United States

Objectives:
Vosoritide is a C-type natriuretic peptide analog which binds its receptor on chondrocytes, leading to increased chondrocyte proliferation and differentiation via its inhibition of the ERK1/2-MAPK pathway. It was recently approved for increasing linear growth in children with achondroplasia. Our study aims to assess the safety and efficacy of vosoritide in children with genetic mutations in 6 categories: hypochondroplasia, Rasopathies (including Noonan syndrome), aggrecan deficiency, carriers of heterozygous NPR2 mutations, CNP deficiency, and SHOX deficiency.
Methods:
This is a prospective, Phase II study with a goal N of 35 subjects. All subjects must have a documented genetic mutation in one of the 6 categories, be prepubertal between the ages of 3 and 11 for boys and 3 and 10 for girls, and have a height &lt; -2.25 SD. Subjects are followed for a 6-month observation period to establish a baseline annualized growth velocity (AGV) and then receive daily subcutaneous vosoritide (15 mcg/kg/day) for 12 months. The primary outcomes are rate of AEs and change in AGV from baseline. Pharmacokinetic studies and pharmacodynamic studies, using cGMP production as a pharmacodynamic marker, are completed at Day 1 and Months 6 and 12.
Results:
To date, 27 subjects have enrolled in the trial (20 hypochondroplasia, 3 Noonan, 2 NPR2, 2 Aggrecan). Median baseline height is -3.1 SD (IQR -3.6, -2.6). 14 subjects have initiated on vosoritide, and 10 completed 6 months of therapy. Median increase in AGV was 3.9 cm/yr (IQR 2.2, 4.6). The two subjects with NPR2 mutations had increased AGVs of 4.4 and 9.2 cm/yr. The two subjects with Noonan syndrome had an increase in AGV of 7.5 and 3.3 cm/yr. One subject with Noonan syndrome, a 4-year-old male, had previously been treated with growth hormone (GH) for 2 years. His AGV was 6.7 cm/yr while on GH, 4.1 cm/yr during the 6-month observation period, and 11.6 cm/year during the first 6 months of vosoritide treatment. There were no serious adverse events related to vosoritide treatment. One subject had a brief episode of syncope with her first injection which self-resolved, and she continued on therapy with no further incidents. PK parameters were similar to previously published parameters for vosoritide in children with achondroplasia. In preliminary data, vosoritide Cmax and AUC correlated strongly with peak increase in cGMP (r=0.70, p=0.01;r=0.84, p&lt;0.01, respectively) but not with increase in AGV (r=0.35, p=0.32).
Conclusions:
This is the first clinical trial of vosoritide for children with genetic short stature who do not have achondroplasia. Vosoritide treatment may work as a precision therapy to improve growth in multiple genetic conditions which interact with the ERK1/2-MAPK pathway.

ENDO 2022

A Prospective Clinical Trial of Vosoritide in Selected Genetic Causes of Short Stature

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more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

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Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Objectives:
Vosoritide is a C-type natriuretic peptide analog which binds its receptor on chondrocytes, leading to increased chondrocyte proliferation and differentiation via its inhibition of the ERK1/2-MAPK pathway. It was recently approved for increasing linear growth in children with achondroplasia. Our study aims to assess the safety and efficacy of vosoritide in children with genetic mutations in 6 categories: hypochondroplasia, Rasopathies (including Noonan syndrome), aggrecan deficiency, carriers of heterozygous NPR2 mutations, CNP deficiency, and SHOX deficiency.
Methods:
This is a prospective, Phase II study with a goal N of 35 subjects. All subjects must have a documented genetic mutation in one of the 6 categories, be prepubertal between the ages of 3 and 11 for boys and 3 and 10 for girls, and have a height < -2.25 SD. Subjects are followed for a 6-month observation period to establish a baseline annualized growth velocity (AGV) and then receive daily subcutaneous vosoritide (15 mcg/kg/day) for 12 months. The primary outcomes are rate of AEs and change in AGV from baseline. Pharmacokinetic studies and pharmacodynamic studies, using cGMP production as a pharmacodynamic marker, are completed at Day 1 and Months 6 and 12.
Results:
To date, 27 subjects have enrolled in the trial (20 hypochondroplasia, 3 Noonan, 2 NPR2, 2 Aggrecan). Median baseline height is -3.1 SD (IQR -3.6, -2.6). 14 subjects have initiated on vosoritide, and 10 completed 6 months of therapy. Median increase in AGV was 3.9 cm/yr (IQR 2.2, 4.6). The two subjects with NPR2 mutations had increased AGVs of 4.4 and 9.2 cm/yr. The two subjects with Noonan syndrome had an increase in AGV of 7.5 and 3.3 cm/yr. One subject with Noonan syndrome, a 4-year-old male, had previously been treated with growth hormone (GH) for 2 years. His AGV was 6.7 cm/yr while on GH, 4.1 cm/yr during the 6-month observation period, and 11.6 cm/year during the first 6 months of vosoritide treatment. There were no serious adverse events related to vosoritide treatment. One subject had a brief episode of syncope with her first injection which self-resolved, and she continued on therapy with no further incidents. PK parameters were similar to previously published parameters for vosoritide in children with achondroplasia. In preliminary data, vosoritide Cmax and AUC correlated strongly with peak increase in cGMP (r=0.70, p=0.01;r=0.84, p<0.01, respectively) but not with increase in AGV (r=0.35, p=0.32).
Conclusions:
This is the first clinical trial of vosoritide for children with genetic short stature who do not have achondroplasia. Vosoritide treatment may work as a precision therapy to improve growth in multiple genetic conditions which interact with the ERK1/2-MAPK pathway.

