Objective: Vascular β-adrenergic receptors (ARs) mediate vessel relaxation. Preclinical work demonstrates enhanced β3-AR–mediated vasodilation in females which is lost following ovariectomy. Unfortunately, ovariectomy (i.e., surgical menopause) fails to provide insight into the temporality of the menopausal transition which occurs in humans (i.e., perimenopause). We hypothesized β3-AR–mediated vasodilation declines progressively across stages of menopause. Methods: Twelve premenopausal (19-41 yr, 24±3 kg/m 2 ), five perimenopausal (42-51 yr, 24±3 kg/m 2 ) and six postmenopausal (57-70 yr, 23±3 kg/m 2 ) female participants completed two study visits randomized and blinded to oral placebo or vibegron (75mg; a β3-AR agonist). One hour following ingestion, forearm blood flow (FBF, venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were assessed during a 10-min quiet rest. FBF was normalized for mean BP (forearm vascular conductance, FVC). A two-way mixed effects ANOVA compared FVC across groups and treatments. A change-point analysis implemented via Markov chain Monte Carlo (MCMC) was applied to estimate the age-dependent change point and associated slope shift in ΔFVC (vibegron – placebo). Results: The effect of vibegron on FVC differed by group (group by treatment interaction, p=0.025); β3-AR–agonism increased resting FVC in premenopausal (p=0.002) but not perimenopausal (p=0.615) or postmenopausal (p=0.680) participants. There was a negative association between age and ΔFVC before 41.4 yr (ΔFVC: B=-0.0895±0.0440 mL/min/100 mmHg, P=0.042). Thereafter, significant associations between age and FVC were not observed (ΔFVC: B=0.0006±0.0361, P=0.987). Conclusion: β3-AR agonism increased FVC in pre- but not peri- or postmenopausal females, supporting an early decline in β-AR function across the menopause transition. Surprisingly, segmented regression analysis identified an age-associated decline in β3-AR mediated vasodilation until 41.4 yrs after which it stabilizes. These preliminary data are the first to show β-AR vasodilation in females begins to decline prior to menopause onset. Future analyses will investigate mechanisms responsible and explore strategies to restore vasodilatory responsiveness. Funding: AHA 909014 (DWJ), HL153523 (JKL), University of Missouri Research Council (NGB, BPB, JKL), APS SURF (VDV) 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.

Introduction: Sympathetic vascular transduction represents beat-to-beat reductions in limb vascular conductance following bursts of sympathetic nerve activity and is mediated by α-adrenergic receptors (AR) in young males. Greater β-AR sensitivity and lower α-AR sensitivity in young females affords potential female-specific adrenergic mediation of sympathetic vascular transduction that remain untested. We aimed to determine the roles of β- and α-AR on beat-to-beat sympathetic vascular transduction at rest in young females. We hypothesized sympathetic vascular transduction would be 1) augmented under β-AR blockade and 2) attenuated under α-AR blockade in young females. Methods: Six premenopausal females (assigned at birth; 29±11 yrs; 25±3 kg/m 2 ; early follicular phase) were instrumented supine for beat-to-beat measures of mean arterial pressure (MAP, finger plethysmography), femoral artery blood flow (FBF, duplex Doppler ultrasound), and muscle sympathetic nerve activity (MSNA, peroneal microneurography). Participants completed three 10-min conditions: 1) baseline, 2) β-AR blockade (intravenous propranolol, 0.0040 mg/kg/min), and 3) combined β- and α-AR blockade (intravenous propranolol + phentolamine, 0.01428 mg/kg/min). Spike-triggered signal averaging characterized beat-to-beat changes in MAP and femoral vascular conductance (FVC=FBF/MAP) for 15 cardiac cycles following each burst of MSNA. Peak (MAP) and nadir (FVC) percent changes were also calculated. Results: MAP increased (P< 0.001) following MSNA bursts at baseline, reaching a peak in the 5th cardiac cycle (+2±1%, Tukey P< 0.001), and FVC decreased (P< 0.001), reaching a nadir in the 8th cardiac cycle (-12±4%, Tukey P< 0.001). Under β-AR blockade, MAP similarly peaked in the 5th cardiac cycle (+2±1%, Tukey P< 0.001) and FVC reached a nadir in the 8th cardiac cycle (-14±5%, Tukey P< 0.001). Under combined β+α-AR blockade, MAP peaked in the 9th cardiac cycle (+1±1%, Tukey P=0.007), but FVC did not significantly change following MSNA bursts (P=0.719). Peak %ΔMAP (P=0.007) was significantly attenuated under combined β+α-AR blockade (+1±1%) vs. baseline (+2±1%, Tukey P=0.024) with no difference between baseline and β-AR blockade (+3±1%, Tukey P=0.789). Nadir %ΔFVC (P< 0.001) was significantly attenuated under combined β+α-AR blockade (-8±6 vs. -18±8% at baseline, Tukey P=0.001) with no effect of β-AR blockade (-18±6%, Tukey P=0.989). Conclusions: These preliminary results show α-AR blockade attenuates beat-to-beat sympathetic vascular transduction at rest in young females. In contrast, β-AR blockade does not alter beat-to-beat sympathetic vascular transduction. Present findings diverge from prior evidence supporting β-AR-mediated blunting of sympathetic blood pressure transduction in young females derived from linear regression analysis. Differences in study findings may be related to differing methodological and analytical approaches to quantify sympathetic transduction. Current data support key α-AR, but not β-AR, contributions to sympathetic-mediated beat-to-beat regulation of vascular tone and blood pressure in healthy young females. Funding: American Heart Association (NGB 25POST1362901; JKL 24TPA1300511) and NextGen Precision Health Postdoctoral Fellowship (NGB). 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.

Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell-specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild-type (ECCD36+/+) and knock-out (ECCD36-/-) mice, aged 6 wk, were provided with either a WD or a standard chow diet for a duration of 16 wk. ECCD36+/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that was blunted in ECCD36-/- mice. Improved insulin sensitivity in ECCD36-/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 wk of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36-/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36-/- mice. These findings demonstrate that endothelial-specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.NEW & NOTEWORTHY ECCD36 exerts "extra endothelial cell" actions in skeletal muscle insulin resistance. ECCD36 is a major mediator of Western diet-induced lipid metabolic disorders and insulin resistance in skeletal muscle. Mitochondrial dysfunction is associated with diet-induced CD36 activation and related skeletal muscle insulin resistance.

Objective: Vascular tone is dictated by the net balance of vasodilatory and vasoconstrictor influences. During hypoxia, systemic sympathetic vasoconstrictor activity is increased but peripheral vasodilation prevails — suggesting vasodilatory factors outweigh sympathetically-mediated vasoconstrictor influences in the healthy state. Given vascular β-adrenergic receptors contribute to hypoxic vasodilation, we hypothesized pharmacological blockade of β-adrenergic receptors would augment the vasoconstrictor response to acute sympathetic activation during hypoxia. Methods: Thirteen young healthy participants (5F/8M, 27±7 yr, 25±3 kg/m2) completed two study visits randomized and blinded to oral placebo or propranolol (1mg/kg, NCT05256069). On each visit, participants completed two trials: 1) 10-min normoxia (0.21 FiO2, 98±0% SpO2) followed by sympathetic activation via a 2-min normoxic cold pressor test (CPT); 2) 5-min steady-state hypoxia (0.10±0.01 FiO2, 81±1% SpO2) followed by a 2-min hypoxic CPT. Forearm blood flow (FBF, venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were assessed. FBF was normalized for mean BP (forearm vascular conductance, FVC). A change in FVC from steady-state to the last 1-min of CPT was calculated (ΔFVC = CPT − steady-state) and expressed as a percent change (%FVC = ΔFVC/steady-state x 100). Results: The vascular response to sympathetic activation (CPT) was unaffected by hypoxia under placebo conditions (normoxia: -34±21%; hypoxia: -29±32%, p=0.33). In contrast, following β-adrenergic blockade with oral propranolol, sympathetically-mediated vasoconstriction was augmented during hypoxia (normoxia: -29±30%; hypoxia: -40±27%, p=0.04). Conclusion: β-adrenergic receptor blockade augments the vasoconstrictor response to acute sympathetic activation during hypoxia in a mixed-sex cohort. These preliminary data indicate functional β-adrenergic receptors are required to restrain sympathetically-mediated vasoconstriction during hypoxia. Based on data supporting sex-related differences in adrenergic control of vascular tone, future work will seek to stratify results by sex. Funding: AHA 909014 (DWJ), APS-SURF (BJB), HL153523 (JKL). 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.

Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease (ESKD). Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation, and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. Although much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial and epithelial cell responses to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein, we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR-based strategies for the treatment and prevention of DKD.

