bluuebunny/crossref_metadata_2025_split huggingface dataset:
8504 Germline VHL-gene Alterations Are Associated With An Increased Risk Of Cardiovascular Disease - A Large Population Study
Authors: Halperin Reut , Tirosh Amit 
Published: October 2024

Abstract
Disclosure: R. Halperin: None. A. Tirosh: None.
Introduction: Von Hippel-Lindau (VHL) is an autosomal dominant disease associated with increased risk for developing hemangioblastomas of the central nervous system and retina, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (PNET), adrenal pheochromocytomas and paraganglioma (PPGL). Loss of function VHL alterations lead to pseudohypoxia and, consequently, to angiogenesis and metabolic derangements (e.g., increased glucose uptake). Little is known about the systemic effects of VHL alterations on the cardiometabolic system. Aim Study whether VHL gene variants are associated with increased cardiometabolic risk. Methods: Data were extracted from the UK Biobank database, including demographic and anthropometric parameters, medical history, and lab testing. Whole exome sequencing data were available for all patients, and a focused variant calling and annotation of the VHL gene region was performed on the DNA-nexus platform. A composite of major adverse cardiovascular events (MACE) per patient consisted of ischemic heart disease (IHD), cerebrovascular accident (CVA), and peripheral artery disease (PVD). VHL variant severity was sub-categorized into low (silent or missense), intermediate (in-frame insertion or deletion and 5’ UTR variants), and high-risk (nonsense or frameshift). Results: Data from 460,430 participants were analyzed (45.8% males, age at inclusion 73.6±8.1 years). IHD, CVA, and PVD rates were 11.5%, 3.0%, and 1.8%, respectively. Germline VHL variants were detected in 2594 participants (0.45%), with 2073 low- (242 silent, 1830 missense), 505 intermediate- (18 in-frame deletion and 23 in-frame insertion and 464 5' UTR variants), and 16 high-risk (3 frameshift insertions, one frameshift deletion, and 12 nonsense) VHL variants. In the multivariable logistic regression analysis, harboring a high-risk VHL variant was associated with an 11-fold increased risk of MACE (odds ratio [OR] 11.1, 95% confidence interval 1.5-54.1, p=0.006), after adjustment for age at inclusion, age at diagnosis with cancer, sex, kidney function, c-reactive protein plasma levels, and diagnosis status with diabetes mellitus, hypertension, dyslipidemia, obesity, and RCC. Conclusions and discussionVHL gene alterations are associated with an increased cardiometabolic risk. Metabolic changes or enhanced drive for angiogenesis might contribute to this association. Further research is needed to verify these results and to assess a possible benefit from early intervention in this population.
Presentation: 6/3/2024
6772 Graves' Wrath on the Heart: A Focus on Pericardial Effusion
Authors: Subramani Rashmi , Zahra Sundas , Manas F N U 
Published: October 2024

Abstract
Disclosure: R. Subramani: None. S. Zahra: None. F. Manas: None.
Introduction: Hyperthyroidism, marked by an overproduction of thyroid hormones, is linked to various cardiovascular issues like high or normal output heart failure, arrhythmias, and tachycardia-related cardiomyopathy. Pericardial effusion is less common in hyperthyroidism compared to hypothyroidism. Here we report a 20 year old with pericardial effusion, later diagnosed with Grave’s disease. Case Summary: A 20-year-old female with a past medical history of anxiety, depression, and seizure disorder presented to the emergency department with chief complaints of dizziness, shortness of breath, palpitations, and chest pain. She complained of tremors, generalized weakness, and weight loss for the last two months. She denied any personal or family history of hypo- or hyper-thyroidism. No history of head or neck irradiation, anterior neck tenderness or pain, dysphagia or hoarseness. No history of recent viral infection. Examination revealed tachycardia with thyromegaly and pericardial friction rub but there was no neck tenderness, exophthalmos or lid lag. Blood work was remarkable for low TSH (&lt;0.02 uIu/ml, normal: 0.27-4.2 uIu/ml) and elevated free T4 (&gt;7.7nd/dl, normal:0.9-1.7ng/dl) and total T3 (&gt;651 ng/dl, normal 80-200 ng/dl). Rest of the blood work, including blood cultures and immunologic workup (antinuclear antibody, anti-neutrophil cytoplasmic antibody, and rheumatoid factor) was negative. EKG showed sinus tachycardia. CT chest confirmed thyromegaly and showed pericardial effusion. Ultrasound neck showed enlarged heterogeneous thyroid gland with relative increased vascularity. Echocardiography showed mild to moderate pericardial effusion with no tamponade physiology and normal ejection fraction. Anti thyroid peroxidase antibodies, thyroid stimulating immunoglobulin, and TSH receptor antibodies were markedly elevated. The patient was diagnosed with Grave’s thyrotoxicosis with thyromegaly and pericardial effusion. Endocrinology was consulted and the patient was started on beta blockers for symptom control and anti-thyroid medication (methimazole). Discussion: Fabowale MO et al highlighted the potential role of immunological mechanisms in causing pericardial effusion, while Fonseca et al focused on pathophysiological changes involving both extravascular and intravascular proteins, coupled with reduced lymphatic drainage. Cardiac complications in Graves' disease tend to occur more frequently when the condition has been poorly managed for an extended period before seeking medical help. If symptoms persist despite achieving proper control, clinicians need to be watchful for potential cardiac complications.
