bluuebunny/crossref_metadata_2025_split huggingface dataset:
Central α2-adrenergic mechanisms differentially affect baroreflex control of sympathetic and cardiovagal outflow
Authors: Spafford Julia , Limberg Jacqueline , Harvey Ronée , Wiggins Chad , Iannarelli Nathan , Senefeld Jonathon , Nicholson Wayne 
Published: May 2024

This study aimed to investigate the impact of central α2-adrenergic mechanisms on arterial baroreflex control of sympathetic and cardiovagal outflow in healthy humans. R-R interval (ECG), blood pressure (brachial arterial catheter), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured in eight healthy participants (5 females; 28±7 years). Sympathetic action potentials (AP) were extracted from the filtered MSNA neurogram (continuous wavelet transform) during a 5-minute baseline (BSL) and an intravenous dexmedetomidine infusion consisting of a loading dose (LD; 10 minutes at 0.225 μg/kg/hr) and a maintenance dose (MD; ~0.15 μg/kg/hr). Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and diastolic blood pressure. The linear relationship between R-R interval and systolic blood pressure (sequence technique) quantified cardiovagal baroreflex gain. Mixed-effects analyses and post-hoc t-tests were performed. Data are reported as mean ± SD. Dexmedetomidine reset the baroreflex threshold operating points for all sympathetic AP clusters downwards to lower firing probabilities (cluster 4; BSL: 20±6, LD: 13±8, MD: 6±5%, both p<0.01 vs. BSL) and leftwards to lower diastolic pressures (BSL: 72±9, LD: 69±8, MD: 65±10 mmHg, both p<0.01 vs. BSL). Dexmedetomidine reduced baroreflex threshold gain for the subpopulation of medium-sized sympathetic APs (cluster 4; BSL: -6.5±2.0, LD: -2.6±1.6, MD: -2.0±0.7 %/mmHg, both p<0.01 vs. BSL). Dexmedetomidine did not affect baroreflex threshold gain of small (cluster 1; BSL: -1.9±1.1, LD: -1.3±1.6, MD: -1.1±0.8 %/mmHg, both P>0.88 vs. BSL) or large AP clusters (cluster 9; BSL: -0.8±0.4, LD: -0.8±1.0, MD: -0.2±0.7 %/mmHg, both P>0.98 vs. BSL). Dexmedetomidine reset the cardiovagal baroreflex to lower systolic pressures but did not affect R-R interval (BSL: 1035±261, LD: 1025±308, MD: 1005±292ms, Main effect P=0.45) or gain (BSL: 24±11, LD: 30±20, MD: 26±25 ms/mmHg, Main effect P=0.63). These findings suggest that central α2-adrenergic mechanisms differentially affect arterial baroreflex control of sympathetic and cardiovagal outflow in humans by minimally affecting cardiovagal baroreflex gain but strongly affecting the baroreflex gain for the subpopulation of medium-sized sympathetic APs. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Presence of XX Sex Chromosome Complement Increases Aortic Circumferential Stiffness in Female Mice
Authors: Kamau Anne , Sakamuri Anil , Sengottaian Divya , O. Ogola Benard 
Published: May 2024

Elastin and collagen uniquely adapt to the mechanical demands of high pulsatile pressure in the vascular system in conjunction with the extracellular matrix (ECM). Elastic fiber networks and collagen are affected by component disorganization, leading to an array of vascular diseases and compromised mechanical behavior. It is shown that women than men have accelerated arterial stiffening. Previously, we have shown increased axial and circumferential linearized material stiffness in the carotid arteries of female than male wildtype mice. Whether sex hormones interact with sex chromosomes is unknown. Therefore, we hypothesize that sex hormones interact with sex chromosomes to increase aortic circumferential stiffening in female than male mice. In this study, we used gonadal intact 15-week-old four core genotype mice (n=4-6/group) comprising female (F) and male (M) mice with either XX or XY sex chromosome complement (SCC). Using a tissue puller, we assessed the stress-strain and displacement-force relationship of the abdominal aorta. Briefly, the aorta was cut into 3mm rings and pulled apart to a range of 1300 μm with a velocity of 35 μm/sec. To determine the load-bearing effect of collagen and elastin, collagenase type II (16 units) and elastase (5 units) were used