bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncoupling of flow‐pressure relationships following sport concussion in elite athletes (1068.14)
Authors: Bishop Scott , Burnett Tanis , Smirl Jonathan , Ainslie Philip , van Donkelaar Paul , Neary Patrick 
Published: June 2021

Introduction: Although sports concussion has the potential to impair the brains ability to protect against changes in blood pressure (BP), this has not been examined in in elite adolescent hockey players. We hypothesised that dynamic cerebral pressure‐flow relationships would be altered following a sports‐related concussion.Methods and Procedure: Using a within‐subject design, 49 elite adolescent hockey players (age = 17.4 ± 1.4 years) were tested. Middle cerebral artery velocity, beat‐to‐beat blood pressure and end‐tidal CO2 were measured. Testing sessions involved resting and driven (squat‐stand maneuvers at very low (VLF, 0.05Hz) frequencies) measures to maximize BP variability and improve assessment of the pressure‐flow relationship using transfer function analysis (TFA). Players recovering from a concussion (n=4) repeated the protocol at day 3 ± 2, day 8 ± 2, and day 16 ± 5.Results and Discussion: Preliminary VLF findings for baseline vs. post‐injury indicate that phase parameters (baseline = 1.01 ± .07 radians, day3 = 0.46 ± .1 radians; p <0.05) decreased during the first 3 ± 2 days post injury. By the third measurement, no significant differences were found, however phase parameters were still not completely returned to baseline. This initial change suggests that a concussion causes a reduction in the buffering capacity of the cerebral pressure‐flow response in elite adolescent hockey players.
Dynamic cerebral autoregulation and tissue oxygenation in amnestic mild cognitive impairment (1068.7)
Authors: Tarumi Takashi , Dunsky David , Ayaz Muhammad , Liu Jie , Hill Candace , Armstrong Kyle , Martin‐Cook Kristin , Cullum Munro , Zhang Rong 
Published: June 2021

Background: Vascular disease and dysfunction elevate the risk of Alzheimer’s disease. The objective of this study was to determine whether dynamic regulation of cerebral blood flow and tissue oxygenation is impaired in patients with amnestic mild cognitive impairment (aMCI). Methods: Twenty‐seven patients with aMCI and 15 control subjects underwent measurements of cerebral hemodynamics, brain MRI, and neurocognitive assessment. Dynamic cerebral autoregulation and tissue oxygenation were assessed by transfer function analysis of mean blood pressure (MBP), normalized cerebral blood flow velocity (CBFV%), and cerebral tissue oxygenation index (TOI) at baseline and during a sit‐stand maneuver. Results: Patients with aMCI demonstrated lower cognitive performance in memory and executive function, accompanied by smaller volumes of entorhinal cortex. At baseline, aMCI patients exhibited lower levels of cerebral TOI. Transfer function gain and phase between MBP and CBFV% and between CBFV% and cerebral TOI did not differ between the groups. Within aMCI patients, greater oscillations and transfer function gain of cerebral TOI were associated with the lower scores on delayed recall. Conclusions: An inverse association between transfer function gain of cerebral TOI and memory performance suggests impairment of oxygen transport from the microcirculation to brain tissue in patients with aMCI.Grant Funding Source: National Institute on Aging
Cerebral hemodynamics in normal aging: associations with central hemodynamics and cerebral small vessel disease (1069.2)
Authors: Tarumi Takashi , Ayaz Muhammad , Liu Jie , Tseng Benjamin , Parker Rosemary , Jonathan Riley , Tinajero Cynthia , Zaidi Waqar , Zhang Rong 
Published: June 2021