technical paper

Background: Turner syndrome (TS) is a chromosomal anomaly occurring in females which presents with numerous medical and developmental manifestations including skeletal deformities. A specific developmental skeletal dyplasia seen in TS patients is Madelung deformity (MD), characterized by a growth deficiency of the distal radial physis that causes excessive radial inclination and volar tilt, with resultant ulnocarpal impaction. Surgical intervention, particularly in early stages, can halt progression of or reverse MD. Despite a considerable body of literature highlighting the presence of MD in TS, it is often underdiagnosed, in part due to a lack of data documenting the epidemiology and natural history. Objective: Analyze the frequency of diagnosis of MD in patients meeting key radiographic threshold criteria and document the time course of the deformity in these patients using these parameters. Methods: From a database of 264 patients with a confirmed diagnosis of TS, bone age radiographs for 187 (71%) were retrospectively measured against generally accepted cutoffs for MD using two parameters: ulnar tilt = UT and lunate subsidence = LS. For patients meeting general inclusion criteria of UT > 33° or LS < 0 mm, historical measurements of UT and LS were obtained using past bone ages and patients' charts were reviewed to determine if a clinical diagnosis of MD was made. Results: 7 patients (7/187 = 3.7%) met overall inclusion criteria and had radiographs consistent with Madelung Deformity. Of these 7, only one clinical diagnosis (14%) of MD was made; this patient underwent subsequent surgical intervention. The 6 undiagnosed patients had an average UT and LS of 40.5 degrees and -4.4 mm at the time of most recent bone age (~16.3 years old). The time-courses for 4 (UT) and 3 (LS) of the 6 non-surgical patients were plotted over time from 7.2 – 18.9 years of age. Patients crossed threshold at an average age of 15.3 and 13.6 years for UT and LS, respectively. Average maximum read-to-read growth rates of 5.3 degrees and 3.5 mm occurred at an average age of 15.3 (UT) and 14.2 years (LS). Conclusion: Our results suggest MD is significantly underdiagnosed in patients with TS, highlighting the need for better screening tools to make this diagnosis. This would include physical examination looking for the characteristic wrist deformity and careful analysis of bone age radiographs at an earlier age, when corrective surgery is more likely to succeed. We recommend careful scrutiny of yearly bone age radiographs from 10-15 years of age to ensure that the diagnosis of MD is not missed, and obtaining bilateral wrist radiographs (PA and Lateral views) for verification. Future research should focus on documenting disease progression using radiographic trends, as well as assessing how onset and progression are affected by therapeutic interventions such as growth hormone.

Tracking the Diagnosis and Progression of Madelung Deformity in Pediatric Turner Syndrome Patients

In many types of cells and tissues, the nuclear receptor corepressor 1 (Ncor1) is known as a main corepressor that interacts with thyroid hormone receptors (i.e., TRα, TRβ1, and TRβ2). In the absence of thyroid hormone (T3), NCOR1 is recruited by TRs to inhibit gene transcription. In the liver, the deletion of Ncor1 increases hepatic triglyceride levels. However, the detailed mechanism of how NCOR1 is involved in thyroid hormone signaling in different types of tissues is not fully understood. Our previous study showed that TRβ1 is expressed in the adrenal gland inner cortex and T3 treatment leads to the hypertrophy of this area. To determine the role of NCOR1 in the regulation of thyroid hormone signaling in adrenocortical cells, we generated the mice with a conditional deletion of Ncor1 in the adrenal cortex by crossing the Ncor1 floxed mice with the steroidogenic factor 1 (SF1) Cre mice. The RNA-seq data showed that only 76 genes were differentially expressed in adrenal glands due to the deletion of Ncor1 in adrenocortical cells. Gene ontology (GO) analysis revealed that 'cholesterol synthesis' was the top GO term associated with these 76 genes. Interestingly, 24-dehydrocholesterol reductase (Dhcr24), the key enzyme for cholesterol synthesis, was upregulated in knockout mice adrenal glands in both sexes. This phenotype fits the results in our previous studies that (1) Dhcr24 is significantly increased under T3 treatment in wild-type mice adrenal glands and (2) the DHCR24-expressing zone in the inner cortex is the primary responsive adrenal cortical layer under T3 treatment which leads to increased lipid accumulation in this area. To further study how DHCR24 is involved in this T3-induced lipid accumulation in the adrenal gland inner cortex, we generated Dhcr24 conditional knockout mice. We found that the T3-induced lipid accumulation in the adrenal gland inner cortex was sharply decreased in the Dhcr24;Sf1-Cre mice. In summary, with the Ncor1 conditional knockout mice, we found that the regulation of the cholesterol synthesis through DHCR24 is the primary function of NCOR1 in the adrenal gland inner cortex; by using the Dhcr24 conditional knockout mice, we further confirmed that the T3-induced lipid accumulation in the adrenal inner cortex can be blocked by the deletion of DHCR24. This study used genetic mouse models to decipher the connection between nuclear receptor corepressor Ncor1, the cholesterol synthesis enzyme Dhcr24, and how they control de novo cholesterol synthesis in the adrenal gland inner cortex.