to digest the aortic ring before pulling. Part of the aortic ring was digested for a PCR array of extracellular matrix and adhesion molecules. We observed a leftward shift of stress-strain in XXF than in XXM (P=0.03). A leftward shift of stress-strain was also indicated in XXF than in XYM mice (P=0.004). Displacement-force tests showed a similar effect with a leftward shift in XXF than XXM (P=0.01). A leftward shift of displacement force was also indicated in XXF than in XYM (P=0.004). Aorta digestion with elastase reversed the phenotype, showing a leftward shift of displacement force in XXM than in XXF (P=0.02). Collagenase digestion removed the observed sex differences in stress-strain and displacement force tests. The PCR array comparing XXF and XXM showed increased fold change in Adamts5 (4.2), Emilin (2.2), Icam1 (2.4), and Thbs2 (3). We also observed the downregulation of Cntn1 (0.4), Cntnna1 (0.5), Ecm1 (0.3), and Fbln1 (4). Our data suggested that XX sex chromosome complement, and ECM genes contribute to the structural stiffness of female mice aorta. Our study will contribute to understanding connective tissue diseases, including arterial stiffness, aortic aneurysms, Marfan and Danlos syndrome. HL105400 and HL155841. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Can the dietary inorganic nitrate supplementation mitigate the vascular dysfunction in elderly with Alzheimer’s disease?
Authors: Venturelli Massimo , Martignon Camilla , Dorelli Gianluigi , Porcelli Simone , Schena Federico , Dalle Carbonare Luca , Giuriato Gaia 
Published: May 2024

Aging and Alzheimer disease (AD) are both characterized by progressive reduction in nitric oxide bioavailability and endothelial function impairment. Promising studies on young healthy individuals underly the positive effect of dietary nitrate supplementation on endothelial function. However, the pharmacokinetics of the plasma nitrate and nitrite (PN) and the accompanying endothelial responsiveness following the oral nitrate ingestion in healthy elderly (HE) and patients with AD is not clear. Our hypothesis was that due to the reduction of nitric oxide bioavailability during aging and AD, an equal dose of oral nitrate (ON) would ameliorate the endothelial responsiveness more in the HE and even more in patients with AD in comparison to healthy young subjects (HY). Therefore, with the aim of investigating the pharmacokinetics of PN and the time-course endothelial responsiveness in response to a single dose ON, 10 HY (25±4 YRS), 10 HE (72±8 YRS) and 13 AD (73±7 YRS) were recruited. PN levels and endothelial responsiveness (single-passive leg movement (ΔPLM)) were measured in the recruited individuals prior to (T0) and hourly for 4 hours (T1, T2, T3, and T4) after: a) a single dose of ON; and b) a single dose of placebo. As expected at T0 both PN and ΔPLM were significantly reduced in the HE and even more reduced in the AD in comparison to the HY (all p<0.001). No changes in PN nor ΔPLM were detected in any group following placebo intake. PN increased significantly in all three groups at T1 (p<0.001) and constantly increased up to T4, but no differences were detected between time points T1 to T4 in any group. ΔPLM increased significantly in all three groups at T2, reaching highest values at T4 (p<0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to HY (p<0.0001) and HE (p<0.001). Significant correlation between PN and ΔPLM was found (p<0.001, R2=0.1654). Contrary to our hypothesis, the results of this study suggest that the PN pharmacokinetics following a single dose of ON is similar in HY, HE and AD. Moreover, the expected time-course amelioration of the endothelial responsiveness was reduced in the HE and even more reduced in the AD, suggesting that other factors, rather than the nitric oxide bioavailability, are playing a role in the age- and AD-related vascular dysfunction. Ricerca di Base 2017 - RBVR17XRSA - Effectiveness of exercise and nitrate supplementation on progression of dementia in patients with Alzheimer’s disease. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Persistent Skeletal Muscle Overexpression of Inflammatory Lipid Mediators After Disuse Corresponds to Impaired Skeletal Muscle Recovery in Aged Mice