Background: Blood ejected from the left ventricle perfuses the brain via central elastic arteries, which stiffen with advancing age and may elevate the risk of end‐organ damage. The current study aimed to determine the impact of central arterial aging on cerebral hemodynamics. Methods: Ninety participants aged 22‐80 years were enrolled. Total and pulsatile cerebral blood flows (CBF) were measured by phase‐contrast MR imaging and transcranial Doppler respectively. Central arterial stiffness, wave reflection, and pressure were recorded using applanation tonometry. White matter hyperintensity, a marker of cerebral small vessel disease, was measured by fluid‐attenuated inversion recovery MR imaging. Results: Total CBF decreased with age while systolic and pulsatile CBF increased and diastolic CBF decreased. In the frequency domain, CBF pulsatility at the fundamental harmonic exhibited a steep curvilinear increase with age. Age‐related differences in CBF pulsatility were independently associated with carotid pressure pulsatility. In middle‐aged and older subjects, the prevalence of white matter hyperintensity increased with age and was independently associated with CBF pulsatility. Conclusions: Central arterial aging plays an important role to determine age‐related differences in cerebral hemodynamics. Cerebral small vessel disease is more closely associated with pulsatile CBF than total CBF.Grant Funding Source: National Institute on Aging
Age‐ and estrogen‐dependent effects on cerebrovascular reactivity: shifting from beneficial to detrimental (1069.6)
Authors: Deer Rachel , Perkins Lisa , Stallone John 
Published: June 2021

Although mechanisms underlying the beneficial effects of estrogen on cerebrovascular (CV) function are well known, the age‐dependent deleterious effects are largely unknown. We hypothesized that age enhances the deleterious effects of estrogen on CV function by altering the role of prostanoids in modulating CV reactivity. Female (F) rats approximating key stages of hormonal aging were studied: pre‐menopausal (mature multigravid, MA), and post‐menopausal (reproductively senescent, RS). Rats underwent bilateral ovariectomy (O); some received estrogen replacement therapy (OE). Reactivity to VP (10‐12‐10‐7M) was measured in pressurized middle cerebral arteries (%vasoconstriction) using COX‐1 (SC560, SC, 1μM) or COX‐2 (NS398, NS, 10μM) selective inhibitors. Maximal VP reactivity in MAO (64±0.7%) was attenuated in MAOE by 21%; in contrast, reactivity in RSO (59±1.1%) was enhanced in RSOE by 27%. In MAO and RSO, SC and NS reduced reactivity similarly. In MAOE, SC reduced reactivity to a greater extent than NS (Δ59% vs Δ34%); however, in RSOE this effect was reversed (Δ65% NS vs Δ36% SC). VP‐stimulated release of PGI2 and TXA2 (radioimmunoassay of 6‐keto‐PGF1α and TxB2, stable metabolites, pg/mg dry wt/45min) in MAO (22,805 ± 3,108) and RSO (18,499±1,563) was increased by estrogen in MAOE (+58%) and RSOE (+56%). In contrast, PGI2 in MAO (22,805±3,108) and MAOE (35,975±2,133) was reduced by age in both RSO (‐19%) and RSOE (‐20%). VP‐stimulated TXA2 in MAO (671±57) and RSO (527±71) was increased by estrogen in MAOE (+62%) and RSOE (+165%). TXA2 in MAOE (1,085±70) was increased by age in RSOE (+21%) with no difference in MAO and RSO. These data reveal that the vascular effects of estrogen are distinctly age‐dependent. In younger F, beneficial effects of estrogen are evident (decreased vasoconstriction, increased dilator function). Conversely, in older F, detrimental effects of estrogen dominate (enhanced vasoconstriction, increased constrictor prostanoid function).Grant Funding Source: NIH: HL‐080402
Vigorous treadmill exercise improves reactivity of cerebral arterioles and reduces brain injury following transient focal ischemia (1070.2)
Authors: Arrick Denise , Yang Shu , Li Chun , Sun Hong , Mayhan William 
Published: June 2021