Introduction: Hypoxia elicits peripheral vasodilation to preserve oxygen delivery to tissues. Approximately 10% of hypoxic vasodilation has been attributed to β-adrenergic receptors on the vascular endothelium and smooth muscle. Based on data supporting greater vascular β-adrenergic receptor responsiveness in females compared to males, we examined the effect of sex on the relative contribution of the β-adrenergic receptors to hypoxic vasodilation. We hypothesized β-adrenergic receptor blockade (oral propranolol, 1 mg/kg) would attenuate hypoxic vasodilation and the effect would be greater in females compared to males. Methods: Five female (26±8 yrs, 22±2 kg/m2) and eight male (27±7 yrs, 26±2 kg/m2) participants completed two randomized, single-blinded, and placebo-controlled visits (NCT05256069). On each visit (placebo, propranolol), forearm blood flow (venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were measured during normoxia (SpO2 ~98%) and hypoxia (SpO2 ~80%). Blood flow was normalized for mean BP and expressed as forearm vascular conductance (FVC). The relative change in FVC with hypoxia (%FVC = Hypoxia − Normoxia / Normoxia x 100) was assessed as an index of hypoxic vasodilation. Differences in %FVC between study visits (propranolol − placebo) are reported. Results: %FVC was unaffected by β-adrenergic blockade in female (placebo 15±14%, propranolol -1±15%, p=0.066) and male (placebo 19±25%, propranolol 16±15%, p=0.755) participants. Any effect of β-adrenergic receptor blockade on hypoxic vasodilation did not differ by sex (females: -16±14%, males -3±29%; p=0.383). Conclusion: These preliminary data suggest any effect of β-adrenergic receptor blockade on hypoxic vasodilation does not differ between young healthy female and male participants, although studies are ongoing. Our results further understanding of the effect of sex on vascular control mechanisms during hypoxia. Funding: AHA 909014 (DWJ), APS-SURF (BJB), HL153523 (JKL). 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.

Introduction Heart transplant is the definitive treatment for many patients with advanced heart failure refractory to medical therapy. Unfortunately, there is an insufficient understanding of the barriers to heart transplant particularly with regards to social determinants of health; importantly race, gender and income distribution. Our objective is to evaluate potential disparities in receiving heart transplant using the newest data available from the National Inpatient Sample (NIS) Database. Methods We performed analysis of discharge data from the NIS between 2016 and 2019. We identified patients who underwent heart transplant using International Disease Classification of Disease 10th Procedure Coding System (ICD-10-PCS). Multivariate logistic regression was used to evaluate for racial, socioeconomic and demographic differences among those who received a heart transplant. Results A total of 2,280 heart transplants were performed over 11,400 weighted admissions. After adjusting for comorbidities, socioeconomic and demographic factors, there were no differences in transplant rates among the three races examined (White, Black, and other). However, patients in the highest income quartile had transplant rates that were twice the rate of the lowest income quartile (adjusted odds ratio [aOR] 2.20; 95% confidence interval [CI] 1.87-2.59, p < 0.001). Additionally, patients with private insurance had greatly increased transplant rates compared to those with Medicaid (aOR 3.89; 95% CI 3.32-4.56, P < 0.001). Female gender was independently associated with a decreased transplant rate (aOR 0.53; 95% CI 0.48-0.59, P < 0.001). Conclusions Our study showed no racial disparities in heart transplantation. Although historically, Blacks were less likely to receive organ transplant, more recent studies have shown that race was not independently associated with transplant candidacy in this cohort of the NIS Database. Our analyses also showed that higher income and private insurance were associated with higher rates of heart transplant. Additionally, gender disparities were found in our analysis, with rates of transplant in females being almost half that of males. Our study confirms, on a national level, the limited studies previously showing disparities in heart transplantation based on low-income status and female gender. This work highlights the important need for further work to analyze and more importantly, alleviate these disparities in transplant rates. However, administrative databases such as NIS provide limited information about why these disparities exist. Prospective studies involving more explicit patient-level data are needed to better understand how these disparities affect transplantation rates and methods for rectifying this disparity.

Background: Multi-territory ST elevation has a broad differential. A STEMI must be recognized and treated emergently. This is accomplished by assessing the complete clinical picture including certain ECG features like the distribution, morphology and reciprocal changes. Case: 55-year-old male with COVID-19 pneumonia developed acute crushing chest pain. ECG revealed ST elevation in V2-V4 consistent with isolated anterior STEMI. However, rather than reciprocal ST depression, concurrent ST elevation in II, III and aVF was seen. Echocardiogram revealed severely reduced ejection fraction. He was taken for an emergent coronary angiography based on the clinical picture and found to have acute embolic occlusion of the proximal LAD and distal RCA [Images 1A-B]. Decision - making: Clinical scenario was most consistent with simultaneous anterior and inferior STEMI. Emergent cardiac catheterization with Impella assisted PCI of both the culprit lesions was performed [Images 1C-D]. Periprocedural period was complicated by profound cardiogenic shock and our patient expired a week later. Conclusion: COVID-19 has been implicated in the etiology of multiple cardiovascular complications. Differentiating STEMI from other conditions with a similar presentation can be challenging and largely depends on the clinical picture. This case illustrates the importance of having a high suspicion for STEMI in patients with COVID-19, despite the disease being commonly associated with myopericardial inflammation.

