bluuebunny/crossref_metadata_2025_split huggingface dataset:
8399 Adherens Junctions Regulate Aldosterone Production and Zona Glomerulosa Morphogenesis
Authors: Berber M , Guagliardo N A , Barrett P Q , Haykir B , Chortis V , Borges K S , Carlone D L , Breault D T 
Published: October 2024

Abstract
Disclosure: M. Berber: None. N.A. Guagliardo: None. P.Q. Barrett: None. B. Haykir: None. V. Chortis: None. K.S. Borges: None. D.L. Carlone: None. D.T. Breault: None.
Primary aldosteronism (PA) caused by the autonomous production of aldosterone by zona Glomerulosa (zG) cells of the adrenal gland is the most common cause of endocrine hypertension, which increases the risk of cardiovascular and renal disease, independent of blood pressure. Current treatments with mineralocorticoid receptor antagonists do not fully mitigate these risks. Thus, a better understanding of the mechanisms underlying PA pathogenesis is important for the development of new therapeutic strategies. zG cells are organized in multicellular rosette structures, which are the functional aldosterone-producing units. Rosettes are stabilized by intercellular adherens junctions (AJs) comprised of cadherins, beta-catenin (βCat) and alpha-catenin (αCat), which link to the actin non-muscle myosin II (NMII) network. Recent data implicate AJs and rosettes in aldosterone-producing cell clusters and an unbiased proteomic analysis of aldosterone-producing adenomas detected an upregulation of the GTPase RhoC, an important regulator of AJ stability.We hypothesized that AJs are potent modulators of aldosterone production and zG morphogenesis with important implications for PA. Using the NCI-H295R cell line with confocal microscopic and co-immunoprecipitation assays, we found that potassium (K+) and angiotensin II (AngII) stimulation markedly enhanced the formation and maintenance of AJs. In addition, treatment with inhibitors of Rho-associated kinase (ROCK) (Y-27632) and NMII (blebbistatin) largely abrogated the effects of K+ and AngII stimulation on AJs, suggesting the Rho-ROCK-NMII pathway regulates AJ stability in the zG. Moreover, disruption of AJs, using either blebbistatin or deletion of αCat using CRISPR, blunted the aldosterone response to K+ stimulation (100% and 50%, respectively). Furthermore, zG-specific deletion of αCat (αCat-LOF) in mice led to disruption of AJs, impaired rosette formation and decreased 24-hour urinary aldosterone excretion on standard (Control 5.6±1.7 ng/mg; αCat-LOF 2.9±0.7 ng/mg (aldosterone/creatinine)) or high K+ (Control: 34.7±13.7 ng/mg; αCat-LOF 19.4±9.5 ng/mg (aldosterone/creatinine)) diets. Finally, mice with zG-specific βcat-GOF demonstrated enhanced AJ stability, increased rosette size and zG hyperplasia, which was abrogated in zG-specific bigenic βCat-GOF::αCat-LOF mice, without affecting gene expression of canonical βcat targets. These data indicate that AJs modulate aldosterone production and zG morphology, revealing AJs as a novel molecular target for the treatment of high-risk patients with PA.
Presentation: 6/3/2024
7551 Association of Remnant Cholesterol with Sarcopenia in Korean Adults: A Nationwide Population-Based Study using Data from the KNHANES
Authors: Jang S , Hwang S Y , Jang A , Kim K , Yu J , Kim N , Yoo H , Seo J , Kim S , Kim N , Baik S , Choi K 
Published: October 2024

Abstract
Disclosure: S. Jang: None. S. Hwang: None. A. Jang: None. K. Kim: None. J. Yu: None. N. Kim: None. H. Yoo: None. J. Seo: None. S. Kim: None. N. Kim: None. S. Baik: None. K. Choi: None.
