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Item Healthy Women Have Higher Systemic Uromodulin Levels: Identification of Uromodulin as an Estrogen Responsive Gene(Wolters Kluwer, 2023) Nanamatsu, Azuma; Micanovic, Radmila; Khan, Shehnaz; El-Achkar, Tarek M.; LaFavers, Kaice A.; Medicine, School of Medicine*Serum uromodulin levels are higher in healthy female participants than healthy male participants. *Serum uromodulin levels in participants with normal kidney function do not correlate with eGFR but do correlate with body mass index. *Estrogen increases uromodulin production, likely because of noncanonical and half estrogen response elements in the UMOD gene.Item Host Factors That Influence Coxsackievirus B3 Replication and Pathogenensis(2023-04) Dhalech, Adeeba Haroon; Robinson, Christopher M.; Hurley, Thomas D.; Katzenellenbogen, Rachel A.; Richer, Martin J.; Spinola, Stanley M.Enteric viruses are infectious human pathogens that initiate infection in the gastrointestinal tract. They follow a fecal-oral route of transmission and are spread by contamination of food, water, or contact between individuals. Furthermore, enteric viruses also cause significant morbidity, mortality, and economic burdens yearly. Coxsackievirus (CV) is commonly isolated among enteric viruses and is an etiological agent of hand, foot, and mouth disease, hemorrhagic conjunctivitis, and myocarditis. The virus predominantly infects infants and young children and accounts for 11% of the fatality rate in neonates. Despite CV’s impact on human health, there are no treatments or vaccines for CV infections. Using a mouse model to study a key CV, Coxsackievirus B3 (CVB3), our laboratory has found two critical factors that impact CVB3 replication and pathogenesis. First, we have demonstrated that intestinal bacteria enhance intestinal CVB3 replication. We found that certain specific bacteria (Salmonella enterica) and its cell wall components, like lipopolysaccharides (LPS), enhanced CVB3 stability and infectivity in vitro. Additionally, we found that particular constituents of LPS are required for stability to occur. These data suggest that specific bacteria may be integral in maintaining CVB3 infectivity in the intestine. Besides virus-microbiome interaction, CVB3 is also impacted by sex hormones. Using castrated mice models, we observed a sex bias to CVB3 infection, with male mice succumbing to CVB3-induced disease at an increased rate compared to female mice. Our data suggest that testosterone, a predominant male sex hormone, enhanced CVB3 intestinal replication and viral dissemination to organs in male and female mice, but lethality only in male mice. Moreover, testosterone also affected the immune response by reducing the activation of the CD8+ T cells. CD8+ T cells are required to clear the viral infection and are integral in vaccine development. In contrast, we found an enhanced CD8+ T cell response in female mice to CVB3 infection, suggesting a sex-dependent T cell response that may underlie the sex bias in disease. Overall, these data represent an essential advancement in the CV field and will help develop future therapeutics and aid in vaccine design to limit CV infections.Item Serum Bile Acids Improve Prediction of Alzheimer's Progression in a Sex-Dependent Manner(Wiley, 2024) Chen, Tianlu; Wang, Lu; Xie, Guoxiang; Kristal, Bruce S.; Zheng, Xiaojiao; Sun, Tao; Arnold, Matthias; Louie, Gregory; Li, Mengci; Wu, Lirong; Mahmoudiandehkordi, Siamak; Sniatynski, Matthew J.; Borkowski, Kamil; Guo, Qihao; Kuang, Junliang; Wang, Jieyi; Nho, Kwangsik; Ren, Zhenxing; Kueider-Paisley, Alexandra; Blach, Colette; Kaddurah-Daouk, Rima; Jia, Wei; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer Disease Metabolomics Consortium (ADMC); Radiology and Imaging Sciences, School of MedicineSex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.Item Sex differences in computed tomography angiography-derived coronary plaque burden in relation to invasive fractional flow reserve(Elsevier, 2023) Han, Donghee; van Diemen, Pepijn; Kuronuma, Keiichiro; Lin, Andrew; Motwani, Manish; McElhinney, Priscilla; Flores Tomasino, Guadalupe; Park, Caroline; Kwan, Alan; Tzolos, Evangelos; Klein, Eyal; Grodecki, Kajetan; Shou, Benjamin; Tamarappoo, Balaji; Cadet, Sebastien; Danad, Ibrahim; Driessen, Roel S.; Berman, Daniel S.; Slomka, Piotr J.; Dey, Damini; Knaapen, Paul; Medicine, School of MedicineBackground: Distinct sex-related differences exist in coronary artery plaque burden and distribution. We aimed to explore sex differences in quantitative