Authors: Bourrant Paul-Emile , J. Ferrara Patrick , M. Yee Elena , NMMP. de hart Naomi , J. Fennel Zachary , J. Petrocelli Jonathan , J. Drummond Micah 
Published: May 2024

Aging is associated with impaired recovery of muscle mass and function after a period of disuse, often leading to an increased risk of falls and fractures. The exact mechanisms behind impaired recovery due to aging after disuse are not fully understood. Membrane-derived lipids mediators (LM) in muscle orchestrate inflammatory actions that are critical for restoration of muscle following injury. We tested the hypothesis that muscle LM associated with inflammation would be dysregulated in adult vs older mice during a time course of recovery following disuse atrophy. Therefore, we designed a study in which adult (3-6m/o) and old (23-26m/o) male mice underwent 14 days of hindlimb unloading followed by 2, 4, or 7 days of reloading. The gastrocnemius muscle was collected at each timepoint and between age groups and processed for lipidomic analysis of the eicosanoids. Gastrocnemius muscle mass showed impaired recovery after HU in the old group when compared to adult, at 4 (P=0.0420) and 7 days reload (P=0.0092). We also observed that muscle LM’s associated with acute inflammation (arachidonic acid, prostaglandins, leukotrienes) were significantly overexpressed in old mice during recovery after disuse. Importantly, several of these lipids corresponded with impaired muscle recovery. PGE2 and PGF2a levels showed a correlation (P=0.03 and P=0.02, respectively) with gastrocnemius mass at the 4 days reload. We conclude that recovery from disuse in aged mice are characterized with the upregulation of pro-inflammatory lipids in muscle and this may be related to poor muscle regrowth. Future studies will be considered to determine the role and cell source of these pro-inflammatory LM during muscle recovery in aged mice. Funding was provided by NIH: R01AG076075 awarded to M.J.D. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Hyperventilation in Patients with Postural Orthostatic Tachycardia Syndrome (POTS): Effects of Tidal Volume versus Hypocapnia on Heart Rate
Authors: Ranada Shaun , Baker Jacquie , Karalasingham Kavithra , Hira Rashmin , Incognito Anthony , Wilson Richard , Phillips Aaron 
Published: May 2024

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic form of orthostatic intolerance that significantly impacts the quality of life and day-to-day functioning of patients. POTS has an estimated prevalence of about 1%, predominantly affecting females of child-bearing age. POTS is characterized by an upright increase in heart rate (HR) of ≥30 bpm, without a drop in blood pressure. POTS is associated with chronic (≥ 3 months) upright symptoms including light-headedness, blurred vision, and cognitive dysfunction. A large proportion of POTS patients also experience hyperventilation when upright. Hyperventilation reduces arterial carbon dioxide (CO2; hypocapnia) and exacerbates tachycardia in POTS. Whether the HR response is due to increased tidal volume (VT) per se or the resulting hypocapnia is unclear. Investigating the independent effects of increased VT versus hypocapnia on HR might identify possible therapeutic targets to reduce HR in patients with POTS. Objective: We aimed to characterize the separate effects of hypocapnia and VT on HR in POTS patients. Hypothesis: We hypothesize that hypocapnia and VT will independently increase HR, with hypocapnia causing the greatest increase in HR in patients with POTS. Methods: Twenty female POTS patients (32±10 years) completed supine normocapnic and hypocapnic breathing tests. To assess the effects of hypocapnia on HR, we compared hypocapnic-hyperventilation versus normocapnic-hyperventilation with constant VT. To assess the effects of VT on HR, we compared increased VT breathing versus normal breathing with constant end-tidal CO2 (ETCO2). Breath-by-breath respiratory (VT, ETCO2) and