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Introduction: Endothelial cell (EC) dysfunction, driven by comorbidities of heart failure with preserved ejection fraction (HFpEF), has emerged as a potential contributor to disease progression, yet the EC specific molecular mediators in HFpEF remain poorly defined. Purpose: To identify EC-specific molecular mediators that are involved in HFpEF and determine their functional roles in disease pathogenesis. Hypothesis: Based on omics analysis of a murine HFpEF model, we hypothesized that EC plasminogen activator inhibitor-1 (PAI-1) is a key mediator of HFpEF pathogenesis. Methods: Male RiboTagEC (Cdh5CreERT2+/Rpl22HA/+) mice were used in a HFpEF model induced by hypertensive/metabolic stresses (60% calories from lard and L-NAME 0.5 g/L in water) or administrated with normal water and diet as controls. Hearts and skeletal muscle were collected for both bulk RNA sequencing (Bulk-seq) and EC-specific translatome analysis using translating ribosome affinity purification assay followed by RNA-sequencing (TRAP-seq). The functional roles of EC PAI-1 were tested using male tamoxifen-inducible, endothelial specific PAI-1 knockout (Cdh5CreERT2+/PAI-1flox/flox, PAI-1iEC KO) and control mice (PAI-1flox/flox, PAI-1iEC+/+) subjected to HFpEF induction. Cardiac function was assessed by echocardiography, pressure–volume (PV) loop analysis, and treadmill exercise testing. Student’s t-test was used (p < 0.05). Results: Bulk-seq and EC-specific TRAP-seq identified PAI-1 as one of the most upregulated genes in both heart and skeletal muscle EC in HFpEF. Bulk-seq demonstrated a 2.5-fold change (FC, log 2 FC=1.35) increases in the heart and 12.2-fold increases (log 2 FC = 3.61) in the skeletal muscle. TRAP-seq showed a 1.75-fold change (log 2 FC=0.81) increases in the heart and 4.76-fold increases (log 2 FC = 2.25) in the skeletal muscle. These consistent findings led us to investigate the functional role of EC PAI-1 in the pathogenesis of HFpEF. With similar body weight (Control: 40±4 g, n=10; KO: 38±6 g, n=11; p=0.319) and ejection fraction (Control: 54±6 %, n=10; KO: 54±5 %, n=12; p=0.686), we found that PAI-1iEC KO mice exhibited improved diastolic function after 10 weeks of HFpEF induction. Specifically, echocardiography demonstrated a significant reduction in E/e′ in KO mice (Control: 27±4, n=10; KO: 24±3, n=12; p=0.018). PV analysis confirmed this improvement with lower end-diastolic pressure (Control: 19±2 mmHg, n=8; KO: 13±5 mmHg, n=10; p=0.009), reduced Tau (Control: 9.7±1.2 ms, n=8; KO: 8.6±1.0 ms, n=10; p=0.047), and a reduced EDPVR constant β (Control: 0.20±0.05, n=6; KO: 0.10±0.03, n=6; p=0.017). KO mice also exhibited improved treadmill running distance (Control: 179±35 m, n=10; KO: 214±40 m, n=12; p=0.043). Conclusion: Endothelial PAI-1 contributes to diastolic dysfunction and reduced exercise capacity in HFpEF. These findings highlight endothelial PAI-1 as a potential therapeutic target for HFpEF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) is a common type of myocardial infarction in females under the age of 50 years, caused by sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is mostly females (~80%) with few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Common triggers for SCAD include sympathoexcitatory stimuli, such as intense physical and emotional stress. This implicates the sympathetic nervous system in the pathophysiology of SCAD. Thus, we aimed to investigate sympathetic nervous system responses to mental stress in patients with a history of SCAD. We hypothesized that females with a history of SCAD exhibit a greater increase in muscle sympathetic nerve activity (MSNA) with acute exposure to mental stress compared to healthy females. Methods: Seven females with a history of SCAD (age: 48±9 yrs, BMI: 29±6 kg/m 2 ) and seven age- and BMI-matched healthy female controls (CON, age: 49±9 yrs, BMI: 26±6 kg/m 2 ) participated in the study (both p>0.05). MSNA was measured via peroneal microneurography during a 2-minute rest, a 5-minute Stroop Color Word Test aimed at inducing mental stress, and a 2-minute recovery. Heart rate (HR, 3-lead electrocardiography) and BP (finger photoplethysmography) were continuously recorded during each stage. Data are presented as an absolute change from rest (Δmean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (MBP, SCAD: 96±14 vs CON: 89±7 mmHg, p=0.27), heart rate (HR, SCAD: 56±11vs CON: 65±16 bpm, p=0.25), MSNA burst frequency (SCAD: 22±9 vs CON: 18±7 bursts/minute, p=0.40) and total MSNA (SCAD: 1135±471 vs CON: 951±245 au/min, p=0.41) were not different between the groups. During the Stroop Color Word Test, average changes in MBP (SCAD: Δ10±9 vs CON: Δ8±5 mmHg, p=0.67) and HR (SCAD: Δ11±7 vs CON: Δ14±5 bpm, p=0.35) were not different between the groups. Similarly, average changes in MBP (SCAD: Δ3±4 vs CON: Δ-2±5 mmHg, p=0.13) and HR (SCAD: Δ3±4 vs CON: Δ3±2 bpm, p=0.62) were not different during the recovery. Changes in MSNA burst frequency with the Stroop Color Word Test (SCAD: Δ1±7 vs CON: Δ6±7 bursts/minute, p=0.22) and recovery (SCAD: Δ0±5 vs CON: Δ4±4 bursts/minute, p=0.13) were not different between the groups. Total MSNA changes were also not different during the Stroop Color Word Test (SCAD: Δ267±335 vs CON: Δ606±432 au/min, p=0.15) and recovery (SCAD: Δ68±666 vs CON: Δ217±217 au/min, p=0.61) between the two groups. Conclusion: These preliminary data suggest that contrary to our hypothesis, sympathetic nervous system responses to acute mental stress exposure are not different between females with a history of SCAD and healthy females. Further investigation is needed to understand MSNA association with chronic stress exposure in females with a history of SCAD. Funding: NIH K23 HL155506 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Our knowledge regarding baroreflex regulation of subpopulations of differently sized sympathetic action potentials (APs) remains incomplete. This study tested the hypothesis that baroreflex sigmoid morphology varies across AP subpopulations. In 12 healthy individuals (6 females; 32 ± 5 years), we measured diastolic blood pressure (DBP; brachial artery catheter) and muscle sympathetic APs (peroneal microneurography; continuous wavelet transform) during a modified Oxford protocol (100 μg nitroprusside bolus, 150 μg phenylephrine bolus). Baroreflex sigmoids (four-parameter logistic functions) modelled the relationship between DBP and sympathetic AP discharge probability for 10 normalized AP clusters. For each AP cluster, baroreflex sigmoid morphology was quantified by max gain, threshold, centering, and saturation pressures, and operating and response ranges. One-way analyses of variance and Dunnett post-hoc tests were performed. Data are mean ± SD. At the centering pressure of the baroreflex sigmoid, max gain was greater for medium APs (e.g., Cluster 3: -5.6 ± 2.9%/mmHg) compared to small (e.g., Cluster 1: -1.4 ± 1.1%/mmHg; P < 0.01) and large APs (e.g., Cluster 9: -0.6 ± 0.4%/mmHg; P < 0.01). Discharge probability at the centering pressure was also greater for medium APs (e.g., Cluster 3: 61 ± 22%) compared to small (e.g., Cluster 1: 12 ± 10%; P < 0.01) and large APs (e.g., Cluster 9: 3 ± 3%; P < 0.01). There were no differences in the saturation pressure (i.e., DBP where any further reduction does not elicit an increase in AP discharge probability) between AP clusters (main effect P = 0.22). The threshold pressure (i.e., DBP where any further reductions elicit an increase in AP discharge probability) was greater for medium (e.g., Cluster 3: 78 ± 8mmHg) compared to large APs (e.g., Cluster 9: 74 ± 11mmHg; P = 0.03). The operating range (i.e., Threshold – Saturation DBP) was greater for medium (e.g., Cluster 3: 14 ± 3mmHg) compared to large APs (e.g., Cluster 9: 8 ± 5mmHg; P < 0.01). There were no differences in the threshold pressure or operating range of medium compared to small APs (both P ≥ 0.82). The response range (i.e., Saturation – Threshold discharge probability) was greater for medium (e.g., Cluster 3: 26 ± 13%) compared to small (e.g., Cluster 1: 5 ± 4%; P < 0.01) and large APs (e.g., Cluster 9: 1 ± 1%; P < 0.01). These data confirm prior work using linear modeling and spontaneous approaches to quantify sympathetic AP baroreflex gain and extend to demonstrate variation in the morphology of the baroreflex sigmoid. During large changes in blood pressures, we identify differences in broader features of baroreflex control (e.g., threshold pressure, operating range, and response range) between AP subpopulations that support strong baroreflex regulation over medium-sized APs. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Vascular endothelial dysfunction is a key antecedent to cardiovascular diseases (CVD) in older adults. Reduced nitric oxide (NO) bioavailability secondary to excess mitochondria-related reactive oxygen species (mitoROS) bioactivity are key mechanisms of endothelial dysfunction with aging. Cellular senescence is a state of largely irreversible cell cycle arrest that drives endothelial dysfunction. This occurs in part through secretion of bioactive factors into serum, collectively referred to as the circulating senescence-associated secretory phenotype (SASP), that promote excess mitoROS and reduce NO. We have shown fisetin improves endothelium-dependent dilation in old mice by reducing cellular senescence and mitoROS. Here, we sought to translate our preclinical findings to older adults. Hypotheses: We tested the primary hypothesis that intermittent fisetin treatment would improve endothelial function in older adults and that this would be mediated by reductions in mitoROS and associated with lower cell senescence. We also determined if fisetin altered the serum to improve endothelial cell (EC) NO and reduce whole-cell ROS and mitoROS ex vivo. Exploratory analyses assessed if fisetin changed circulating SASP factors. Methods: In a randomized, placebo-controlled, parallel-group design pilot trial, 41 older men and postmenopausal women were randomized to fisetin (2 mg/kg/day) (age: 71±1 yrs [mean±SEM], n=22 [13 W]) or placebo (age: 71±1 yrs, n=19 [12 W]) administered in an intermittent manner (2, 3-day dosing periods separated by 14 days). Outcomes were measured at baseline and 1-3 weeks after the final dose. Endothelial function was assessed as brachial artery flow-mediated dilation (FMDBA). The change in FMDBA with an acute supratherapeutic dose (160mg) of the mitochondrial antioxidant MitoQ was used to assess mitoROS-related inhibition of endothelial function. Gene expression of cellular senescence markers Cdkn1a (encodes p21) and Lmnb1 (encodes Lamin B1) were assessed in peripheral blood mononuclear cells (PBMCs) by Q-PCR. Human aortic ECs (HAECs) in culture were exposed to 10% participant serum for 2 hrs; acetylcholine (ACh)-stimulated NO production (DAR-4M-AM) and basal whole-cell ROS (CellROX) and mitoROS (MitoBright Deep Red) bioactivity were assessed via immunofluorescence. Luminex analyses (Biotechne) measured circulating levels of SASP factors in serum. Results: FMDBA was improved by 41% with fisetin (pre: 3.9±0.4%, post: 5.5±0.5%, P< 0.0001), but unchanged with placebo (pre: 4.4±0.5%, post: 4.5±0.4%) (group x time interaction effect: P< 0.01). Similar efficacy was observed in men and women. Acute MitoQ enhanced FMDBA at baseline and after placebo (all P< 0.05) but led to no further improvements in FMDBA after fisetin treatment. Consistent with lower cell senescence, expression of Cdkn1a was reduced (P< 0.05) by 12% and expression of Lmnb1 increased (P=0.06) by 16% in PBMCs collected after fisetin but not placebo. Compared with pre-intervention, serum collected after fisetin, but not placebo, increased HAEC ACh-stimulated NO by 6% (P< 0.01) and lowered whole-cell and mitoROS bioactivity by ~10% (both P< 0.05). Protein levels of CXCL12 in serum were 5% lower (P< 0.05) after fisetin compared with pre-intervention and after placebo. Traditional cardiometabolic risk factors were unchanged. Conclusions: Intermittent fisetin treatment improves vascular endothelial function in older adults in part by suppressing mitoROS. These effects are linked to reduced cell senescence and select changes to the circulating SASP. Funding: AHA 23CDA1056582; NIH F31AG087709; NIH/NCATS CTSA UL1TR002535; Life Extension® provided fisetin (BioFisetin) and placebo. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

Cancer-induced muscle wasting affects many people with cancer, reducing treatment tolerance and survival. We identified a natural dietary compound, ursolic acid, that attenuates muscle atrophy across five preclinical cancer models spanning pancreatic, colon, and lung cancer. Ursolic acid inhibits cancer-induced changes in muscle mRNA expression, preserves muscle strength, and remains protective during chemotherapy, without affecting food intake or tumor burden. These results identify ursolic acid as a promising, translatable dietary supplement for supportive cancer care.