Exercise training (ExT) has been shown to play a significant role in the prevention of cardiovascular‐related diseases. Our goal was to examine whether vigorous exercise training (ExT) could influence nitric oxide synthase (NOS)‐dependent dilation of cerebral arterioles and transient focal ischemia‐induced brain injury in rats. Sprague‐Dawley rats were divided into sedentary (SED) or exercised trained (ExT) groups. Treadmill exercise was carried out 5 days/week for a period of 6‐8 weeks. In the first series of studies, a craniotomy was made over the parietal cortex and we measured responses of pial arterioles to eNOS‐dependent (ADP), nNOS‐dependent (NMDA) and NOS‐independent (nitroglycerin) agonists. In a second series of studies, we measured infarct volume in SED and ExT rats following right middle cerebral artery occlusion (MCAO) for 2 hours followed by 24 hours of reperfusion. In a third series of studies, we measured eNOS, nNOS, SOD1 and SOD2 protein levels in cerebral vessels and brain tissue of SED and ExT rats. We found that eNOS‐ and nNOS‐dependent, but not NOS‐independent vasodilation, was increased in ExT compared to SED rats. In addition, we found that ExT significantly reduced total, cortical and subcortical infarct volumes following ischemia/reperfusion when compared to sedentary rats. Surprisingly, we found that eNOS and nNOS protein levels were similar in ExT and SED rats, but SOD1 and SOD2 protein levels were increased by ExT. We suggest that ExT improves NOS‐dependent vascular function and reduces infarct volume by mechanisms that appear to be related to alterations in oxidative stress. We suggest that ExT may be a viable preventative therapeutic approach to lessen ischemia‐induced brain injury.Grant Funding Source: NIH HL090657
Dysregulation of intracellular Ca2+ in lymphocytes and neutrophils in type 2 diabetic patients (1072.11)
Authors: Singh Jaipaul , Kappala Shanti , Espino Javier , Pariente Jose , Rodriguez Ana , Bidasee Keshore 
Published: June 2021

Background: Patients with T2D are immune‐compromised, making them more susceptible to infections and long term complications than non‐diabetic individuals. Neutrophils and lymphocytes play key roles in host‐immune responses to infections, and their phagocytic and chemotatic activities are reduced in diabetes. To date, the underlying causes for impairment in neutrophils and lymphocytes functions in T2D remain poorly defined. Dysregulation of intracellular Ca2+ cycling is a common phenotype in many diabetic cells. This study investigated if intracellular Ca2+ cycling is also defective in neutrophils and lymphocytes isolated from individuals with T2D.Methods and results: Neutrophils and lymphocytes were obtained from patients with T2D and healthy controls with consent, and their intracellular Ca2+ cycling kinetics when challenged with thapsigargin (TG), formyl‐methionyl‐leucyl‐phenylalanine (fMLP) and hydrogen peroxide (H2O2), were compared using time‐lapsed Ca2+ imaging assays. All cells from T2D and control patients responded to TG, fMLP and H2O2. However, the rate of cytoplasmic Ca2+ rise, peak Ca2+ transient amplitude and Ca2+ transient decay times were significantly compromised in neutrophils and lymphocytes from T2D patients compared to healthy controls.Conclusion: From these data we concluded that neutrophils and lymphocytes from T2DM patients are less responsive to this wide array of intracellular Ca2+ mobilizing agonists compared to control. Moreover, the decreased [Ca2+]i in immune cells might be one of the possible mechanisms of impaired immunity in diabetic patients.
The contribution of cardiac mechanics to isolated increases in peripheral blood flow (1073.4)
Authors: Stöhr Eric , van Mil Anke , Drane Aimee , Pearson James 
Published: June 2021

