Novel Techniques For Investigating The Regulation Of Skeletal Muscle Hemodynamics

The effect of the sympathetic nervous system (SNS) on blood flow distribution within skeletal muscle microvasculature is conditional upon regional activation of SNS receptors. Due to a lack of appropriate experimental models and techniques, no study has systematically evaluated the effect of SNS receptor activation in continuously branching skeletal muscle arteriolar trees. In line with previous work, we hypothesize that there will be a spatially-dependent distribution of sympathetic receptor activation along the arteriolar tree. Specifically, we anticipate a progressive decrease of adrenergic activation and a progressive increase of peptidergic and purinergic activation with increasing arteriolar order. We developed a novel rat gluteus maximus (GM) muscle preparation which provided access to a large vascular network, from which we developed an experimental method for collecting cell velocity profiles in fast-flowing arterioles. Using these data, we derived an empirical relationship between velocity ratio (VMax/VMean) and arteriolar diameter, collected novel data on cell free layer width and estimated wall shear rates, and derived a wall shear rate equation from experimental data that can be used for calculating wall shear rates in skeletal muscle microvasculature. We evaluated SNS receptor activation (α1R, α2R, NPY1R, and P2X1R) in continuously branching arteriolar trees in the rat GM, as a function of network topology. A computational flow model estimated the total flow, resistance, and red blood cell flow heterogeneity. For the first time, we highlight effects of SNS receptor activation on network hemodynamics, where proximal arterioles responded most to adrenergic activation, while distal arterioles responded most to Y1R and P2X1R activation. Our data highlight the functional consequences of topologically-dependent SNS receptor activation. The tools developed in this thesis are beneficial for computing hemodynamic parameters from in vivo data, as well as providing input variables to and validation of computational flow models

Sodium nitroglycerin induces middle cerebral artery vasodilatation in young, healthy adults

© 2018 The Authors Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society New Findings: What is the central question of this study? Nitric oxide causes dilatation in peripheral vessels; however, whether nitric oxide affects basal cerebral artery dilatation has not been explored. What is the main finding and its importance? This study demonstrated that vasodilatation occurs in the right middle cerebral artery in response to exogenous nitric oxide. However, blood velocity decreased and, therefore, overall cerebral blood flow remained unchanged. This study provides new insight into the role of nitric oxide in cerebral blood flow control. Abstract: Recent evidence indicates that basal cerebral conduit vessels dilate with hypercapnia, with a nitric oxide (NO) mechanism explaining one way in which parenchymal cerebral arterioles dilate. However, whether NO affects basal cerebral artery dilatation remains unknown. This study quantified the effect of an exogenous NO donor [sodium nitroglycerin (NTG); 0.4 mg sublingual spray] on the right middle cerebral artery (rMCA) cross-sectional area (CSA), blood velocity and overall blood flow. Measures of vessel CSA (7 T magnetic resonance imaging) and MCA blood velocity (transcranial Doppler ultrasound) were made at baseline (BL) and after exogenous NTG or placebo (PLO) administration in young, healthy individuals (n = 10, two males, age range 20–23 years). The CSA increased in the rMCA [BL, 5.2 ± 1.2 mm2; PLO, 5.4 ± 1.5 mm2; NTG, 6.6 ± 1.5 mm2, P \u3c 0.05; mean ± SD]. Concurrently, rMCA blood velocity decreased from BL during NTG compared with PLO (BL, 67 ± 10 cm s−1; PLO, 62 ± 10 cm s−1; NTG, 59 ± 9.3 cm s−1, P \u3c 0.05; mean ± SD]. However, total MCA blood flow did not change with NTG or PLO [BL, 221 ± 37.4 ml min−1; PLO, 218 ± 35.0 ml min−1; NTG, 213 ± 46.4 ml min−1). Therefore, exogenous NO mediates a dilatory response in the rMCA, but not in its downstream vascular bed

An automated cell-counting algorithm for fluorescently-stained cells in migration assays

A cell-counting algorithm, developed in Matlab®, was created to efficiently count migrated fluorescently-stained cells on membranes from migration assays. At each concentration of cells used (10,000, and 100,000 cells), images were acquired at 2.5 ×, 5 ×, and 10 × objective magnifications. Automated cell counts strongly correlated to manual counts (r2 = 0.99, P < 0.0001 for a total of 47 images), with no difference in the measurements between methods under all conditions. We conclude that our automated method is accurate, more efficient, and void of variability and potential observer bias normally associated with manual counting

