Impact of Water- and Land-Based Exercise Training on Risk Factors and Vascular Function in Middle-Aged and Older Men and Women.

INTRODUCTION: Exercise improves vascular function, but it is unclear whether benefits are mediated by traditional cardiovascular risk factors or whether sex differences in training effects exist in older adults. We hypothesized that exercise would improve cardiovascular risk factors, that males and females would benefit similarly, and that improvements in risk factors would correlate with changes in vascular function. METHODS: Seventy-two healthy middle-aged/older adults (age, 62 ± 7 yr; 26%♂) were randomized to a land-walking ( n = 23), water-walking ( n = 25), or a nonexercise control group (C; n = 23). The exercise groups undertook supervised and monitored training three times a week for 50 min per session, across 24 wk. Blood pressure, body composition (dual x-ray absorptiometry), blood lipids and glucose, and flow-mediated brachial artery dilation were assessed in all participants at weeks 0 and 24. To maximize power for sex differences and correlation analyses, we pooled the training groups (land-walking + water-walking). RESULTS: Training prevented increases in LDL and total cholesterol/HDL ratio observed in the nonexercise control group. No group by time interactions were observed for other risk factors. Sex differences in training effects existed for visceral fat (-187 ± 189 g♂ vs -15 ± 161 g♀; P = 0.006) and lean mass (-352 ± 1045 g♂ vs 601 ± 1178 g♀; P = 0.008). Improvement in flow-mediated brachial artery dilation was correlated with decreased waist girth ( r = -0.450, P = 0.036), but not with other risk factors. CONCLUSIONS: Exercise training prevented deterioration in lipid levels, whereas sex differences existed for body composition changes with training. Improvement in vascular function was not dependent on changes in risk factors in middle-aged/older adults, suggesting that artery health may be dependent on other exercise-related stimuli.

Comparison of computational fluid dynamics with transcranial Doppler ultrasound in response to physiological stimuli.

Cerebrovascular haemodynamics are sensitive to multiple physiological stimuli that require synergistic response to maintain adequate perfusion. Understanding haemodynamic changes within cerebral arteries is important to inform how the brain regulates perfusion; however, methods for direct measurement of cerebral haemodynamics in these environments are challenging. The aim of this study was to assess velocity waveform metrics obtained using transcranial Doppler (TCD) with flow-conserving subject-specific three-dimensional (3D) simulations using computational fluid dynamics (CFD). Twelve healthy participants underwent head and neck imaging with 3 T magnetic resonance angiography. Velocity waveforms in the middle cerebral artery were measured with TCD ultrasound, while diameter and velocity were measured using duplex ultrasound in the internal carotid and vertebral arteries to calculate incoming cerebral flow at rest, during hypercapnia and exercise. CFD simulations were developed for each condition, with velocity waveform metrics extracted in the same insonation region as TCD. Exposure to stimuli induced significant changes in cardiorespiratory measures across all participants. Measured absolute TCD velocities were significantly higher than those calculated from CFD (P range < 0.001-0.004), and these data were not correlated across conditions (r range 0.030-0.377, P range 0.227-0.925). However, relative changes in systolic and time-averaged velocity from resting levels exhibited significant positive correlations when the distinct techniques were compared (r range 0.577-0.770, P range 0.003-0.049). Our data indicate that while absolute measures of cerebral velocity differ between TCD and 3D CFD simulation, physiological changes from resting levels in systolic and time-averaged velocity are significantly correlated between techniques.

Dynamic onset response of the internal carotid artery to hypercapnia is blunted in children compared with adults.

Intracranial blood velocity reactivity to a steady-state hypercapnic stimulus has been shown to be similar in children and adults, but the onset response to hypercapnia is slower in the child. Given the vasodilatory effect of hypercapnia on the cerebrovasculature, assessment of vessel diameter, and blood flow are vital to fully elucidate whether the temporal hypercapnic response differs in children versus adults. Assessment of internal carotid artery (ICA) vessel diameter (ICAd), blood velocity (ICAv), volumetric blood flow (QICA ), and shear rate (ICASR ) in response to a 4 min hypercapnic challenge was completed in children (n = 14, 8 girls; 9.8 ± 0.7 years) and adults (n = 17, 7 females; 24.7 ± 1.8 years). The dynamic onset responses of partial pressure of end-tidal CO2 (PET CO2 ), QICA , ICAv, and ICASR to hypercapnia were modeled, and mean response time (MRT) was computed. Following 4 min of hypercapnia, ICA reactivity and ICAd were comparable between the groups. Despite a similar MRT in PET CO2 in children and adults, children had slower QICA (children 108 ± 60 s vs. adults 66 ± 37 s; p = 0.023), ICAv (children 120 ± 52 s vs. adults 52 ± 31 s; p = 0.001), and ICASR (children 90 ± 27 s vs. adults 47 ± 36 s; p = 0.001) MRTs compared with adults. This is the first study to show slower hypercapnic hyperemic kinetic responses of the ICA in children. The mechanisms determining these differences and the need to consider the duration of hypercapnic exposure when assessing CVR in children should be considered in future studies.