BACKGROUND Filamin C (FLNC) is an actin crosslinking protein that provides structural support for the sarcomere. The exact function of FLNC is unknown; however, mutations have been reported in myopathies and cardiomyopathies, but rarely both. In this paper, we describe a case of adult-onset camptocormia, proximal myopathy, and cardiomyopathy and an intronic FLNC mutation. CASE REPORT A 56-year-old man was referred to the neurology clinic for truncal weakness. The patient reported having curvature of his spine, which he said his mother also had prior to her dying suddenly due to a "cardiac issue." The patient was found to have fatty infiltration of the periscapular and paraspinal muscles. Additionally, electromyography revealed irritable myopathy of the paraspinal muscles, and an echocardiogram revealed an ejection fraction of 40%. A genetic panel conducted through PerkinElmer Genomics revealed a heterozygous mutation c.1210+3A>G in the intron region of FLNC. Due to his low ejection fraction and family history of sudden cardiac death, he received an implantable cardioverter-defibrillator and began carvedilol. The patient received physical therapy for camptocormia. CONCLUSIONS The variability in genotypic-phenotypic relationships of FLNC mutations is a growing area of research. It is important to increase awareness to further the development of gene-targeted therapies. We hope this unique clinical presentation of co-occurring skeletal and cardiomyopathy secondary to an intronic mutation will increase awareness of the broad phenotypic spectrum of FLNC mutations.

Introduction: Immune checkpoint inhibitors have emerged as a promising, novel therapy for multiple malignancies. Immune-related adverse reactions pose a serious concern with use of these agents and reportedly involve multiple organ systems, notably cardiotoxicity. Early identification and management of these adverse events is essential in the prevention of morbidity and mortality. Hypothesis: Immune checkpoint inhibitors cause multiple cardiotoxic effects, and patients with prior cardiac history have a higher likelihood of cardiotoxicity. Methods: 1. A retrospective analysis of 150 patients was performed who had received immunotherapy with either the cytotoxic T lymphocyte associated antigen 4 inhibitors (CTLA4) or with the programmed cell death inhibitors (PD1) or programmed death-ligand 1 (PD-L1) inhibitors for a period of two years at a Tertiary health Care from 7/1/2016-6/30/2018. 2. Patients' cardiac diagnoses prior to the initiation of therapy were noted and included, including history of heart failure, coronary artery disease, atrial fibrillation, and sudden cardiac arrest. 3. Patients’ clinic visits and hospitalizations with admitting and discharge diagnosis, electrocardiogram, echocardiogram, troponin T, and NT-proBNP were reviewed. Results: 6% of patients had new onset heart failure (both preserved and reduced), 1.3% had evidence of myocardial infarction, 2% had new atrial fibrillation with rapid ventricular rate, and 0.6% had fulminant myocarditis. Of patients with new cardiac events, 60% had a history of cardiac disease, which was significantly higher than in patients without (p< 0.05). There were no age or sex differences between the groups with and without cardiotoxicity. Conclusion: Immunotherapy with immune checkpoint inhibitors have broadened the horizon for treatment of multiple solid and hematological malignancies. Nonetheless, new adverse effects on multiple organ systems, specifically cardiac involvement, occur with these therapies, which are important and potentially detrimental toxicities. Patients with a history of prior cardiovascular disease have higher likelihood to develop cardiotoxicity.

Objective: Obesity is associated with myocardial fibrosis and impaired diastolic relaxation, abnormalities that are especially prevalent in women. Normal coronary vascular endothelial function is integral in mediating diastolic relaxation, and recent work suggests increased activation of the endothelial cell (EC) mineralocorticoid receptor (ECMR) is associated with impaired diastolic relaxation. As the endothelial Na+ channel (EnNaC) is a downstream target of the ECMR, we sought to determine whether EC-specific deletion of the critical alpha subunit, alpha EnNaC, would prevent diet induced-impairment of diastolic relaxation in female mice. Methods and materials: Female alpha EnNaC KO mice and littermate controls were fed a Western diet (WD) high in fat (46%), fructose corn syrup (17.5%) and sucrose (17.5%) for 12-16 weeks. Measurements were conducted for in vivo cardiac function, in vitro cardiomyocyte stiffness and EnNaC activity in primary cultured ECs. Additional biochemical studies examined indicators of oxidative stress, including aspects of antioxidant Nrf2 signaling, in cardiac tissue. Results: Deletion of aEnNaC in female mice fed a WD significantly attenuated WD mediated impairment in diastolic relaxation. Improved cardiac relaxation was accompanied by decreased EnNaC-mediated Na+ currents in ECs and reduced myocardial oxidative stress. Further, deletion of aEnNaC prevented WD-mediated increases in isolated cardiomyocyte stiffness. Conclusion: Collectively, these findings support the notion that WD feeding in female mice promotes activation of EnNaC in the vasculature leading to increased cardiomyocyte stiffness and diastolic dysfunction. Published by Elsevier Inc.