Exploring Cerebrovascular Function in Osteoarthritis: Heads-up

ndividuals with osteoarthritis (OA) are at greater risk of cardiovascular and cerebrovascular incidents; yet, cerebrovascular control remains uncharacter- ized. Our primary outcome was to acquire cerebrovascular control metrics in patients with OA and compare measures to healthy control adults (CTL) without OA or cardiovascular complications. Our primary covariate was a 10- year risk factor for cardiovascular and stroke incidents, and secondary covari- ates were other cardiovascular disease risk factors (i.e., body mass index, caro- tid intima media thickness, and brachial flow-mediated dilation). Our secondary outcomes were to assess anatomical and functional changes that may be related to cerebrovascular reactivity were also acquired such as white matter lesion volume and brief cognitive assessments. In 25 adults (n = 13 CTL, n = 12 OA), under hypercapnia, magnetic resonance imaging (3T) was used to acquire a “Global Cerebrovascular Reactivity” index across the larger intracranial cerebral arteries and white matter lesions, and transcranial Doppler was used for both middle cerebral artery hemodynamic responses to hypercapnia and to assess autoregulation via a sit-to-stand task. Compared to CTL, OA had lower “Global Cerebrovascular Reactivity” index responses to hypercapnia, autoregulatory responses, and greater white matter lesions (P \u3c 0.05). These differences persisted after covarying for the outlined primary and secondary covariates. Patients with OA, in the absence of known cardio- vascular disease, can exhibit pre-clinical and impaired (compared to CTL) peripheral and cerebrovascular control metrics

Protocol-dependence of middle cerebral artery dilation to modest hypercapnia.

There is a need for improved understanding of how different cerebrovascular reactivity (CVR) protocols affect vascular cross-sectional area (CSA) to reduce error in CVR calculations when measures of vascular CSA are not feasible. In human participants, we delivered ∼±4 mm Hg end-tidal partial pressure of CO2 (PETCO2) relative to baseline through controlled delivery, and measured changes in middle cerebral artery (MCA) CSA (7 Tesla magnetic resonance imaging (MRI)), blood velocity (transcranial Doppler and Phase contrast MRI), and calculated CVR based on a 3-minute steady-state (+4 mm Hg PETCO2) and a ramp (-3 to +4 mm Hg of PETCO2). We observed that (1) the MCA did not dilate during the ramp protocol (slope for CSA across time P \u3e 0.05; R2 = 0.006), but did dilate by ∼7% during steady-state hypercapnia (P \u3c 0.05); and (2) MCA blood velocity CVR was not different between ramp and steady-state hypercapnia protocols (ramp: 3.8 ± 1.7 vs. steady-state: 4.0 ± 1.6 cm/s/mm Hg), although calculated MCA blood flow CVR was ∼40% greater during steady-state hypercapnia than during ramp (P \u3c 0.05) with the discrepancy due to MCA CSA changes during steady-state hypercapnia. We propose that a ramp model, across a delta of -3 to +4 mm Hg PETCO2, may provide an alternative approach to collecting CVR measures in young adults with transcranial Doppler when CSA measures are not feasible. Novelty: We optimized a magnetic resonance imaging sequence to measure dynamic middle cerebral artery (MCA) cross-sectional area (CSA). A ramp model of hypercapnia elicited similar MCA blood velocity reactivity as the steady-state model while maintaining MCA CSA

Roles of Hormone Replacement Therapy and Menopause on Osteoarthritis and Cardiovascular Disease Outcomes: A Narrative Review

Osteoarthritis (OA) is a highly prevalent condition characterized by degradation of the joints. OA and cardiovascular disease (CVD) are leading contributors to disease burden worldwide, with a high level of overlap between the risk factors and occurrence of both conditions. Chief among the risk factors that contribute to OA and CVD are sex and age, which are both independent and interacting traits. Specifically, the prevalence of both conditions is higher in older women, which may be mediated by the occurrence of menopause. Menopause represents a significant transition in a women's life, and the rapid decline in circulating sex hormones, estrogen and progesterone, leads to complex physiological changes. Declines in hormone levels may partially explain the increase in prevalence of OA and CVD in post-menopausal women. In theory, the use of hormone therapy (HT) may buffer adverse effects of menopause; however, it is unclear whether HT offers protective effects for the onset or progression of these diseases. Studies have shown mixed results when describing the influence of HT on disease risk among post-menopausal women, which warrants further exploration. The roles that increasing age, female sex, HT, and CVD play in OA risk demonstrate that OA is a multifaceted condition. This review provides a timely consolidation of current literature and suggests aims for future research directions to bridge gaps in the understanding of how OA, CVD, and HT interact in post-menopausal women