The human heart responds to whole‐body increases in cardiovascular demand by enhancing heart rate (HR) and intrinsic cardiac muscle function. However, it is not known if enhanced left ventricular (LV) muscle function ('LV mechanics') also contributes to localized increases in peripheral blood flow and, if so, whether enhanced peripheral blood flow per se or other arterial hemodynamic signals are the mechanism for acutely adjusting LV mechanics. We performed cardiac and vascular ultrasonography in eight healthy individuals (4 women) during 1) Baseline, 2) Bilateral arm heating (BAH), and 3) BAH with partial brachial artery occlusion (BAH+OCC) at mean arterial pressure (MAP, 85±15 mmHg). BAH markedly increased skin temperatures (32.71±0.69 to 39.21±0.60 deg. C, p<0.0001) while rectal core temperature was unaltered (p=0.54). Brachial artery blood flow measured in the left arm increased almost threefold with BAH (98±46 to 266±96 mL/min, P<0.0001) and returned to baseline levels with BAH+OCC. Arterial wave reflection, as assessed by applanation tonometry, had a tendency to increase with BAH and remained elevated with BAH+OCC (p=0.07). Increased cardiac output (p=0.02) was entirely explained by increased HR of 3‐4 bpm (P=0.002). In contrast, LV mechanics ‐ evaluated by systolic longitudinal strain and diastolic untwisting velocity ‐ did not change with BAH but they declined significantly with BAH+OCC (both p<0.05), which was accompanied by a rise in MAP (P<0.0001).In conclusion, the heart contributes to isolated increases in peripheral blood flow by enhancing HR but not its intrinsic LV muscle mechanics. Because LV output was maintained during the period of enhanced blood flow demand and increased afterload (=BAH+OCC), reduced systolic and diastolic LV mechanics during this condition may reflect an intrinsic protection of LV myofibers from pressure stress rather than a decline in LV function.
Isoketals in monocyte‐derived dendritic cells activate T cells and promote hypertension (1074.2)
Authors: Loperena Roxana , Kirabo Annet , Roberts L. , Davies Sean , Harrison David 
Published: June 2021

Fatty acid oxidation leads to formation of highly reactive γ‐ketoaldehydes termed isoketals that adduct to protein lysines. We have shown that hypertension causes isoketals to accumulate in dendritic cells (DCs) and activate T cells. Others have shown that human monocytes traversing the endothelium differentiate into monocyte‐derived DCs (mo‐DCs) that express CD83, MHC‐II, CD11b, and CD11c. We hypothesized that isoketal formation promotes transformation of monocytes to mo‐DCs and that this is fundamental to the genesis of hypertension. Thus, we co‐cultured human monocytes with aortic endothelial cells exposed to a hypertensive (10%) stretch for 48 hours. Using flow cytometry, we detected markers for maturation of mo‐DCs expressing CD14low and CD83high with increased isoketals and CD86 activation marker. Exposure of murine DCs to the oxidant tert‐Butyl hydroperoxide (t‐BHP) also led to formation of mo‐DCs expressing CD11b and CD11c with a 3‐fold increase in isoketals. Co‐culture of t‐BHP treated DCs with T cells after 7 days promoted survival and proliferation of CD8+ T cells and a modest proliferation of CD4+ T cells. Moreover, adaptive transfer of t‐BHP treated DCs to mice elevated the hypertensive response to a generally subpressor dose of angiotensin‐II (128 ± 0.80 vs. 114 ± 0.48 in controls). We conclude that oxidant stress and isoketal formation in murine monocytes promote T cell activation and hypertension. Increased stretch of endothelial cells might transfer an oxidant signal to monocytes and promote their transformation to mo‐DCs to mediate this response. These findings provide a mechanism as to how T cells are activated in hypertension and provide insight into the inflammatory nature of this disease.Grant Funding Source: Supported by NHLBI 5P01 HL0580000‐16
Targeted glyoxalase‐1 gene transfer to prevent cardiac dysfunction in diabetes (1078.8)
Authors: Bidasee Keshore , Alomar Fadhel , Rozanski George , Singh Jaipaul 
Published: June 2021