Presentation: 6/3/2024
8521 Increased Blood Pressure SDS in Boys With Early Onset Hypogonadism
Authors: Lucas-Herald A K , McNeilly J D , Ahmed S F 
Published: October 2024

Abstract
Disclosure: A.K. Lucas-Herald: None. J.D. McNeilly: None. S.F. Ahmed: None.
Introduction: Androgens are essential for normal vascular function. As such, early onset hypogonadism may be associated with an increased risk of accelerated vascular ageing and early vascular dysfunction. Methods: Boys aged 12-18 years were recruited from a tertiary paediatric endocrine clinic for non-invasive vascular phenotyping. Cases were boys who had proximal hypospadias and had undergone surgical repair for this or boys with genetically confirmed Klinefelter Syndrome. Controls were either healthy volunteers or boys who had undergone review for constitutional delay of puberty but had not required intervention. Vascular assessment was undertaken to assess blood pressure (BP), arterial stiffness (pulse wave velocity), subclinical atherosclerosis (carotid artery intima media thickness (CIMT)) and endothelial function (brachial artery flow mediated dilatation (FMD)). Where appropriate, standard deviation scores (SDS) were used for comparisons adjusting for sex, age and height. Statistical analysis was done by Graphpad Prism v 8.0. Comparisons between groups were via ANOVA or Mann-Whitney U tests with p&lt;0.05 representing statistical significance. Results: Twenty-two boys with conditions that may have been associated with a period of intra-uterine hypogonadism(hypospadias (n=11), Klinefelter Syndrome (n=11) (median age (range) 14.3 yrs (6.2, 16.9) and 11 healthy controls were recruited (median age 15.5 (6.8, 16.5)). There were no differences between the groups in terms of birthweight SDS, gestation at birth or presence of co-existing conditions. Systolic BP SDS was higher in boys with early onset hypogonadism (median (range) 1.25 vs. 0.5, p=0.01) compared to controls. There was no difference in SBP SDS between those with Klinefelter Syndrome and those with hypospadias (median (range) 1.0 vs. 1.5, p=0.6). CIMT SDS (1.75 vs. 0.0, p=0.02) and pulse pressure (34 vs. 30 mmHg, p=0.03) were increased in boys with early onset hypogonadism compared to controls but there were no differences in body mass index SDS, pulse wave velocity, FMD or mean arterial pressure. Conclusions: Adolescents with potential early onset hypogonadism have higher systolic BP SDS compared to healthy controls. There is a need to consider regular monitoring and early intervention in boys with early onset hypogonadism for risk stratification to prevent the development of cardiovascular disease later in life
Presentation: 6/3/2024
7482 Mechanisms Secondary to Biologic Sex Differences in Aldosterone and Plasma Renin Activity (PRA): Does Responsiveness to PRA/Angiotensin II differ between sexes?
Authors: Guzelce Ezgi Caliskan , heydarpour Mahyar , Romero Jose Ricardo , Pojoga Luminita , Williams Jonathan S , Adler Gail Kurr , Williams Gordon H 
Published: October 2024

Abstract
Disclosure: E. Caliskan Guzelce: None. M. heydarpour: None. J. Romero: None. L. Pojoga: None. J.S. Williams: None. G.K. Adler: None. G.H. Williams: None.
