide-ranging array of impacts that exercise exerts on atherosclerosis and the cardiovascular system. We discuss the validity and limitations of the concept that low dose cardiovascular polypills, already in large scale trials, may represent one form of cardiovascular exercise mimetic. Finally, given that some calls for an exercise pill stem from a response to the perceived failure of expert advice, evidence-based guidelines and current public health approaches, we explore possible strategies that might address the global rise in inactivity. In the event that a broad spectrum exercise mimetic might ever be developed, we discuss some generic issues related to adoption and adherence of therapeutic interventions.

Resistance, but not endurance exercise training, induces changes in cerebrovascular function in healthy young subjects.

It is generally considered that regular exercise maintains brain health and reduces the risk of cerebrovascular diseases such as stroke and dementia. Since the benefits of different "types" of exercise are unclear, we sought to compare the impacts of endurance and resistance training on cerebrovascular function. In a randomized and crossover design, 68 young healthy adults were recruited to participate in 3 mo of resistance and endurance training. Cerebral hemodynamics through the internal carotid, vertebral, middle and posterior cerebral arteries were measured using Duplex ultrasound and transcranial Doppler at rest and during acute exercise, dynamic autoregulation, and cerebrovascular reactivity (to hypercapnia). Following resistance, but not endurance training, middle cerebral artery velocity and pulsatility index significantly decreased (P < 0.01 and P = 0.02, respectively), whereas mean arterial pressure and indices of cerebrovascular resistance in the middle, posterior, and internal carotid arteries all increased (P < 0.05). Cerebrovascular resistance indices in response to acute exercise and hypercapnia also significantly increased following resistance (P = 0.02), but not endurance training. Our findings, which were consistent across multiple domains of cerebrovascular function, suggest that episodic increases in arterial pressure associated with resistance training may increase cerebrovascular resistance. The implications of long-term resistance training on brain health require future study, especially in populations with pre-existing cerebral hypoperfusion and/or hypotension.NEW & NOTEWORTHY Three months of endurance exercise did not elicit adaptation in any domain of cerebrovascular function in young healthy inactive volunteers. However, resistance training induced decreased pulsatility in the extracranial arteries and increased indices of cerebrovascular resistance in cerebral arteries. This increase in cerebrovascular resistance, apparent at baseline and in response to both hypercapnia and acute exercise, may reflect a protective response in the face of changes in arterial pressure during resistance exercise.

Testosterone and exercise: effects on fitness, body composition, and strength in middle-to-older aged men with low-normal serum testosterone levels.

As men age, serum testosterone (T) concentrations decrease, as do fitness, strength, and lean mass. Whether testosterone treatment confers additive benefit to reverse these changes when combined with exercise training in middle-to-older aged men remains unclear. We assessed the effects of T treatment and exercise, alone and in combination, on aerobic capacity (V̇o2peak), body composition, and muscular strength in men 50-70 yr, waist circumference ≥95 cm and low-normal serum T (6-14 nmol·L-1). Participants (n = 80) were randomized to AndroForte5 (testosterone 5.0% wt/vol, 100 mg/2 mL) cream (T), or matching placebo (P), applied transdermally daily, and supervised center-based exercise (Ex) or no additional exercise (NEx), for 12-wk. Exercise increased V̇o2peak and strength versus nonexercise (V̇o2peak: T + Ex: +2.5 mL·kg-1·min-1, P + Ex: +3.2 mL·kg-1·min-1, P < 0.001; leg press: T + Ex: +31 kg, P + Ex: +24 kg, P = 0.006). T treatment did not affect V̇o2peak or strength. Exercise decreased total (T + Ex: -1.7, P + Ex: -2.3 kg, P < 0.001) and visceral fat (T + Ex: -0.1 kg, P + Ex: -0.3 kg, P = 0.003), and increased total (T + Ex: +1.4 kg, P + Ex: +0.7 kg, P = 0.008) and arm lean mass (T + Ex: +0.5 kg, P + Ex: +0.3 kg, P = 0.024). T treatment did not affect total or visceral fat, but increased total (T + Ex: +1.4 kg, T + NEx: +0.7 kg, P = 0.015), leg (T + Ex: +0.3 kg, T + NEx: +0.2 kg, P = 0.024), and arm lean mass (T + Ex: +0.5 kg, T + NEx: +0.2 kg, P = 0.046). T + Ex increased arm lean mass (T + Ex: +0.5 kg vs. P + NEx: -0.0 kg, P = 0.001) and leg strength (T + Ex: +31 kg vs. P + NEx: +12 kg, P = 0.032) compared with P + NEx, with no other additive effects. Exercise training was more effective than T treatment in increasing aerobic capacity and decreasing total and visceral fat mass. T treatment at therapeutic doses increased lean mass but conferred limited additional benefit when combined with exercise. Exercise should be evaluated as an antiaging intervention in preference to testosterone treatment in men.NEW & NOTEWORTHY We illustrate that exercise training generates superior outcomes to testosterone treatment for improving aerobic fitness, muscular strength, and total and visceral fat mass in men 50-70 yr with low-normal serum testosterone concentrations. Adding testosterone treatment to exercise did not provide any additive benefit for these variables. Testosterone treatment alone and exercise alone had similar impacts on lean mass. Therefore, men unable to exercise may obtain benefit from testosterone treatment alone to improve lean mass.

Acute effects of interrupting prolonged sitting on vascular function in type 2 diabetes.

In healthy and overweight/obese adults, interrupting prolonged sitting with activity bouts mitigates impairment in vascular function. However, it is unknown whether these benefits extend to those with type 2 diabetes (T2D), nor whether an optimal frequency of activity interruptions exist. We examined the acute effects on vascular function in T2D of interrupting prolonged sitting with simple resistance activities (SRA) at different frequencies. In a randomized crossover trial, 24 adults with T2D (35-70 yr) completed three 7-h conditions: 1) uninterrupted sitting (SIT), 2) sitting with 3-min bouts of SRA every 30 min (SRA3), and 3) sitting with 6 min bouts of SRA every 60 min (SRA6). Femoral artery flow-mediated dilation (FMD), resting shear rate, blood flow, and endothelin-1 were measured at 0, 1, 3.5, 4.5, and 6.5-7 h. Mean femoral artery FMD over 7 h was significantly higher in SRA3 (4.1 ± 0.3%) compared with SIT (3.7 ± 0.3%, P = 0.04) but not in SRA6. Mean resting femoral shear rate over 7 h was increased significantly for SRA3 (45.3 ± 4.1/s, P < 0.001) and SRA6 (46.2 ± 4.1/s, P < 0.001) relative to SIT (33.1 ± 4.1/s). Endothelin-1 concentrations were not statistically different between conditions. Interrupting sitting with activity breaks every 30 min, but not 60 min, significantly increased mean femoral artery FMD over 7 h, relative to SIT. Our findings suggest that more frequent and shorter breaks may be more beneficial than longer, less frequent breaks for vascular health in those with T2D.NEW & NOTEWORTHY This is the first trial to examine both the effects of interrupting prolonged sitting on vascular function in type 2 diabetes and the effects of the frequency and duration of interruptions. Brief, simple resistance activity bouts every 30 min, but not every 60 min, increased mean femoral artery flow-mediated dilation over 7 h, relative to uninterrupted sitting. With further supporting evidence, these initial findings can have important implications for cardiovascular health in type 2 diabetes.