Objectives: Mounting evidences indicate the importance of interplay between skeletal muscle and lipid metabolism. Remnant cholesterol (remnant-C) is considered as one of the principal residual risk factors for atherosclerotic cardiovascular disease (ASCVD) as well as metabolic disorders, but there is limited study about the impact of remnant-C on sarcopenia. Research design and Methods: Data from the Korea National Health and Nutrition Examination Surveys (KNHANES) between 2008 and 2011 was used in this nationwide population-based study. A total of 17,408 participants were enrolled. Subjects were categorized into 4 groups according to the quartile of remnant-C values. We conducted multivariable logistic regression analysis to evaluate the association between remnant-C and muscle mass measured using dual-energy X-ray absorptiometry (DXA). Results: 1,989 participants (11.4%) presented low muscle mass, and there was a sequential increase in the percentage of low muscle mass across remnant-C quartiles (Q1, 5.8%; Q2, 9.9%; Q3, 12.9%; Q4, 17.1%). In the full adjusted model, those in the highest remnant-C quartile group showed the highest odds ratio for low muscle mass after adjusting for various confounding factors (Q2, 1.18 [0.95-1.47]; Q3, 1.12 [0.9-1.39]; Q4, 1.37 [1.1-1.71], P &lt;0.05). A wide range of subgroup and sensitivity analyses showed consistent results, which may support the robustness of the present findings. Conclusions: Increased remnant-C value is related to high risk of low muscle mass in Korean population. Remnant-C may be a novel marker to predict and manage sarcopenia in the aging society. There should be future research to verify its clinical usefulness.
Presentation: 6/2/2024
7093 Atherogenic Index of Plasma Is Strongly Correlated With Cardiovascular Disease Independent of LDL level in the US Population
Authors: Ayesh Hazem , Dean Niswender Kevin , Carranza Leon Barbara Gisella 
Published: October 2024

Abstract
Disclosure: H. Ayesh: None. K.D. Niswender: None. B.G. Carranza Leon: None.
Introduction: Cardiovascular disease (CVD) poses a global health challenge, prompting exploration of risk factors. The Atherogenic Index of Plasma (AIP), calculated as the readily available TG/HDL-C ratio, stands out as a promising avenue for investigation. Previous studies have reported an independent association between AIP and cardiovascular disease across diverse populations. Despite this recognized significance, there exists a gap in understanding its relevance in the US. This research aims to bridge this gap by examining the AIP-CVD relationship within the US population, utilizing data from the National Health and Nutrition Examination Survey (NHANES). Methods: The study included 4,784 NHANES subjects, with AIP values calculated using the established formula. The outcome was assessed using a combined variable (stroke, myocardial infarction, and CAD). Statistical analysis employed logistic regression to evaluate the AIP-CVD relationship, controlling for age, BMI, hemoglobin A1c, blood pressure, smoking, and LDL levels. Results/Discussion: We observed a significant correlation between AIP and CVD (odds ratio: 1.77, P = 0.026, 95% CI: 1.07-2.94), which persisted after controlling for common risk factors, including HbA1c, BMI, blood pressure, smoking, and LDL levels. Importantly, our findings highlighted the independence of this association from LDL levels—a pivotal observation with implications for healthcare strategies. Our study suggests that even with optimized LDL levels, AIP maintains an independent association with CVD. Existing literature supports the notion that AIP levels are strongly correlated with small dense LDL and remnant cholesterol levels. The pragmatic utility of AIP as a cardiovascular risk marker is evident due to the impracticality and costliness of testing for small dense LDL and remnant cholesterol. Given AIP is based on routine lipid profiles, our data underscores the potential integration of AIP into clinical practice, streamlining risk assessment. As we delve into our findings, the optimization of cardiovascular risk beyond LDL levels emerges as a tangible goal, with AIP emerging as a valuable tool. Larger studies are needed to validate and generalize these findings in the US population.
Presentation: 6/2/2024
6824 Bile Acid Elevation in Nonalcoholic Steatohepatitis Correlates With Fibrogenesis and Mitochondrial Dysfunction In Vitro
Authors: Dinesh Patel Nrupa , Li Yuchang , Chandrakant Raul Mahima , Sottas Chantal , Papadopoulos Vassilios 
Published: October 2024

Abstract
Disclosure: N. Patel: None. Y. Li: None. M. Raul: None. C. Sottas: None. V. Papadopoulos: None.
Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease. It is estimated that over 115 million adults are affected by NASH worldwide. The causes of NASH are unclear, and no treatment is yet available. Bile acids (BAs) are steroids synthesized in the liver, promoting lipid absorption. The levels of BAs are tightly regulated in the body. Patients diagnosed with NASH frequently exhibit increased levels of BAs in both liver tissue and plasma, indicating a potential association between elevated BA concentrations and the pathogenesis of NASH. In an in vivo study using a high-fat diet rat model of NASH, we measured plasma BA composition and levels. The results obtained indicated substantial increases in the concentrations of glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA) in NASH compared to controls. These findings suggested their potential implication in the development of NASH. To elucidate the mechanistic link between changes in BA synthesis and fibrogenesis, in vitro experiments were conducted using the LX-2 humane hepatic stellate and Huh7 human hepatocellular carcinoma cells. First, the concentrations of the selected bile acids (GCA, GCDCA, GDCA, and TDCA) used in our studies were found to be non-toxic to the cells using the MTT assay. Subsequent qPCR analyses demonstrated the upregulation of key fibrotic genes (TGFβ, COL1A1, ACTA2) in LX-2 cells following exposure to individual bile acids GCA, GCDCA, GDCA, and TDCA. Immunocytochemistry (ICC) studies further demonstrated fibrogenesis by revealing increased expression of COL1A1 following treatment with each of the four bile acids. These data suggest that changes in BA formation are linked to fibrogenesis. We subsequently explored the impact of BAs on mitochondrial function using the Seahorse XF Cell Mito Stress Test in Huh7 cells. The results obtained revealed a reduction in the oxygen consumption rate and ATP production in response to BA treatment. This observation suggests a potential role for modified BAs in disrupting mitochondrial homeostasis, a recognized contributor to the progression of NASH. In summary, the data presented provide valuable insights into the complex effects of modified BAs on NASH pathogenesis, establishing connections between changes in BA composition and fibrogenesis, mitochondrial dysfunction.
Presentation: 6/2/2024
12369 Clinical Experience With Inclisiran At An Academic Center
Authors: Marin L Chavez , Gonzalez M , Linton M F , Leon B G Carranza 
Published: October 2024

Abstract
Disclosure: L. Chavez Marin: None. M. Gonzalez: None. M.F. Linton: None. B.G. Carranza Leon: None.
Background: Inclisiran, a small interfering RNA (siRNA) molecule designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), is the only siRNA approved for management of elevated low-density lipoprotein cholesterol (LDL-C) in both primary (for patients with familial hypercholesterolemia) and secondary prevention of cardiovascular disease. In clinical trials, Inclisiran has been shown to reduce LDL-C by more than 50% in populations at high cardiovascular risk. However, real world data about its tolerability and efficacy is still limited. Methods: We conducted an electronic medical record search to identify subjects who were prescribed Inclisiran at a lipid clinic within Vanderbilt University Medical Center (Nashville, USA). Subjects were included if they received at least one dose of Inclisiran and had pre- and post- LDL-C levels. Subjects taking other LDL-C lowering medications like statins, ezetimibe, bempedoic acid, and PCSK-9 inhibitors were included. Pre- and post- LDL-C averages were calculated and analyzed with 95% confidence intervals. The reasons for medication discontinuation were also examined. Results: Out of 69 subjects identified, only 19 met criteria for inclusion, while 32 never received a dose due to cost burden and insurance denial. The other 18 subjects were not included due to inadequate lab results at the time of data collection. In subjects who received at least one dose of Inclisiran, average pre-LDL-C was 142 mg/dL [CI: 34.7] while post-LDL-C was 77 mg/dL [CI: 24.0], notable for a 46% decrease in LDL-C levels. These subjects were also receiving another lipid lowering agent, like a statin, or had previously used a monoclonal antibody-PCSK-9 inhibitor. Those without prior use of PCSK-9 inhibitors were also analyzed. Average pre-LDL-C was 109.5 mg/dL [CI: 15.8] while post-LDL-C was 39.8 mg/dL [CI: 17.2], which revealed a 64% decrease in LDL-C levels. The main reason for discontinuation of Inclisiran was insurance denial followed by individual preference. Only one subject discontinued Inclisiran due to experiencing a generalized rash. Conclusions: Inclisiran is an effective and overall well-tolerated medication indicated for the management of elevated LDL cholesterol. Our study revealed that for individuals with above goal LDL-C, despite maximum tolerated therapy with a statin, additional LDL-C lowering benefits can be seen with Inclisiran use. However, insurance approval and cost burden seem to be the main barriers for access.