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.

Trans-cerebral HCO3- and PCO2 exchange during acute respiratory acidosis and exercise-induced metabolic acidosis in humans.

This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO3-]) and carbon dioxide tension (PCO2) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO2 (PaCO2) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO3-] increased by 0.15 ± 0.05 mmol ⋅ l-1 per mmHg elevation in PaCO2 across a wide physiological range (35 to 60 mmHg PaCO2; P < 0.001). The narrowing of the venous-arterial [HCO3-] and PCO2 differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO3-] exchange (CBF × venous-arterial [HCO3-] difference) was reduced indicating a shift from net release toward net uptake of [HCO3-] (P = 0.004). Arterial [HCO3-] was reduced by -0.48 ± 0.15 mmol ⋅ l-1 per nmol ⋅ l-1 increase in arterial [H+] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO3-] difference and arterial [H+] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO3-] exchange was unaltered throughout exercise when indexed against arterial [H+] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO3-] - during acute respiratory/exercise-induced metabolic acidosis, respectively - differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO3-] exchange).

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.

The influence of sex and maturation on carotid and vertebral artery hemodynamics and associations with free-living (in)activity in 6-17-year-olds.

We explored the influence of sex and maturation on resting cervical artery hemodynamics (common carotid artery, CCA; internal carotid artery, ICA; and vertebral artery, VA), free-living physical activity, and sedentary behavior in children 6-17 yr of age. In addition, we investigated the relationship between physical activity, sedentary behavior, and cervical artery hemodynamics. Seventy-eight children and adolescents, girls (n = 42; mean age, 11.4 ± 2.5 yr) and boys (n = 36; mean age, 11.0 ± 2.6 yr), completed anthropometric measures, duplex ultrasound assessment of the cervical arteries, and wore an activPAL accelerometer to assess physical activity (indexed by steps/day) and sedentary behavior for 7 days. The ICA and VA diameters were similar between prepubertal and pubertal groups, as was volumetric blood flow (Q); however, the CCA diameter was significantly larger in the pubertal group (P < 0.05). Boys were found to have larger diameters in all cervical arteries than girls, as well as higher QCCA, QICA, and global cerebral blood flow (P < 0.05). The pubertal group was more sedentary (100 min/day more; P < 0.05) and took 3,500 fewer steps/day than the prepubertal group (P < 0.05). Shear rate (SR) and Q of the cervical arteries showed no relationship to physical activity or prolonged bouts of sedentary behavior; however, a significant negative relationship was apparent between total sedentary time and internal carotid artery shear rate (ICASR) after covarying for steps/day and maturation (P < 0.05). These findings provide novel insight into the potential influence sedentary behavior may have on cerebrovascular blood flow in healthy girls and boys.NEW & NOTEWORTHY Cerebral blood flow is known to change with age; however, assessing these age-related changes is complex and requires consideration of pubertal status. This, to our knowledge, is the first study to investigate the influence of sex and maturation on resting cervical artery hemodynamics and subsequently explore associations with physical activity and sedentary behavior in healthy children and adolescents. Our findings suggest that habitual sedentary behavior may influence cervical artery hemodynamics in youth, independent of physical activity, maturation, and sex.

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.

Impact of acute changes in blood pressure and arterial stiffness on cerebral pulsatile haemodynamics in young and middle-aged adults.