Targeted glyoxalase‐1 gene transfer to prevent cardiac dysfunction in diabetes Keshore R. Bidasee1,2, Fadhel Alomar1, George Rozanski1,2, and Jaipaul Singh3, 1Pharmacol and Exp’t Neurosci, Univ. of Nebraska Medical, Omaha, NE 68198, 2Nebraska Redox Biology Center, Lincoln, Nebraska and 3Forensic and Investigative Sciences, UCLAN, UK.Background: Heart failure is a common pathophysiology in individuals with diabetes. We attributed this defect to dysregulation of key excitation‐contraction (E‐C) coupling proteins arising from post‐translational modifications by the di‐carbonyl methylglyoxal (MG). MG increases mitochondrial ROS production which further compromises contractile function. Since MG regulates physiologic functions, globally lowering it will precipitate undesired side effects. In this project, we identified a sub‐pool of MG responsible for causing heart failure in diabetes.Methods and results: In isolated ventricular myocytes, MG induced Ca2+ waves and impaired contractile kinetics. Daily i.p. injections (21 days) of MGO to control rats to attain serum levels similar to that in diabetes did not impair cardiac ejection fraction or fractional shortening. Immuno‐histochemical analyses of hearts from diabetic animals revealed showed increased expression of the MG‐synthesizing enzyme vascular adhesion protein 1 (VAP‐1) and the MG adduct, argpyrimidine in microvascular smooth muscle cells (SMC). Overexpression the MG‐degrading enzyme glyoxalase‐1 (Glo‐1) in SMC after the onset of diabetes (rodent models of type 1 and type 2 diabetes), blunted cardiac function loss, decreased expression of VAP‐1 and argpyrimidine in SMC, and normalized evoked Ca2+ transient and contraction kinetics in ventricular myocytes without lowering serum MG levels.Conclusion: These data identified for the first time SMC of the microvasculature as a source of myocyte‐damaging MG in diabetes, and pharmacologically lowering this sub‐pool of MG blunts heart failure development.Grant Funding Source: HL085061, GRTP#1053
Calcium alternans induced by enhanced dephosphorylation of phospholamban predisposes to inducibility of ventricular tachycardia in the type I diabetic Akita mouse (1078.9)
Authors: Jin Hongwei , Rajab Mohammad , Aronovitz Mark , Wang Bo , Park Ho‐Jin , Link Mark , Noujaim Sami , Galper Jonas 
Published: June 2021

Introduction: Diabetes mellitus is associated with increased risk of sudden cardiac death. Little evidence exists to support specific mechanisms to account for this association. We studied the inducibility of ventricular tachycardia (VT) in the type I diabetic Akita mouse and ionic and molecular mechanisms of arrhythmogensis. Methods: Inducibility of VT was studied by programmed ventricular stimulation and optical mapping. Left ventricular myocytes were isolated for electrophysiology and calcium imaging studies. Sarcomere shortening and Ca2+ transients were measured using the Ionoptix system. Results: Programmed ventricular stimulation of Akita mice resulted in VT in 80% of mice compared to 20% of WT. Optical mapping of perfused hearts demonstrated multifocal breakthroughs which occasionally gave rise to short lived rotors consistent with focal initiation and maintenance of VT. Both contractile and Ca2+ transient alternans were observed in single ventricular myocytes of Akita mice at field stimulations above 4 Hz. 100nM Iso induced triggered activity in 90% of myocytes from Akita and 7% in WT mice. Ventricular myocytes from Akita mice demonstrated decreased SR Ca2+ reuptake (τ= 170±10 ms vs.138±7ms, n=20, p<0.01) compared to WT and increased cytosolic Ca2+[[Unsupported Character ‐ Codename &amp;shy;]][[Unsupported Character ‐ Codename &amp;shy;]]. Caffeine induced Ca2+ release was significantly decreased in Akita mice vs. WT. Western blot analysis showed that phosphorylated ser16 phospholamban (PLB) and the ratio of SERCA2a/total PLB were significantly decreased in Akita mice. Conclusions: Increased dephosphorylation of PLB caused abnormal SR Ca2+ loading resulting in cardiac alternans predisposing to the development of VT in type 1 diabetic Akita mice.Grant Funding Source: NIH
TRPA1 mediates NADPH oxidase‐dependent cerebral artery dilation (1079.1)
Authors: Sullivan Michelle , Gonzales Albert , Bruhl Allison , Leo M. , Jaggar Jonathan , Welsh Donald , Earley Scott 
Published: June 2021

