Nitric Oxide-Dependent Micro-and Macro-Vascular Dysfunction Occurs Early in Adolescents with Type 1 Diabetes

Background: Arterial stiffness and endothelial dysfunction are both reported in children with type 1 diabetes (DM1) and may predict future cardiovascular events. In health, nitric-oxide (NO) relaxes arteries and increases microvascular perfusion. The relationships between NO-dependent macro- and microvascular functional responses and arterial stiffness have not been studied in adolescents with DM1. Here we assessed macro- and microvascular function in DM1 adolescents and aged-matched controls at baseline and during an oral glucose challenge (OGTT). Methods: DM1 adolescents (n=16) and controls (n=14) were studied before and during an OGTT. At baseline we measured: A) large artery stiffness using both aortic augmentation index (AI) and carotid-femoral pulse wave velocity (cfPWV); B) brachial flow-mediated dilation (FMD) and forearm endothelial function using post-ischemic flow velocity (PIFV); and C) forearm muscle microvascular blood volume (MBV) using contrast-enhanced ultrasound. Following OGTT, AI, cfPWV and MBV were reassessed at 60 min and MBV again at 120 min. Within individual and between-group comparisons were made by paired and unpaired t-tests or repeated measures ANOVA. Results: Baseline FMD was lower (p=0.02) in DM1. PWV at 0 and 60 min did not differ between groups. Baseline AI did not differ between groups but declined with OGTT only in controls (p=0.02) and was lower than DM1 at 60 min (p<0.03). Baseline MBV was comparable in DM1 and control groups, but declined in DM1 at 120 min (p=0.01) and was lower than the control group (p<0.03). There was an inverse correlation between plasma glucose and MBV at 120 min (r= -0.523, p<0.01). No differences were noted between groups for VO2max (ml/min/kg), body fat (%), or BMI. Conclusions: NO-dependent macro- and microvascular function, including FMD and AI, and microvascular perfusion respectively are impaired early in the course of DM1, precede increases of arterial stiffness, and may provide an early indicator of vascular risk.

Heterogeneity of Tau Deposition and Microvascular Involvement in MCI and AD

Background: Reduced cerebrovascular function and accumulation of tau pathology are key components of cognitive decline in Alzheimer’s disease (AD). Recent multimodal neuroimag- ing studies show a correlation between cortical tau accumulation and reduced cerebral perfusion. However, animal models predict that tau exerts capillary-level changes that may not be fully cap- tured by standard imaging protocols. Objective: Using newly-developed magnetic resonance imaging (MRI) technology to measure cap- illary-specific perfusion parameters, we examined a series of mild cognitive impairment (MCI) and AD patients with tau positron emission tomography (PET) to observe whole-brain capillary perfu- sion alterations and their association with tau deposition. Methods: Seven subjects with MCI or AD received Flortaucipir PET to measure tau deposition and spin-echo dynamic susceptibility contrast (SE-DSC) MRI to measure microvascular perfusion (<10μm radius vessels). Gradient-echo (GE) DSC and pseudocontinuous arterial spin labeling (P- CASL) MRI were also acquired to assess macrovascular perfusion. Tau PET, microvascular perfu- sion, and cortical thickness maps were visually inspected in volumetric slices and on cortical sur- face projections. Results: High tau PET signal was generally observed in the lateral temporal and parietal cortices, with uptake in the occipital cortex in one subject. Global blood flow measured by PCASL was re- duced with increasing tau burden, which was consistent with previous studies. Tau accumulation was spatially associated with variable patterns of microvascular cerebral blood flow (CBF) and oxy- gen extraction fraction (OEF) in the cortex and with increased capillary transit heterogeneity (C- TH) in adjacent periventricular white matter, independent of amyloid-β status. Conclusions: Although macrovascular perfusion generally correlated with tau deposition at the whole-cortex level, regional changes in microvascular perfusion were not uniformly associated with either tau pathology or cortical atrophy. This work highlights the heterogeneity of AD-related brain changes and the challenges of implementing therapeutic interventions to improve cerebrovas- cular function.