Impaired dynamic cerebral autoregulation in trained breath-hold divers

Breath-hold divers (BHD) experience repeated bouts of severe hypoxia and hypercapnia with large increases in blood pressure. However, the impact of long-term breath-hold diving on cerebrovascular control remains poorly understood. The ability of cerebral blood vessels to respond rapidly to changes in blood pressure represents the property of dynamic autoregulation. The current investigation tested the hypothesis that breathhold diving impairs dynamic autoregulation to a transient hypotensive stimulus. Seventeen BHD (3 women, 11 ± 9 yr of diving) and 15 healthy controls (2 women) completed two or three repeated sit-tostand trials during spontaneous breathing and poikilocapnic conditions. Heart rate (HR), finger arterial blood pressure (BP), and cerebral blood flow velocity (BFV) from the right middle cerebral artery were measured continuously with three-lead electrocardiography, finger photoplethysmography, and transcranial Doppler ultrasonography, respectively. End-tidal carbon dioxide partial pressure was measured with a gas analyzer. Offline, an index of cerebrovascular resistance (CVRi) was calculated as the quotient of mean BP and BFV. The rate of the drop in CVRi relative to the change in BP provided the rate of regulation [RoR; (δCVRi/δT)/δBP]. The BHD demonstrated slower RoR than controls (P ≤ 0.001, d = 1.4). Underlying the reduced RoR in BHD was a longer time to reach nadir CVRi compared with controls (P = 0.004, d = 1.1). In concert with the longer CVRi response, the time to reach peak BFV following standing was longer in BHD than controls (P = 0.01, d = 0.9). The data suggest impaired dynamic autoregulatory mechanisms to hypotension in BHD. NEW & NOTEWORTHY Impairments in dynamic cerebral autoregulation to hypotension are associated with breath-hold diving. Although weakened autoregulation was observed acutely in this group during apneic stress, we are the first to report on chronic adaptations in cerebral autoregulation. Impaired vasomotor responses underlie the reduced rate of regulation, wherein breath-hold divers demonstrate a prolonged dilatory response to transient hypotension. The slower cerebral vasodilation produces a longer perturbation in cerebral blood flow velocity, increasing the risk of cerebral ischemia

Are we missing the target? Are we aiming too low? What are the aerobic exercise prescriptions and their effects on markers of cardiovascular health and systemic inflammation in patients with knee osteoarthritis? A systematic review and meta-analysis

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. Objectives We systemically reviewed published studies that evaluated aerobic exercise interventions in patients with knee osteoarthritis (OA) to: (1) report the frequency, intensity, type and time (FITT) of exercise prescriptions and (2) quantify the changes in markers of cardiovascular health and systemic inflammation. Data sources PubMed, CINAHL, Scopus; inception to January 2019. Eligibility criteria Randomised clinical trials (RCT), cohort studies, case series. Design We summarised exercise prescriptions for all studies and calculated effect sizes with 95% CIs for between-group (RCTs that compared exercise and control groups) and within-group (pre-post exercise) differences in aerobic capacity (VO 2), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and inflammatory markers (interleukin-6 (IL-6), tumour necrosis factor-alpha). We pooled results where possible using random effects models. Results Interventions from 49 studies were summarised; 8% (4/49) met all FITT guidelines; 16% (8/49) met all or most FITT guidelines. Fourteen studies (10 RCTs) reported at least one marker of cardiovascular health or systemic inflammation. Mean differences (95% CI) indicated a small to moderate increase in VO 2 (0.84 mL/min/kg; 95% CI 0.37 to 1.31), decrease in HR (-3.56 beats per minute; 95% CI -5.60 to -1.52) and DBP (-4.10 mm Hg; 95% CI -4.82 to -3.38) and no change in SBP (-0.36 mm Hg; 95% CI -3.88 to 3.16) and IL-6 (0.37 pg/mL; 95% CI -0.11 to 0.85). Within-group differences were also small to moderate. Conclusions In studies of aerobic exercise in patients with knee OA, very few interventions met guideline-recommended dose; there were small to moderate changes in markers of cardiovascular health and no decrease in markers of systemic inflammation. These findings question whether aerobic exercise is being used to its full potential in patients with knee OA. PROSPERO registration number CRD42018087859

The human cortical autonomic network and volitional exercise in health and disease

© 2018, Canadian Science Publishing. All rights reserved. The autonomic nervous system elicits continuous beat-by-beat homeostatic adjustments to cardiovascular control. These modifications are mediated by sensory inputs (e.g., baroreceptors, metaboreceptors, pulmonary, thermoreceptors, and chemoreceptors afferents), integration at the brainstem control centres (i.e., medulla), and efferent autonomic neural outputs (e.g., spinal, preganglionic, and postganglionic pathways). However, extensive electrical stimulation and functional imaging research show that the brain’s higher cortical regions (e.g., insular cortex, medial prefrontal cortex, anterior cingulate cortex) partake in homeostatic regulation of the cardiovascular system at rest and during exercise. We now appreciate that these cortical areas form a network, namely the “cortical autonomic network” (CAN), which operate as part of a larger central autonomic network comprising 2-way communication of cortical and subcortical areas to exert autonomic influence. Interestingly, differential patterns of CAN activity and ensuing cardiovascular control are present in disease states, thereby highlighting the importance of considering the role of CAN as an integral aspect of cardiovascular regulation in health and disease. This review discusses current knowledge on human cortical autonomic activation during volitional exercise, and the role of exercise training on this activation in both health and disease