plaque burden by coronary CT angiography (CCTA) in relation to ischemia by invasive fractional flow reserve (FFR). Methods: This post-hoc analysis of the PACIFIC trial included 581 vessels in 203 patients (mean age 58.1 ± 8.7 years, 63.5% male) who underwent CCTA and per-vessel invasive FFR. Quantitative assessment of total, calcified, non-calcified, and low-density non-calcified plaque burden were performed using semiautomated software. Significant ischemia was defined as invasive FFR ≤0.8. Results: The per-vessel frequency of ischemia was higher in men than women (33.5% vs. 7.5%, p < 0.001). Women had a smaller burden of all plaque subtypes (all p < 0.01). There was no sex difference on total, calcified, or non-calcified plaque burdens in vessels with ischemia; only low-density non-calcified plaque burden was significantly lower in women (beta: -0.183, p = 0.035). The burdens of all plaque subtypes were independently associated with ischemia in both men and women (For total plaque burden (5% increase): Men, OR: 1.15, 95%CI: 1.06-1.24, p = 0.001; Women, OR: 1.96, 95%CI: 1.11-3.46, p = 0.02). No significant interaction existed between sex and total plaque burden for predicting ischemia (interaction p = 0.108). The addition of quantitative plaque burdens to stenosis severity and adverse plaque characteristics improved the discrimination of ischemia in both men and women. Conclusions: In symptomatic patients with suspected CAD, women have a lower CCTA-derived burden of all plaque subtypes compared to men. Quantitative plaque burden provides independent and incremental predictive value for ischemia, irrespective of sex.Item Sex differences in right ventricular adaptation to pressure overload in a rat model(American Physiological Society, 2022) Cheng, Tik-Chee; Tabima, Diana M.; Caggiano, Laura R.; Frump, Andrea L.; Hacker, Timothy A.; Eickhoff, Jens C.; Lahm, Tim; Chesler, Naomi C.; Medicine, School of MedicineWith severe right ventricular (RV) pressure overload, women demonstrate better clinical outcomes compared with men. The mechanoenergetic mechanisms underlying this protective effect, and their dependence on female endogenous sex hormones, remain unknown. To investigate these mechanisms and their impact on RV systolic and diastolic functional adaptation, we created comparable pressure overload via pulmonary artery banding (PAB) in intact male and female Wistar rats and ovariectomized (OVX) female rats. At 8 wk after surgery, right heart catheterization demonstrated increased RV energy input [indexed pressure-volume area (iPVA)] in all PAB groups, with the greatest increase in intact females. PAB also increased RV energy output [indexed stroke or external work (iEW)] in all groups, again with the greatest increase in intact females. In contrast, PAB only increased RV contractility-indexed end-systolic elastance (iEes)] in females. Despite these sex-dependent differences, no statistically significant effects were observed in the ratio of RV energy output to input (mechanical efficiency) or in mechanoenergetic cost to pump blood with pressure overload. These metrics were similarly unaffected by loss of endogenous sex hormones in females. Also, despite sex-dependent differences in collagen content and organization with pressure overload, decreases in RV compliance and relaxation time constant (tau Weiss) were not determined to be sex dependent. Overall, despite sex-dependent differences in RV contractile and fibrotic responses, RV mechanoenergetics for this degree and duration of pressure overload are comparable between sexes and suggest a homeostatic target. NEW & NOTEWORTHY: Sex differences in right ventricular mechanical efficiency and energetic adaptation to increased right ventricular afterload were measured. Despite sex-dependent differences in contractile and fibrotic responses, right ventricular mechanoenergetic adaptation was comparable between the sexes, suggesting a homeostatic target.Item Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles(Elsevier, 2021) Fei, Yu-Dong; Chen, Mu; Guo, Shuai; Ueoka, Akira; Chen, Zhenhui; Rubart-von der Lohe, Michael; Everett, Thomas H., IV.; Qu, Zhilin; Weiss, James N.; Chen, Peng-Sheng; Medicine, School of MedicineBackground: Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong. Objective: The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline. Methods: We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes. Results: ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former. Conclusion: ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.