Differential effects of four intramuscular sedatives on cardiorespiratory stability in juvenile guinea pigs (Cavia porcellus)

Background Non-invasive physiological monitoring can induce stress in laboratory animals. Sedation reduces the level of restraint required, thereby improving the validity of physiological signals measured. However, sedatives may alter physiological equilibrium introducing unintended bias and/or, masking the experimental outcomes of interest. We aimed to investigate the cardiorespiratory effects of four short-acting sedatives in juvenile guinea pigs. Method 12 healthy, 38 (26–46) day-old Dunkin Hartley guinea pigs were included in this blinded, randomised, crossover design study. Animals were sedated by intramuscular injection using pre-established minimum effective doses of either alfaxalone (5 mg/kg), diazepam (5 mg/kg), ketamine (30 mg/kg), or midazolam (2 mg/kg) administered in random order with a minimum washout period of 48 hours between agents. Sedative depth, a composite score comprised of five assessment criteria, was observed every 5-min from dosing until arousal. Physiological monitoring of cardiorespiratory status included measures of heart rate, blood pressure, respiratory rate, and peripheral microvascular perfusion. Results Ketamine and alfaxalone were most effective in inducing stable sedation suitable for physiological monitoring, and diazepam less-so. Midazolam was unsuitable due to excessive hypersensitivity. All sedatives significantly increased heart rate above non-sedated control rates (P<0.0001), without altering blood pressure or microvascular perfusion. Alfaxalone and ketamine reduced respiratory rate relative to their control condition (P<0.0001, P = 0.05, respectively), but within normative ranges. Conclusion Ketamine and alfaxalone are the most effective sedatives for inducing short duration, stable sedation with minimal cardiorespiratory depression in guinea pigs, while diazepam is less-so. However, alfaxalone is the most appropriate sedative for longitudinal studies requiring multiple physiological timepoints.

Acute Effects of Foam Rolling on Hamstrings After Half-Marathon: A Muscle Functional Magnetic Resonance Imaging Study

Purpose: Foam rolling (FR) is widely used for post-exercise muscle recovery; yet, the effects of FR on skeletal muscle inflammation and microvascular perfusion following prolonged exercise are poorly understood. We aim to address the gap in knowledge by using magnetic resonance imaging (MRI) T2 mapping and intravoxel incoherent motion (IVIM) sequences to study the acute effects of FR on hamstrings following half-marathon running in recreational runners.Methods: Sixteen healthy recreational marathon runners were recruited. After half-marathon running, FR was performed on the hamstrings on the dominant side, while the other limb served as a control. MRI T2 and IVIM scans were performed bilaterally at baseline (pre-run), 2–3 h after running (post-run), immediately after FR (post-FR0), 30 min after FR (post-FR30) and 60 min after FR (post-FR60). T2, a marker for inflammatory edema, as well as IVIM microvascular perfusion fraction index f for biceps femoris long head (BFL), semitendinosus (ST) and semimembranosus (SM) were determined. Total Quality Recovery (TQR) scale score was also collected.Results: Both T2 and f were higher at post-run compared to pre-run in all hamstrings on both sides (all p &lt; 0.05; all d &gt; 1.0). For the FR side, T2 decreased, and f increased significantly at post-FR0 and post-FR30 compared to post-run in all muscles (p &lt; 0.05; all d &gt; 0.4) except for f at BFL and SM at post-FR30 (both p &gt; 0.05), though f at BFL was still marginally elevated at post-FR30 (p = 0.074, d = 0.91). Both parameters for all muscles returned to post-run level at post-FR60 (all p &gt; 0.05; all d &lt; 0.4) except for T2 at SM (p = 0.037). In contrast, most MRI parameters were not changed at post-FR0, post-FR30 and post-FR60 compared to post-run for the control side (p &lt; 0.05; d &lt; 0.2). TQR scores were elevated at post-FR0 and post-FR30 compared to post-run (both p &lt; 0.05; both d &gt; 1.0), and returned to the post-run level at post-FR60 (p &gt; 0.99; d = 0.09). Changes in TQR scores compared to post-run at any time points after FR were correlated to T2 for ST at post-FR30 (r = 0.50, p = 0.047) but not T2 for other muscles and any changes in f values.Conclusions: Hamstrings inflammatory edema and microvascular perfusion were elevated following half-marathon running, which were detectable with MRI T2 mapping and IVIM sequences. FR resulted in acute alleviation in inflammation and greater microvascular perfusion; however, the effects seemed to last only for a short period of time (30–60 min). FR can provide short-term benefits to skeletal muscle after prolonged running.