NEW FINDINGS: What is the central question of this study? Does cerebrovascular pulsatility respond differently to acute increases in arterial stiffness in middle-aged compared with young adults? What is the main finding and its importance? Compared with young adults, middle-aged adults exhibited similar changes in cerebral pulsatile damping despite attenuated changes in carotid diameter and cerebrovascular pulsatility during blood pressure-dependent, but not blood pressure-independent, increases in large artery stiffness. ABSTRACT: Acute manipulation of arterial stiffness through interventions that increase sympathetic activity might provoke cerebral pulsatility and damping and reveal whether cerebrovascular haemodynamics respond differently to transient elevations in arterial stiffness in middle-aged compared with young adults. We compared cerebral pulsatility and damping in middle-aged versus young adults during two different sympathetic interventions [cold pressor test (CP) and lower-body negative pressure (LBNP)] that increase arterial stiffness acutely. Cerebrovascular haemodynamics were assessed in 15 middle-aged (54 ± 7 years old; 11 female) and 15 sex-matched young adults (25 ± 4 years old) at rest and during the CP test (4 min, 6.4 ± 0.8°C) and LBNP (6 min, -20 mmHg). Mean blood pressure was measured continuously via finger photoplethysmography. Carotid-femoral pulse wave velocity (cfPWV) and carotid stiffness were measured via tonometry and ultrasound. Blood velocity pulsatility index (PI) was measured at the middle cerebral (MCA) and common carotid artery (CCA) using Doppler, with pulsatile damping calculated as CCA PI divided by MCA PI. Increases in cfPWV were driven by changes in mean pressure during CP but not during LBNP in both groups (P < 0.05). Pulsatile damping decreased in both groups (P < 0.05) despite reductions in MCA PI and greater carotid dilatation during CP in young compared with middle-aged adults (P < 0.05). Pressure-independent increases in cfPWV during LBNP did not alter pulsatile damping but decreased MCA PI in both young and middle-aged adults (P < 0.05). These data suggest that changes in carotid diameter and cerebrovascular pulsatility differ between young and middle-aged adults despite similar changes in cerebral pulsatile damping during blood pressure-dependent, but not blood pressure-independent, increases in large artery stiffness.

Regulation of cerebral blood flow by arterial PCO2 independent of metabolic acidosis at 5050 m.

KEY POINTS: We investigated the influence of arterial PCO2 (PaCO2 ) with and without experimentally altered pH on cerebral blood flow (CBF) regulation at sea level and with acclimatization to 5050 m. At sea level and high altitude, we assessed stepwise alterations in PaCO2 following metabolic acidosis (via 2 days of oral acetazolamide; ACZ) with and without acute restoration of pH (via intravenous sodium bicarbonate; ACZ+HCO3- ). Total resting CBF was unchanged between trials at each altitude even though arterial pH and [HCO3- ] (i.e. buffering capacity) were effectively altered. The cerebrovascular responses to changes in arterial [H+ ]/pH were consistent with the altered relationship between PaCO2 and [H+ ]/pH following ACZ at high altitude (i.e. leftward x-intercept shifts). Absolute cerebral blood velocity (CBV) and the sensitivity of CBV to PaCO2 was unchanged between trials at high altitude, indicating that CBF is acutely regulated by PaCO2 rather than arterial pH. ABSTRACT: Alterations in acid-base balance with progressive acclimatization to high altitude have been well-established. However, how respiratory alkalosis and the resultant metabolic compensation interact to regulate cerebral blood flow (CBF) is uncertain. We addressed this via three separate experimental trials at sea level and following partial acclimatization (14 to 20 days) at 5050 m; involving: (1) resting acid-base balance (control); (2) following metabolic acidosis via 2 days of oral acetazolamide at 250 mg every 8 h (ACZ; pH: Δ -0.07 ± 0.04 and base excess: Δ -5.7 ± 1.9 mEq⋅l-1 , trial effects: P < 0.001 and P < 0.001, respectively); and (3) after acute normalization of arterial acidosis via intravenous sodium bicarbonate (ACZ + HCO3- ; pH: Δ -0.01 ± 0.04 and base excess: Δ -1.5 ± 2.1 mEq⋅l-1 , trial effects: P = 1.000 and P = 0.052, respectively). Within each trial, we utilized transcranial Doppler ultrasound to assess the cerebral blood velocity (CBV) response to stepwise alterations in arterial PCO2 (PaCO2 ), i.e. cerebrovascular CO2 reactivity. Resting CBF (via Duplex ultrasound) was unaltered between trials within each altitude, indicating that respiratory compensation (i.e. Δ -3.4 ± 2.3 mmHg PaCO2 , trial effect: P < 0.001) was sufficient to offset any elevations in CBF induced via the ACZ-mediated metabolic acidosis. Between trials at high altitude, we observed consistent leftward shifts in both the PaCO2 -pH and CBV-pH responses across the CO2 reactivity tests with experimentally reduced arterial pH via ACZ. When indexed against PaCO2 - rather than pH - the absolute CBV and sensitivity of CBV-PaCO2 was unchanged between trials at high altitude. Taken together, following acclimatization, CO2 -mediated changes in cerebrovascular tone rather than arterial [H+ ]/pH is integral to CBF regulation at high altitude.