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract Introduction Once-nightly sodium oxybate (ON-SXB) is approved to treat cataplexy or excessive daytime sleepiness (EDS) in patients ≥7 years of age with narcolepsy. ON-SXB demonstrated significant improvements in both objective (Maintenance of Wakefulness Test) and subjective (Epworth Sleepiness Scale [ESS] score) measurements of sleepiness in the REST-ON trial and via the ESS in the real-world REFRESH study. Assessing ON-SXB ESS data from a specialty pharmacy and outside of clinical studies further informs the generalizability of effectiveness. Methods Demographic and clinical data were collected from Optum Frontier Therapies pharmacy for patients with ≥1 filled ON-SXB prescription, ≥1 ON-SXB-related clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). Participation in ESS assessment was voluntary. ESS scores were assessed for patients who switched from twice-nightly oxybate (TN-OXB) treatment (first ON-SXB prescription filled ≤30 days of last TN-OXB prescription [switch]) and those new to oxybate or with &gt;30 days between TN-OXB and ON-SXB prescription fills (not-on-oxybate) who had ESS data at initial ON-SXB prescription and at each follow-up assessment. Results Of 452 identified patients, 215 had ≥1 follow-up ESS score (switch, n=82 [mean age, 38.4 years; female, 71%]; not-on-oxybate, n=133 [mean age, 40.0 years; female, 71%]). Of patients who had any prior oxybate use (switch, 100%; not-on-oxybate, 46%), the most common prior oxybate was mixed-salt oxybates (switch, 59%; not-on-oxybate, 70%). Stimulants/wake-promoting agents were taken by 51% of switch and 65% of not-on-oxybate patients. Baseline mean (SD) ESS scores were 11.3 (5.5) for switch and 12.5 (5.6) for not-on-oxybate patients; 23% of switch and 38% of not-on-oxybate patients experienced severe EDS. By the first follow-up (median [IQR], 49 [28-94] days), mean (SD) ESS scores were within the normal EDS range with ON-SXB for both subgroups (ie, ESS &lt; 10; switch, 9.7 [5.5]; not-on-oxybate, 9.5 [5.2]); the majority reported normal levels of daytime sleepiness (switch, 56%; not-on-oxybate, 57%). Mean (SD) change in ESS score from baseline to follow-up was -1.6 [4.5] for switch and -3.1 [5.0] for not-on-oxybate groups. Conclusion Patients who initiated ON-SXB experienced improvements in daytime sleepiness regardless of prior TN-OXB use, and many achieved normal levels of daytime sleepiness in ≤2 months of starting ON-SXB. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Once-nightly sodium oxybate (ON-SXB; LUMRYZ™) is approved to treat excessive daytime sleepiness (EDS) or cataplexy in patients ≥7 years of age with narcolepsy. Findings from 2 studies have demonstrated improvements in objective and subjective EDS with ON-SXB in patients with narcolepsy type 1 (NT1) or 2 (NT2) (NCT02720744, NCT06792708). To evaluate the effect of ON-SXB on EDS in a larger, more diverse narcolepsy patient population, changes in Epworth Sleepiness Scale (ESS) score were analyzed using specialty pharmacy data. Methods Demographic/clinical data were collected from Optum Frontier Therapies pharmacy for adults with NT1 or NT2 with ≥1 filled ON-SXB prescription, ≥1 ON-SXB clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). ESS total scores were assessed at baseline and at each follow-up assessment after ON-SXB initiation. ESS assessment participation was voluntary. Data were analyzed descriptively and stratified by narcolepsy subtype. Results Of 452 patients identified, 195 had ≥1 follow-up ESS score and reported narcolepsy type (NT1, n=123 [63%; mean age, 38.6 years; female, 69%]; NT2, n=72 [37%; mean age, 40.7 years; female, 