beat-to-beat hemodynamic parameters (stroke volume [SV], HR) were continuously measured. Data were analyzed with paired t-tests, and are reported as mean ± SD. Results: ETCO2 was lower ( p<0.001) with similar VT during hypocapnia compared to normocapnia. Hypocapnia reduced SV (63.3±11.8 mL vs. 72.4±12.3 mL; p<0.001), and increased HR (99±13 bpm vs. 81±9 bpm; p<0.001). Compared to normal breathing, increased VT ( p<0.001) with constant ETCO2 led to a smaller reduction in SV (72.4±12.3 mL vs. 76.0±14.3 mL; p=0.04), and increase in HR (81±9 bpm vs. 75±9 bpm; p<0.001). Conclusion: Our results suggest that hypocapnia and increased VT independently reduce SV and increase HR in POTS patients. The increase in HR was greater during hypocapnia (+18 bpm) compared to increased VT (+6 bpm). Reducing hypocapnia presents an attractive therapeutic target. Disclosures: This work was supported by Standing up to POTS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
PVN predisposes microglia to be susceptible to hemodynamic signals and promote sympathetic excitation in hypertension
Authors: Wei Bo , Cheng Guo , Bi Qianqian , Shen Xiao , Shi Peng 
Published: May 2024

Hypertension is usually accompanied with an elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not fully understood. Recent advances reveal that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels, and found that microglia in the hypothalamic paraventricular nucleus (PVN) were early responders to hypertensive challenges. PVN is the central hub for maintaining cardiovascular function via regulation of fluid balance and sympathetic outflow. Comprehensive vasculature analyses unveiled that PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology among brain regions. As such, PVN is susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. ATP ligation to microglial P2Y12 receptor is responsible for the microglial accumulation and activation in the PVN. Both pharmacological blockade and genetic ablation of microglial P2Y12 could substantially restrain blood pressure increase under hypertensive challenge. Together, these findings disclose that a unique vasculature pattern results in the vulnerability of PVN pre-sympathetic neurons to hypertension-associated inflammatory insults, which is mediated by microglia. NSFC82170441. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Exploring Contribution of HMGA2 to the Aggressive Tumor Structure in Urothelial Carcinoma to Identify Prospective Clinical Applications
Authors: Liu Hui-Ying , Luo Hao-Lun 
Published: May 2024

For patients with advanced upper tract urothelial carcinoma (UTUC), the five-year survival rate is approximately 20-40%. In previous real-world data analyses, we observed that UTUC patients with a sessile tumor architecture tend to exhibit more aggressive behavior and concurrently have poorer outcomes in terms of metastasis-free and cancer-specific survival. This suggests that tumor architecture may serve as a crucial prognostic factor for predicting outcomes. We utilized various tumor tissue specimens, categorizing them based on tumor architecture into papillary and sessile groups. RNA sequencing was used to analyze the two groups, and significant differences in the expression levels of high mobility group AT-hook 2 (HMGA2) were found. In the more aggressive sessile tumor architecture, HMGA2 exhibited higher expression levels. HMGA2 is currently known to participate in various biological processes, including the cell cycle, DNA damage repair, apoptosis, and epithelial-mesenchymal transition. Additionally, HMGA2 is abnormally regulated in several human cancers, such as lung, breast, ovarian, and bladder cancers. Elevated expression of HMGA2 is associated with a higher risk of tumor recurrence and cancer progression. Hence, we hypothesize that HMGA2 may regulate tumor cell epithelial-mesenchymal transition through the PI3K-Akt cell signaling pathway, influencing tumor architecture and cancer prognosis. Attempting to downregulate HMGA2 should theoretically enhance the effectiveness of chemotherapeutic drugs in achieving an