Presentation: 6/3/2024
12463 Effect Of Multiple Blood Sampling In A Single Session On Adrenal Vein Sampling For Identification Of Primary Aldosteronism
Authors: Yagishita Nobuyuki , Kometani Mitsuhiro , Aiga Ko , Mizoguchi Ren , Yoneda Takashi 
Published: October 2024

Abstract
Disclosure: N. Yagishita: None. M. Kometani: None. K. Aiga: None. R. Mizoguchi: None. T. Yoneda: None.
Context: Adrenal vein sampling (AVS) is recognized as the gold standard method to distinguish subtypes of primary aldosteronism (PA), helps differentiating the pathogenic side and determining the appropriate treatment strategies. The Selectively Index (SI) and Lateralization Index (LI), which are based on aldosterone and cortisol levels, are used to determine the success rate of AVS and to diagnose PA subtypes. On the other hand, determining the success of adrenal vein insertion and disease type remains controversial, and various methods to improve its accuracy are still being reported. Objective: Evaluate the impact of performing multiple blood samplings from the inferior vena cava (IVC) and each adrenal vein (AV) during a single AVS session and its impact on the success rate of said AVS and the consequent accuracy of PA subtype diagnosis. Patients: A total of 48 patients who were diagnosed as PA and underwent multiple AVS procedures at Kanazawa University Hospital or Houju Memorial Hospital. Protocol: This study involved 48 patients diagnosed with PA. AVS was performed using the following procedure. A catheter is inserted into the IVC through the right or left femoral vein. A sample is first taken from the IVC (IVC-1). AVS was then performed in the order of right adrenal vein and left adrenal vein or vice versa. After cannulation of each adrenal vein, samples were taken three times before switching to the other adrenal vein. After the collection of each adrenal vein was completed, samples were taken again from the IVC (IVC-2). Results: Of the 48 patients, 44 patients were included in the study, for whom all sets of AVS samples were available. For each patient, six SI's were calculated per AV. Multiple AV samples did not affect the success rate of AVS. Regardless of the cortisol level in the AV, the SI calculated using the cortisol level in IVC -2 was significantly higher in most patients (P &lt; 0.0001). Only patients in whom AVS was successful in all cases were selected to determine lateralization. Since nine different LI’s could be calculated, there were nine chances to determine subtypes for each patient. 18 patients in IVC-1 (left: 2, right: 4, bilateral: 12), 17 patients in IVC-2 (left: 3, right 2, bilateral: 12) all exhibited consistencies in lateralization. Except four patients which in both cases exhibited inconsistencies in lateralization. Conclusions: These results revealed that multiple blood samplings resulted in lateralization discrepancies that could not be determined with a single blood sampling. Although it was not possible to confirm that multiple blood samplings influence the success rate of AVS, it was newly confirmed that the timing of blood sampling from IVC impacts it.
Presentation: 6/1/2024
8697 Effects of Fibrate Combination Therapy on the Prevention and Progression of Non-Alcoholic Fatty Liver Disease in Patients with Dyslipidemia Undergoing Statin Treatment: A Retrospective Cohort Study Using Dada from the Korean National Health Insurance Service
Authors: Choi Jong Han , Kim Suk Kyeong , Lim Dong-Lim , Song Kee-Ho 
Published: October 2024

Abstract
Disclosure: J. Choi: None. S. Kim: None. D. Lim: None. K. Song: None.