74%]). More patients with NT1 vs NT2 (72% vs 58%) had any prior oxybate use. Baseline concomitant stimulant/wake-promoting agent use was 58% and 64% for NT1 and NT2, respectively. Mean (SD) ESS total scores at baseline were 12.1 (5.7) and 12.2 (5.3) for patients with NT1 and NT2, respectively; 31% of NT1 and 33% of NT2 had severe EDS. For both subtypes, mean (SD) ESS scores were within the normal EDS range (≤10) by the first follow-up (median time, 52 days; NT1, 10.0 [5.5]; NT2, 9.6 [4.8]). At first follow-up, more than half of patients in the NT1 (55%) and NT2 (54%) subgroups achieved normal levels (ESS total score ≤10) of sleepiness, while 20% of NT1 patients and 10% of NT2 patients had severe EDS. Mean (SD) change from baseline in ESS score was -2.1 (4.3) and -2.6 (5.3) in the NT1 and NT2 subgroups, respectively. Conclusion In this real-world dataset, both NT1 and NT2 patients quickly experienced clinically meaningful improvements in ESS score after initiating ON-SXB. These results support ON-SXB as an effective EDS treatment, regardless of narcolepsy subtype. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Once-nightly sodium oxybate (ON-SXB [LUMRYZ™]) is approved to treat excessive daytime sleepiness (EDS) or cataplexy in patients ≥7 years of age with narcolepsy. Real-world demographic/clinical characteristics and treatment adherence in patients with narcolepsy who received ON-SXB from a specialty pharmacy were assessed. Methods Baseline demographic/clinical data were collected from Optum Frontier Therapies pharmacy for patients with ≥1 filled ON-SXB prescription, ≥1 ON-SXB-related clinical assessment, and baseline Epworth Sleepiness Scale (ESS) score from 6/1/2023-9/30/2024. Adherence (≥80% of days covered) was assessed for patients with ≥3 months of ON-SXB use. Data were stratified by narcolepsy subtype (narcolepsy type 1 [NT1] and 2 [NT2] when available) and prior oxybate use (transitioned from prior oxybate therapy to ON-SXB ≤30 days of index [switch]/were oxybate-naive or discontinued oxybate &gt;30 days before index [not-on-oxybate]). Data were analyzed descriptively. Results 452 patients were identified (NT1, 55%; NT2, 37%; NT unknown, 9%; switch, 40%; not-on-oxybate, 60% [oxybate-naive, n=147/271]). Mean (range) age was 38.9 (16.0-88.0) years. Most patients were female (68%) and had commercial insurance (78%). Overall, 67% of patients had prior oxybate use (NT1, 72% [n=179/247]; NT2, 59% [n=98/166]; switch, 100%; not-on-oxybate, 46% [n=124/271]); for these patients, the most common oxybate (65%) was mixed-salt oxybates (NT1, 61%; NT2, 70%; switch, 61%; not-on-oxybate, 70%). Overall, 64% of patients used stimulants/wake-promoting agents (WPAs) (NT1, 64%; NT2, 65%; switch, 60%; not-on-oxybate, 67%). Overall, the mean (SD) baseline ESS score was 12.0 ([5.5]; NT1, 11.7 [5.5]; NT2, 12.5 [5.3]; switch, 11.0 [5.7]; not-on-oxybate, 12.7 [5.3]). At baseline, 29% of patients experienced severe EDS (ESS score ≥16: NT1, 26%; NT2, 30%; switch, 20%; not-on-oxybate, 34%). Of 269 patients with ON-SXB use ≥3 months, 84% (NT1, 84%; NT2, 89%; switch, 94%; not-on-oxybate, 76%) demonstrated adherence. Conclusion Patients not on an oxybate had the highest baseline ESS scores and proportion with severe EDS, despite greater stimulant/WPA utilization. Patients with NT1 used oxybates more frequently than those with NT2 despite those with NT2 having higher baseline ESS scores and a greater proportion having severe EDS, suggesting oxybates merit earlier consideration in patients with NT2. Most patients demonstrated ON-SXB adherence, indicating they would likely receive full therapeutic benefit. Support (if any) Avadel Pharmaceuticals