Men have higher baseline supine levels of Aldosterone (ALDO) than women, but women have a greater ALDO response to angiotensin II (Ang II) and greater salt sensitivity of blood pressure (SSBP). We hypothesize that the sex difference in ALDO levels is mainly driven by the response to the plasma renin activity (PRA) in men compared to women. We compared the ALDO levels of 846 individuals from the HyperPATH study to assess the potential underlying mechanism for observed sex differences in ALDO. Baseline supine ALDO levels were higher in men than women on both low and liberal salt diets (p&lt;0.0001, p&lt;0.0001), and baseline supine PRA levels were higher in men than women on both low and liberal salt diets (p&lt;0.0001, p=0.003). Conversely, the change in ALDO level from baseline supine to the response to the Ang II infusion and upright posture (delta ALDO levels) were greater in women than men (p&lt;0.0001, p&lt;0.0001). Other potential ALDO secretagogues, ACTH, or serum potassium could not explain the sex differences. In both sexes, the basal renal plasma flow was not significantly different on both low and liberal salt diets. The Ang II administration decreased renal plasma flow but increased blood pressure. The heightened delta ALDO response to Ang II in vasculature was generalizable as delta systolic blood pressure and delta renal plasma flow were also higher in women than men both on low salt (p=0.02, p&lt;0.0001), and liberal salt (p=0.009, p=0.0005) diets. Endogenous Ang II levels were higher in men than women on a low salt diet (p=0.01). Women had greater SSBP than men (p&lt;0.0001), secondary to a lower BP on a low salt diet rather than an increase in BP on a liberal salt diet. In summary, 1) higher baseline supine PRA and concomitant higher baseline supine endogenous Ang II levels were associated with higher baseline supine ALDO levels in men than women on controlled sodium diets. Lower Ang II responsiveness in Ang II targeted organs was observed in men compared to women despite higher endogenous Ang II levels. This can be explained by already saturated AT1 receptors in men, resulting in less response to additional Ang II stimulation. 2) SSBP is greater in women than men because their BP is significantly lower on a low salt diet, potentially secondary to their reduced PRA-Ang II-ALDO response to the stress of a low salt diet.
Presentation: 6/3/2024
12585 Metabolic Profile In Familial Partial Lipodystrophy Type 3: Case Series Of A Family
Authors: de Souza V P , Calmon J R , Pacheco V , Muniz R d , Muniz R B , Valerio C M , Godoy-Matos A F 
Published: October 2024

Abstract
Disclosure: V.P. de Souza: None. J.R. Calmon: None. V. Pacheco: None. R.D. Muniz: None. R.B. Muniz: None. C.M. Valerio: None. A.F. Godoy-Matos: None.
Background: Familial partial lipodystrophy (FPLD) is a group of genetic disorders, generally autosomal dominant, caused by heterozygous pathogenic variants, characterized by abnormal distribution of body fat and metabolic complications. We will present a series of three cases of patients from the same family, with involvement of the PPARG variant c.846delC p.Leu283*, associated with type 3 FPLD. Case 1. Index patient, a 17-year-old woman hospitalized with pancreatitis. On physical examination, she presents with acanthosis nigricans, hirsutism and a skinfold measurement on the thigh of 21mm (RR &lt; 22mm in women). At the time, she had triglycerides (TG) of 1529 mg/dL (RR &lt; 150 mg/dL) and HbA1c of 8.4% (RR &lt; 5.7%), and was positive for PPARG mutation. The patient started fibrate, regular and NPH insulins, metformin and pioglitazone, with good response to clinical treatment during the follow-up. Nowadays, she maintains use of oral antidiabetics, lowering TG down to 217 mg/dL and HbA1c to 6.3%. She has a recent liver ultrasound with mild steatosis - US fat fraction of 11% (RR mild 5-15%), and elastography with METAVIR F0 - 4.8 kPa (RR &lt; 5 kPa) IQR 7.9%. Case 2. A 41-year-old female patient, mother of the index patient, has a previous history of gestational diabetes that progressed to DM with multiple complications, associated with hypertriglyceridemia and metabolic dysfunction-associated fatty liver disease (MAFLD). At the first consultation, the patient presented a TG value of 396 mg/dL and HbA1c of 10.8%, already in use of multiple-dose insulin therapy at 1.2 units/kg/day. During investigation, the patient was also confirmed to have a mutation in the PPARG. Pioglitazone was introduced and insulin adjustment was made, but the patient continued to have difficult glycemic control until the present date. Her most recent liver ultrasound reveals mild steatosis - US fat fraction of 11.5%, and elastography with METAVIR F0 - 4.0 kPa. Case 3. A 14-year-old male, brother of the index patient, was recently brought to our specialized care as an asymptomatic case without comorbidities. He presents no changes on physical examination, a HbA1c of 5.6%, but already with hypertriglyceridemia (TG 310 mg/dL). Conclusion: The clinical features of FPLD3 may exhibit significant diversity, even among individuals sharing identical mutation. However, most cases converge in the severity of metabolic impairments, although experiencing a milder reduction in adipose tissue compared to FPLD2. Mild steatosis at US-derived fat fraction in cases 1 and 2 support less severe changes in fat distribution in FPLD3, leading to suspicion about the influence of the PPARG mutation on insulin sensitivity and metabolic changes.