Adaptation to Exercise Training in Conduit Arteries and Cutaneous Microvessels in Humans: An Optical Coherence Tomography Study.

INTRODUCTION: Exercise training has antiatherogenic effects on conduit and resistance artery function and structure in humans and induces angiogenic changes in skeletal muscle. However, training-induced adaptation in cutaneous microvessels is poorly understood, partly because of technological limitations. Optical coherence tomography (OCT) is a novel high-resolution imaging technique capable of visualizing cutaneous microvasculature at a resolution of ~30 µm. We utilized OCT to visualize the effects of training on cutaneous microvessels, alongside assessment of conduit artery flow-mediated dilation (FMD). METHODS: We assessed brachial FMD and cutaneous microcirculatory responses at rest and in response to local heating and reactive hyperemia: pretraining and posttraining in eight healthy men compared with age-matched untrained controls (n = 8). Participants in the training group underwent supervised cycling at 80% maximal heart rate three times a week for 8 wk. RESULTS: We found a significant interaction (P = 0.04) whereby an increase in FMD was observed after training (post 9.83% ± 3.27% vs pre 6.97% ± 1.77%, P = 0.01), with this posttraining value higher compared with the control group (6.9% ± 2.87%, P = 0.027). FMD was not altered in the controls (P = 0.894). There was a significant interaction for OCT-derived speed (P = 0.038) whereby a significant decrease in the local disk heating response was observed after training (post 98.6 ± 3.9 µm·s-1 vs pre 102 ± 5 µm·s-1, P = 0.012), whereas no changes were observed for OCT-derived speed in the control group (P = 0.877). Other OCT responses (diameter, flow rate, and density) to local heating and reactive hyperemia were unaffected by training. CONCLUSIONS: Our findings suggest that vascular adaptation to exercise training is not uniform across all levels of the arterial tree; although exercise training improves larger artery function, this was not accompanied by unequivocal evidence for cutaneous microvascular adaptation in young healthy subjects.

Assessment of cerebrovascular responses to physiological stimuli in identical twins using multimodal imaging and computational fluid dynamics.

There is acknowledged variability in the Circle of Willis (CoW) in the general population, yet the structure and function relationship of the cerebrovasculature is poorly understood. We aimed to demonstrate the feasibility of combining high-resolution imaging techniques and computational fluid dynamics (CFD) to describe cerebrovascular structure and function in vivo. We tested our methodology by examining the null hypothesis that monozygotic twins (18-30 yr) would exhibit similar CoW structure and function. Six twin pairs underwent 3T magnetic resonance angiography of the head and neck and B-mode Doppler ultrasound for velocity and diameter recordings in the vertebral and internal carotid arteries under three conditions (rest, hypercapnia, and exercise). Artery diameter, length, tortuosity, and bifurcation angle were assessed in regions of interest of the CoW. We simulated hemodynamics to determine the cardiac-cycle time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT). We observed low and insignificant intraclass correlations (ICC) between twins in all regions for diameter (ICC range 0.000-0.657, P > 0.05), two of four regions for length (ICC range 0.355-0.368, P > 0.05), all regions for tortuosity (ICC range 0.270-0.505, P > 0.05), and all bifurcation angles (ICC range 0.000-0.547, P > 0.05). Similarly, no significant correlations were apparent for cerebral blood flow or CFD-derived measures of TAWSS, OSI, and RRT, at rest or in response to hypercapnia or exercise. Therefore, differences exist in CoW structure and associated shear stress in response to physiological stimulation. These data suggest that the structure, function, and health of cerebrovascular arteries are not primarily genetically dependent.NEW & NOTEWORTHY There is acknowledged variability in the Circle of Willis in the general population, yet the structure and function relationship of the cerebrovasculature is poorly understood. Using a combination of magnetic resonance imaging, high-resolution Doppler ultrasound, and computational fluid dynamic modeling, we show that monozygotic twins exhibit differences in cerebrovascular structure and function when exposed to physiological stimuli. These data suggest that the morphology, function, and health of cerebrovascular arteries are not primarily genetically determined.