Activation of the Ca2+‐permeable transient receptor potential (TRP) ankyrin (A) channel TRPA1 in the cerebral artery endothelium with electrophilic compounds induces dilation. Endogenous agonists for endothelial TRPA1 have not been reported. We hypothesized that H2O2 is an endogenous agonist for TRPA1 in this tissue. H2O2 can be generated by NADPH oxidase (NOX) activity via production of a O2‐ intermediate or directly by NOX isoform NOX4. We find that activation of NOX with its substrate, NADPH, increases TRPA1 activity and induces dilation of pressurized cerebral arteries (80 mmHg) that is blocked by TRPA1 inhibitor HC‐030031 (HC) and H2O2 degradation by catalase. In the presence of iron, H2O2 is converted to highly reactive oxygen radicals, such as OH•, by the Fenton reaction. To distinguish between direct effects of H2O2 vs. those of OH• or OH• metabolites we inhibited the Fenton reaction by chelating iron with deferoxamine. Deferoxamine attenuated NADPH‐induced TRPA1 activation and vasodilation, suggesting that OH• formation is required for NOX‐dependent TRPA1 activation. OH• peroxidizes membrane lipids yielding lipid peroxidation products (LPP). The LPP 4‐hydroxynonenal increased TRPA1 activity and induced cerebral artery dilation that was blocked by HC. Together, these data suggest that NOX‐dependent LPP generation activates TRPA1 in cerebral artery endothelial cells to induce vasodilation.Grant Funding Source: Supported by HL091905
Functional hyperemia requires ATP‐sensitive potassium channels and hydrogen peroxide and not adenosine in isolated mice hearts (1079.17)
Authors: Zhou Xueping , Teng Bunyen , Mustafa S. Jamal 
Published: June 2021

We previously demonstrated that adenosine contributes to coronary ischemic vasodilation through A2A AR‐mediated H2O2 production and opening of ATP‐sensitive potassium channels (KATP). Whether the same mechanism applies to functional hyperemia remains unknown. This study aims to investigate the role of adenosine, KATP, and H2O2 in pacing‐induced coronary hyperemia using pharmacological approaches combined with adenosine receptor knockout (KO) mice. Coronary flow was measured in isolated Langendorff perfused hearts paced at a graded rate from 400 to 650 bpm. Coronary flow increased linearly from 17.1 ± 0.7 to 24.1 ± 0.8 ml/min/g with increased HR in WT mice (n=7). Neither non‐selective blockade of adenosine receptor by 8‐(p‐Sulfophenyl) theophylline (8‐SPT, 50 μM, n=6), nor selective A2A AR blockade by SCH58261 (1 μM, n=4) or A2A AR KO (n=9) affected the pacing‐induced coronary hyperemia, though the relationship between coronary flow and rate‐pressure product was shifted downward in a parallel manner. Combined A2A KO with A2B selective blockade (CVT6883, 1 μM, n=3) or vice versa (n=3) showed similar effect as 8‐SPT. Inhibition of nitric oxide synthesis by L‐NAME (100 μM) or combined administration with 8‐SPT did not affect the pacing‐induced coronary hyperemia, but attenuated the resting flow to a similar extent (by ~20%, n=5 per group). However, glibenclamide (KATP channel blocker, 10 μM) significantly decreased both pacing‐induced hyperemia (by ~80%) and baseline flow (by ~45%, n=4). Scavenging of H2O2 by catalase (2500 U/min) also decreased baseline flow (by ~16%) and pacing‐induced coronary hyperemia (by ~24%, n=4), but to a lesser extent than glibenclamide. These findings suggest that adenosine modulates coronary vascular tone under both resting and ischemic conditions but not functional hyperemia. However, H2O2 and KATP channels are important local mechanisms responsible for both coronary ischemic and metabolic vasodilation.Grant Funding Source: Supported by HL027339 and HL 094447