Presentation: 6/3/2024
12428 Modulation Of Calcium Signaling On Demand To Decipher The Molecular Mechanisms Of Primary Aldosteronism
Authors: Fedlaoui B , Cosentino T , Al Sayed Z R , Giscos-Douriez I , Hulot J S , Simon T A , Baron S , Fernandes-Rosa F L , Zennaro M C , Boulkroun S 
Published: October 2024

Abstract
Disclosure: B. Fedlaoui: None. T. Cosentino: None. Z.R. Al Sayed: None. I. Giscos-Douriez: None. J. Hulot: None. T. Simon: None. S. Baron: None. F.L. Fernandes-Rosa: None. M. Zennaro: None. S. Boulkroun: None.
Primary aldosteronism (PA) is the most frequent form of secondary hypertension and is due to autonomous aldosterone production by the adrenal gland. During the last decades, major advances have been made in our understanding of the disease with the identification of germline or somatic mutations in ion channels and pumps. These mutations enhance calcium signaling, the main trigger of aldosterone biosynthesis. The objective of our work was to elucidate, using chemogenetic tools, the molecular mechanisms underlying the development of PA by modulating sodium entry into the cells “on demand” leading to calcium signaling activation. We have developed an adrenocortical H295R-S2 cell line stably expressing a chimeric ion channel receptor formed by the extracellular ligand-binding domain of the α7 nicotinic acetylcholine receptor fused to the ion pore domain of the serotonin receptor 5HT3a named α7-5HT3. Its activation by a selective agonist, the PSEM-817, leads to sodium entry into the cells and activation of calcium signaling. In parallel, we have developed a mouse model expressing the α7-5HT3 receptor specifically in the adrenal cortex. Cells expressing the α7-5HT3 receptor recapitulate the major characteristics of KCNJ5 mutations, the most frequent genetic alteration identified in aldosterone producing adenoma. Stimulation of the α7-5HT3 receptor by PSEM-817 resulted in a significant increase in intracellular calcium concentrations, CYP11B2 mRNA expression, and aldosterone biosynthesis and was associated with a decrease in cell proliferation. RNA sequencing and steroidome analyses revealed unique profiles associated with sodium entry. Exploration of adult mice expressing the α7-5HT3 receptor specifically in the adrenal cortex, generated in our laboratory, is ongoing. Preliminary results revealed a significant increase in plasma aldosterone and 18-hydroxycorticosterone levels in male and female mice expressing the α7-5HT3 receptor after four weeks of treatment with PSEM-817 but no major adrenal abnormalities. Our results suggest that increased sodium influx leading to increased calcium signaling is not sufficient to promote both increased aldosterone production and cell proliferation, strongly supporting the need for additional mechanisms for the development of aldosterone producing adenoma. Overall, this work provides valuable insights into the role of sodium-induced calcium signaling in the development of PA and paves the way for the development of new therapeutic strategies.
Presentation: 6/1/2024
7259 Optimizing the Aldosterone-to-Renin Ratio Cut-off for Screening Primary Aldosteronism Based on Cardiovascular Risk: A Collaborative Study
Authors: Hu J , Yang J 
Published: October 2024

Abstract
Disclosure: J. Hu: None. J. Yang: None.