Noninvasive Assessment of Foot Perfusion in a Rabbit Model of Atherosclerosis Using Dynamic Volume Perfusion CT with an Upslope Method

Objectives: To evaluate the feasibility of foot dynamic volume CT with the upslope method and to demonstrate macrovascular reactivity and microvascular perfusion during cuff-induced reactive hyperemia state in a rabbit model of atherosclerosis.Materials and Methods: 30 New Zealand male rabbits were divided into 2 groups: dietary hypercholesterolemia induced atherosclerosis (n=10) and normal diet control (n=20). To measure for macrovascular reactivity, perfusion parameters of the left posterior tibial artery was measured at baseline and at reactive hyperemia state. For the evaluation of microvascular perfusion, color-coded perfusion map of the plantar dermis was generated for perfusion CT scan by an in-house dedicated analysis software based on upslope method. Dermal perfusion values were measured and analyzed before and after cuff-induced reactive hyperemia.Results: Foot dynamic volume CT with the upslope method demonstrated significant impairment of both macrovascular reactivity and microvascular perfusion in atherosclerotic rabbits during cuff-induced reactive hyperemia (CRH) state. Arterial time-to-peak of cholesterol-fed rabbits failed to show acceleration while healthy rabbits showed significant decrease in time. Microvascular perfusion calculated by perfusion value (P<0.01) and perfusion ratio (P=.014) showed decreased microvascular perfusion in cholesterol fed rabbits compared to healthy rabbits during CRH state. Post-CT pathologic examination revealed decreased endothelial cell density in cholesterol-fed rabbits (P<0.001).Conclusions: Foot perfusion CT using upslope method provides perfusion parameters for large arteries and a perfusion map of the foot during cuff-induced reactive hyperemia in rabbit models of atherosclerosis. It may be a useful tool for the quantitative and functional evaluation of atherosclerotic peripheral arterial disease.

Association of preoperative plasma suPAR levels with intraoperative sublingual microvascular perfusion in patients undergoing major non-cardiac surgery

Introduction: The plasma suPAR level has previously been associated with postoperative complications and has been shown to be an independent predictor of coronary microvascular function and flow reserve. We investigated the association between preoperative suPAR levels and intraoperative sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery. Methods: This study included 100 patients undergoing major non-cardiac surgery between February 2019 and September 2020. The primary objective was to investigate the association between preoperative suPAR and intraoperative sublingual De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and Consensus PPV (small). Secondary objectives were to investigate the associations between these sublingual microcirculatory variables and (1) complications and (2) mean arterial pressure. EDTA blood was collected before induction of anesthesia and plasma suPAR levels were determined using the suPARnostic quick triage lateral flow assay. Sublingual microcirculation was monitored with Sidestream DarkField (SDF+) imaging technique at 20 minutes after induction of anesthesia before surgical incision (baseline) and then every 30 minutes until emergence from anesthesia. Results: A decrease of 0.7 mm-1 in the De Backer score, 2.5% in the Consensus PPV, and 2.8% in the Consensus PPV (small) from baseline measurement was observed for every 1 ng/ml increase of suPAR or 1 additional minute of intraoperative time. De Baker score did not change significantly from baseline (p=0.404), while Consensus PPV and Consensus PPV (small) decreased significantly from baseline (p<0.001 in both cases). The De Backer score, the Consensus PPV, and the Consensus PPV (small) correlated with postoperative complications. Mean arterial pressure correlated with De Backer score (p=0.487) but not with Consensus PPV (p=0.506) or Consensus PPV (small) (p=0.697) during the intraoperative period. Conclusion: Preoperative suPAR levels and prolonged operative duration were associated with intraoperative impairment of sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.