Cerebral blood flow responses to exercise are enhanced in left ventricular assist device patients after an exercise rehabilitation program.

Cerebral blood flow during exercise is impaired in patients with heart failure implanted with left ventricular assist devices (LVADs). Our aim was to determine whether a 3-mo exercise training program could mitigate cerebrovascular dysfunction. Internal carotid artery (ICA) blood flow and intracranial middle (MCAv) and posterior cerebral (PCAv) artery velocities were measured continuously using Doppler ultrasound, alongside cardiorespiratory measures at rest and in response to an incremental cycle ergometer exercise protocol in 12 LVAD participants (5 female, 53.6 ± 11.8 yr; 84.2 ± 15.7 kg; 1.73 ± 0.08) pre- (PreTR) and post- (PostTR) completion of a 3-mo supervised exercise rehabilitation program. At rest, only PCAv was different PostTR (38.1 ± 10.4 cm/s) compared with PreTR (43.0 ± 10.8 cm/s; P < 0.05). PreTR, the reduction in PCAv observed from rest to exercise (5.2 ± 1.8%) was mitigated PostTR (P < 0.001). Similarly, exercise training enhanced ICA flow during submaximal exercise (~8.6 ± 13.7%), resulting in increased ICA flow PostTR compared with a reduced flow PreTR (P < 0.001). Although both end-tidal partial pressure of carbon dioxide and mean arterial pressure responses during incremental exercise were greater PostTR than PreTR, only the improved PETCO2 was related to the improved ICA flow (R2 = 0.14; P < 0.05). Our findings suggest that short-term exercise training improves cerebrovascular function during exercise in patients with LVADs. This finding should encourage future studies investigating long-term exercise training and cerebral and peripheral vascular adaptation.NEW & NOTEWORTHY Left ventricular assist devices, now used as destination therapy in end-stage heart failure, enable patients to undertake rehabilitative exercise training. We show, for the first time in humans, that training improves cerebrovascular function during exercise in patients with left ventricular assist devices. This finding may have implications for cerebrovascular health in patients with heart failure.

Visualizing and quantifying the impact of reactive hyperemia on cutaneous microvessels in humans.

The mechanisms underlying reactive hyperemia (RH) responses in microvessels are poorly understood. Previous assessment tools have not been capable of directly visualizing microvessels during physiological stimulation in humans. Optical coherence tomography (OCT) is capable of imaging and quantifying subcutaneous microvessels as small as ~30 µm. In this study we use OCT to visualize and quantify skin microvascular changes in response to RH for the first time in humans. We also assessed the reproducibility of this technique. OCT and laser Doppler flowmetry (LDF) were used simultaneously to scan cutaneous microvessels in 10 young healthy subjects on 2 days. We applied a speckle decorrelation algorithm to assess OCT images and calculated flow rate, speed, diameter, and density parameters. Measures were obtained at rest (baseline) and 30-s following a 5-min cuff inflation (RH). All data were compared between days. The RH stimulus significantly increased (P < 0.0001) OCT-derived microvascular diameter (37.6 ± 3.4 vs. 44.5 ± 5.2 µm), flow rate (82.4 ± 23.4 vs. 240.1 ± 58.6 pl/s), speed (48 ± 5.7 vs. 101.5 ± 17.1 µm/s), density (5.1 ± 1.7 vs. 14.6 ± 2.6%), and also LDF-derived flux (12.3 ± 5.7 vs. 31.6 ± 9.1 perfusion units). At baseline, OCT-derived diameter (r = 0.55), flow rate (r = 0.64), speed (r = 0.55), and density (r = 0.75) showed significant between-day correlations (P < 0.05), as did LDF results (r = 0.74). In response to RH, OCT-derived diameter (r = 0.63) and density (r = 0.64) showed significant correlations (P < 0.05), whereas flow rate (r = 0.45), speed (r = 0.43), and LDF (r = 0.26) were less reproducible. Our study is novel in that it establishes the feasibility of using OCT to visualize and quantify microvascular structure and function responses to RH in humans.NEW & NOTEWORTHY This study describes the first evidence in humans that optical coherence tomography provides direct visualization and comprehensive quantification of cutaneous microvascular hemodynamics as a response to reactive hyperemia. This imaging technique will greatly improve human cutaneous microvascular assessment in physiological and clinical settings.