Objectives: Aldosterone-to-renin ratio (ARR) based screening is the first step in the diagnosis of primary aldosteronism (PA). However, the guideline-recommended ARR cut-off covers a wide range, from the equivalent of 1.3 to 4.9 ng·dl-[1]/mIU·l-[1]. We aimed to optimize the ARR cut-off for PA screening based on the risk of cardiovascular diseases (CVD). Methods: Longitudinally, we included hypertensive participants from the Framingham Offspring Study (FOS) who attended the sixth examination cycle and followed up until 2014. At baseline (1995-1998), we used circulating concentrations of aldosterone and renin to calculate ARR (unit: ng·dl-[1]/mIU·l-[1]) among 1,433 subjects who were free of CVD. We used spline regression to calculate the ARR threshold based on the incident CVD. We used cross-sectional data from the Chongqing Primary Aldosteronism Study (CONPASS) to explore whether the ARR cut-off selected from FOS is applicable to PA screening. Results: In FOS, CVD risk increased with an increasing ARR until a peak of ARR 1.0, followed by a plateau in CVD risk (hazard ratio 1.49, 95%CI 1.19-1.86). In CONPASS, when compared to essential hypertension with ARR&lt;1.0, PA with ARR≥1.0 carried a higher CVD risk (odds ratio 2.24, 95%CI 1.41-3.55), while essential hypertension with ARR≥1.0 had an unchanged CVD risk (1.02, 0.62-1.68). Setting ARR cut-off at 2.4∼4.9, 10%∼30% of PA subjects would be unrecognized although they carried a 2.45∼2.58-fold higher CVD risk than essential hypertension. Conclusions: The CVD risk-based optimal ARR cut-off is 1.0 ng·dl-[1]/mIU·l-[1] for PA screening. The current guideline-recommended ARR cut-off may miss patients with PA and high CVD risk.
Presentation: 6/3/2024
7098 Paradoxical Worsening of Dyslipidemia with Tirzepatide
Authors: Pruett Jacob E , Carranza Leon Barbara Gisella 
Published: October 2024

Abstract
Disclosure: J.E. Pruett: None. B. Carranza Leon: None.
Background: While weight loss typically is associated with improvement in dyslipidemia (DLD), certain instances of extreme weight loss have been implicated in paradoxical worsening of DLD. For example, underweight women with anorexia nervosa have higher serum low-density lipoprotein cholesterol (LDL-C) than normal weight healthy counterparts (1). However, this has yet to be shown with dual incretin receptor agonist therapies such as tirzepatide. Clinical Case: A 75-year-old female with dyslipidemia treated with evolocumab (LDL-C 183 mg/dLbefore treatment), type 2 diabetes mellitus, and class 1 obesity was switched from glimepiride to tirzepatide in an effort to address the above conditions. Over the span of 6 months, tirzepatide was uptitrated to 15 mg, and the patient lost over 70 pounds with hemoglobin A1c decreasing to 5.8%. However, LDL-C more than doubled from 155 to 342, with high-density lipoprotein cholesterol (HDL-C) dropping from 57 to 42. Interestingly, triglycerides stayed the same from 124 to 122 during this timeframe. Out of concern for inefficacy of evolocumab, she was switched to inclisiran. Two months later, LDL-C was even higher at 360 with unchanged HDL-C and a moderate increase in triglycerides to 154. Given prior case reports of extreme weight loss worsening DLD along with the LDL-C skyrocketing upon tirzepatide initiation, the decision was made to decrease tirzepatide from 15 mg to 5 mg. Within the next three months, though her weight only changed by one pound, her LDL-C subsequently dropped to 114, HDL-C rose to 65, and triglycerides dropped to 71. Conclusion: To our knowledge, this is the first case report linking dual incretin receptor agonist therapy with worsening dyslipidemia. Reference: (1) Weinbrenner, T.; Züger, M; Jacoby, G.E; et al. Lipoprotein metabolism in patients with anorexia nervosa: a case-control study investigating the mechanisms leading to hypercholesterolaemia. British Journal of Nutrition. 2004;91:959-969.
Presentation: 6/3/2024