Background and Hypothesis: Non-alcoholic fatty liver disease (NAFLD), recognized as part of the metabolic syndrome, has become a significant public health issue. However, there has been no suitable pharmacological treatment beyond lifestyle management due to the lack of appropriate modalities for early diagnosis and treatment response assessment. Fibrates, potent drugs for treating hypertriglyceridemia, have been considered potential therapeutic candidates for hepatic steatosis due to their capacity to reduce liver lipid accumulation. However, they have failed to demonstrate histopathological improvement and lack large-scale randomized controlled trials showing radiological improvement. Purpose: We aimed to evaluate the effectiveness of fibrates in improving hepatic steatosis using the fatty liver index (FLI) and hepatic steatosis index (HSI). These are presented as predictive panels for hepatic steatosis by the Korean Association for the Study of the Liver, having been well validated in large-scale epidemiological studies for Koreans through radiological examinations. They are also independently valuable as they utilize different serological and clinical indicators. The analysis was feasible using claim data and health examination records from the Korean National Health Insurance Service. Research Method: This study was conducted on individuals with dyslipidemia receiving statin treatment, who had undergone consecutive health examinations provided by the KNHIS. Among these, patients newly starting fibrates treatment for moderate hypertriglyceridemia (triglyceride levels 150-500 mg/dl) were selected as the treatment group (n=10,616). A control group (n=10,616) was established using 1:1 propensity score matching. The odds ratios (ORs) for the hepatic steatosis were analyzed by the FLI and HSI between these two groups, respectively. Additionally, the fibrates treatment group was categorized based on medication possession ratio (MPR), and the ORs were evaluated accordingly. Results: The fibrate treatment group reduced hepatic steatosis by 10.8% according to the FLI and 17.6% according to the HSI, compared to the control group. Notably, in the subgroup with a high MPR of over 80%, there was a substantial decrease in hepatic steatosis, with a 69.8% reduction observed for FLI and a 66.3% reduction for HSI. Conclusion: Fibrate treatment in patients with hypertriglyceridemia who are already on statin therapy can significantly reduce the prevalence of hepatic steatosis.
Presentation: 6/3/2024
12607 Female Mice Exhibit Sex-specific Steatosis Patterns With Aging
Authors: Landgraf A , Okada J , Xiaoli A , Qiu Y , Eliscovich C , Viswanathan P , Schuster V , Kurland I J , Shinoda K , Pessin J E 
Published: October 2024

Abstract
Disclosure: A. Landgraf: None. J. Okada: None. A. Xiaoli: None. Y. Qiu: None. C. Eliscovich: None. P. Viswanathan: None. V. Schuster: None. I.J. Kurland: None. K. Shinoda: None. J.E. Pessin: None.
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 38% of the global population and is becoming a leading cause of liver transplant and hepatocellular carcinoma (HCC). MASLD affects adult men at higher rates than adult women, but during aging, women lose their protection from MASLD. Declines in serum estrogen during menopause are the suspected cause of this aging-associated loss of protection, but the molecular effects of estrogen loss on the liver have not been fully characterized. Here, we modeled the effect of menopause on MASLD using young and aged female mice on high fat diet and characterized the liver steatosis profile associated with menopause. Male and female C57BL/6J mice were placed on high fat diet (HFD) or low fat chow diet (NCD) for 15 weeks from 6-21 wks/old (young cohort) or 64-79 wks/old (aged cohort). Body weight and fat composition were tracked throughout the experiment. Extracted livers were used to perform hepatic triglyceride (TG) analysis, liver H&E staining, whole liver RT-qPCR, proteomics, and lipidomics. Liver TG analysis showed young female mice had almost no HFD-induced liver steatosis after 15wks while aged female mice develop extensive steatosis. Additionally, aged female mice on HFD gained weight at significantly faster rate than young female mice. Liver H&E staining demonstrated that the steatosis type in aged female mice was exclusively macro-vesicular and located in zone II (mid-zone) of the hepatic lobule compared to combined micro-vesicular and macro-vesicular patterns originating from zone III (pericentral) in male mice. In humans, micro-vesicular steatosis is more severe and associated with disruptions in mitochondrial fatty acid oxidation while macro-vesicular steatosis is more benign1. Proteomic and lipidomic analysis clustered samples according to their steatosis type (macro, micro, or combined) and identified distinct lipid and protein signatures of each steatosis type. These findings suggest there may be two distinct, sex-specific mechanisms by which mammals accumulate fat in the liver: an estrogen-mediated mechanism controlling macro-steatosis and an alternative mechanism regulating micro-vesicular steatosis possibly through impairments in pericentral fatty acid oxidation. This model would have broad implications for MASLD therapeutic strategy. (1) Fromenty, B. & Roden, M. Mitochondrial alterations in fatty liver diseases. J Hepatol78, 415-429, doi:10.1016/j.jhep.2022.09.020 (2023).
Presentation: 6/3/2024