anti-cancer effect. We discovered that inhibiting the expression of HMGA2 using siRNA in UTUC cells, such as BFTC909, significantly reduces cell proliferation and migration. Moreover, the addition of an HMGA2 inhibitor known as suramin enhances cytotoxic effects and decreases cell migration. Our preliminary findings provide evidence indicating a correlation between high levels of HMGA2 expression and aggressive tumor architecture in UTUC. We designed UTUC patient-derived organoids (PDO). The test results revealed that the organoids, as indicated by HE stain and Ki67 immunohistochemical (IHC) staining, closely resembled their corresponding parental tumors. Currently, it appears that the organoids have retained the original tumor structure and protein molecular expression characteristics. The PDO model is hoped to serve as a valuable tool in aiding the selection of suitable therapeutic strategies as clinical applications. This study was funded by the Chang Gung Medical Foundation, Taiwan (CMRPG8M0131, and CMRPG8M0132) and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-182A-140). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Obesity and Ventilatory Effciency During Exercise in the Fitness Registry and the Importance of Exercise National Database (FRIEND)
Authors: Bissen Thomas , Arena Ross , Harber Matthew , Kaminsky Leonard , Myers Jonathan , Watso Joseph 
Published: May 2024

Background: A high minute ventilation/rate of carbon dioxide production (V̇E/V̇CO2) slope during exercise (i.e., ventilatory ineffciency) is more common in patients with cardiovascular disease and is prognostic of cardiovascular mortality. Interestingly, recent data in adults with obesity suggest that V̇E/V̇CO2 slopes are lower with higher body mass index (BMI) values in the context of adults with and without comorbidities. However, it is unclear whether obesity is associated with V̇E/V̇CO2 slope in adults without comorbidities. Therefore, we used the Fitness Registry and the Importance of Exercise National Database (FRIEND) to test the hypothesis that adults with obesity would have a reduced V̇E/V̇CO2 slope compared with adults without obesity in the context of no known comorbidities. Methods: We used the CDC definition for obesity as a BMI of ≥30 kg/m2. We excluded those with known chronic disease, smoking status, or any medication use. We only included adults with a respiratory exchange ratio >1.00 at peak exercise. All data are presented as median[IQR] because they failed Shapiro-Wilk normality tests ( p>0.05). For our primary analyses, we compared groups using a Mann-Whitney U test (unadjusted) and linear regression adjusted for age, sex, and race (cardiorespiratory fitness was not a significant covariate). We set α a priori to <0.05. Results: The sample (n=3588) characteristics were as follows: 1) age = 40[18] years (range 18-91 years); 2) 20% female; 3) 0.4% American Indian, 3% Asian, 14% Black, 8% Hispanic, 3% Other, 66% White, and 5% Unknown; 4) cardiorespiratory fitness = 27.8[10.8] mLO2·kg−1·min−1; and 5) 17% with obesity. As expected, BMI was different between groups (obese: 32.1[3.0], non-obese: 24.6[4.0] kg/m2, rank biserial correlation[rbc]=1.00, p<0.001). The V̇E/V̇̇CO2 slope was higher in adults with obesity (obese: 25.0[3.5], non-obese: 24.7[3.6], rbc=0.07, p=0.009). Obesity was a significant predictor of the V̇̇E/V̇̇CO2 slope (standard error of the estimate: 0.16 [95% CI 0.09-0.70], p=0.01) after covariate adjustment (model: R2=0.174, F4,3583=188, p<0.001). BMI was also related to the V̇E/V̇̇CO2 slope (ρ=0.07, p<0.001). Finally, the proportion of V̇̇E/V̇̇CO2 slope values >45 was not different between groups (obese: 0.2%, non-obese: 0.3%, X2=0.48, p=0.49). Conclusion: In contrast to our hypothesis, data from the FRIEND indicate that those with obesity exhibit mildly greater ventilatory ineffciency during exercise than those without obesity in the context of no known comorbidities. Funding: National Institutes of Health K01HL160772 (JCW), American Heart Association 23CDA1037938 (JCW). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.