Morning exercise mitigates the impact of prolonged sitting on cerebral blood flow in older adults.

Preventing declines in cerebral blood flow is important for maintaining optimal brain health with aging. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cerebral blood velocity over 8 h in older adults. In a randomized crossover trial, overweight/obese older adults ( n = 12, 70 ± 7 yr; 30.4 ± 4.3 kg/m2), completed three acute conditions (6-day washout); SIT: prolonged sitting (8 h, control); EX+SIT: sitting (1 h), moderate-intensity walking (30 min), followed by uninterrupted sitting (6.5 h); and EX + BR: sitting (1 h), moderate-intensity walking (30 min), followed by sitting (6.5 h) interrupted with 3 min of light-intensity walking every 30 min. Bilateral middle cerebral artery velocities (MCAv) were determined using transcranial Doppler at 13 time points across the day. The temporal pattern and average MCAv over 8 h was determined. The pattern of MCAv over 8 h was a negative linear trend in SIT ( P < 0.001), but a positive quadratic trend in EX + SIT ( P < 0.001) and EX + BR ( P < 0.01). Afternoon time points in SIT were lower than baseline within condition ( P ≤ 0.001 for all). A morning dip in MCAv was observed in EX + SIT and EX + BR ( P < 0.05 relative to baseline), but afternoon time points were not significantly lower than baseline. The average MCAv over 8 h was higher in EX + SIT than SIT ( P = 0.007) or EX + BR ( P = 0.024). Uninterrupted sitting should be avoided, and moderate-intensity exercise should be encouraged for the daily maintenance of cerebral blood flow in older adults. The clinical implications of maintaining adequate cerebral blood flow include the delivery of vital oxygen and nutrients to the brain. NEW & NOTEWORTHY This is the first study to measure the combined effects of an exercise bout with breaks in sitting on cerebral blood velocity in older adults. Using frequent recordings over an 8-h period, we have performed a novel analysis of the pattern of cerebral blood velocity, adjusting for concurrent measures of mean arterial pressure and other potential confounders in a linear mixed effects regression.

Cerebral Blood Flow during Exercise in Heart Failure: Effect of Ventricular Assist Devices.

INTRODUCTION: In healthy individuals, cerebral blood flow (CBF) increases during exercise, but few studies have compared changes in CBF during exercise in patients with heart failure (HF) to healthy controls (CTRL) or assessed the effects of left ventricular assist devices (LVAD). We hypothesized that subjects implanted with LVAD would exhibit impaired cerebrovascular responses to cycle exercise when compared with age- and sex-matched healthy CTRL subjects but would have enhanced responses relative to subjects with HF. METHODS: Internal carotid artery (ICA) blood flow and intracranial middle (MCAv) and posterior cerebral (PCAv) artery velocities were measured continuously using Doppler ultrasound, alongside cardiorespiratory measures at rest and in response to an incremental submaximal cycle ergometer exercise protocol in nine LVAD participants (58 ± 15 yr, 87 ± 16 kg, 172 ± 8 cm, six females), nine age- and sex-matched subjects with HF (58 ± 8 yr, 84 ± 11 kg, 177 ± 6 cm), and nine CTRL (55 ± 14 yr, 74 ± 16 kg, 168 ± 10 cm). RESULTS: At rest, ICA hemodynamics (velocity, shear rate, and flow) were greater in CTRL and LVAD than that in HF (P < 0.05). Higher MCAv (+5.52 ± 1.59 cm·s, P = 0.003) and PCAv (+5.82 ± 1.41 cm·s, P = 0.001) were also observed in LVAD subjects than healthy CTRL. During exercise, ICA flow increased at all workloads in CTRL, but not in HF or LVAD groups. MCAv increased from baseline in both HF and CTRL participants (P = 0.0001), but not in LVAD subjects. Nonetheless, CTRL and LVAD showed higher MCAv (P = 0.006) and PCAv (P < 0.0001) values throughout exercise than HF. CONCLUSION: Our findings indicate that LVAD subjects exhibit higher CBF at rest and during exercise than matched HF participants but attenuated brain blood flows during exercise when compared with healthy subjects. CBF should be considered when designing exercise training interventions in patients with HF and LVAD.