Ncor1 Regulates the Expression of Dhcr24, which Controls de novo Cholesterol Synthesis in the Adrenal Gland Inner Cortex

Programmed death-ligand 1 (PD‐L1) is a strong immunosuppressor that inhibits T-cell activation by binding to its receptor (PD-1) on T-cells. Blocking the PD-L1/PD-1 interaction by monoclonal antibodies (mAbs) is an effective therapy for several cancers via activation of T-cells. Destructive thyroiditis and hypothyroidism often develop during anti-PD-L1 (αPD-L1) therapy but the pathogenic mechanisms are not known. We evaluated in vivo, the role of PD-L1 and its interactions with inflammatory triggers in the development of autoimmune thyroiditis (AIT). NOD.H-2h4 mice were treated with either αPD-L1 or isotype control (CTR) for two weeks and AIT evaluated after six weeks. αPD-L1 treated mice showed significantly higher Abs (p = 6x10e-4) and T-cell responses (p = 0.02) to thyroglobulin (Tg) compared with CTR mice. Serum fT4 levels were lower (p = 0.01) and TSH higher (p = 0.05) in αPD-L1 treated vs. CTR mice. Seven of the eight αPD-L1 treated mice (and none of the CTR mice) developed thyroid lymphocytic infiltration characterized by the presence of the CD4+, CD8+, FoxP3+ T- cells and B220+ B- cells. To gain insight into the pathways regulated by PD-L1 in the thyroid we assessed gene expression in the thyroid of αPD-L1 treated mice using RNA-seq. PD-L1 blockade was associated with upregulation of pathways of lymphocyte activation (p = 1.3x10e-5), lymphocyte proliferation (p = 2x10e-5), chemotaxis (p = 3.8x10e-12), and inflammatory response (p = 7.9x10e-7). Specifically, blocking PD-L1 was associated with upregulation of cytokine/chemokine genes that have a critical role in Th1 differentiation: IFNγ, IL-12, IL-15, CCL1 to CCL5, CD300, CXCL10, CXCL11. Ingenuity Pathway Analysis identified IFNγ and TNF as the top regulators of these activated gene networks. These results indicate that blockade of PD-L1 in thyroid promoted the Th1 mediator, IFNγ, inducing activation and proliferation of thyroidal CD4+ and CD8+ T cells, triggering thyroid tissue damage and AIT. Since PD-L1 mediates immune responses to inflammatory stressors (e.g. viral infections), we evaluated PD-L1 interaction with a known inflammatory trigger of AIT, interferon alpha (IFNα). Treatment with αPD-L1 + IFNα accelerated AIT in NOD.H-2h4 mice that developed high Tg Ab and T-cell responses and thyroidal lymphocytic infiltration only two weeks after treatment. Moreover, thyroiditis was more severe in mice receiving αPD-L1 + IFNα than αPD-L1 alone, manifesting by higher T-cell responses (p = 5x10e-3), and significantly more profound hypothyroidism. These results suggest that PDL-1 has a protective role in the thyroid against inflammatory stressors, and that its blockade exposes the thyroid to inflammatory damage. Therefore, in patients undergoing αPD-L1 therapy, inflammatory conditions (e.g. infections) can be a "second hit" that accelerates the onset of thyroiditis and augments thyroidal inflammation.

Dissecting Thyroidal Pathways Activated by PD-L1 Blockade Identifies New Mechanisms for Thyroiditis Triggered by Immune Checkpoint Inhibitors

Introduction: Low levels of triiodothyronine (T3) are common in patients with heart failure (HF). It has been proposed that the decreased levels of T3 contribute to metabolic and cardiac dysfunction in HF. We aimed to evaluate the effects of treatment with low dose and high dose of T3 in an animal model of HF with preserved ejection fraction (HFpEF). Materials and Methods: We evaluated four groups: ZSF1 Lean (Lean-Ctrl, n=8), ZSF1 obese (rat model of metabolic syndrome with HFpEF, HFpEF-Ctrl, n=13), ZSF1 obese supplemented with a replacement dose of T3 (initially 0.04mg/ml, increased to 0.06mg/ml after 4 weeks; HFpEF-T3high, n=8), and ZSF1 Obese supplemented with a low-dose of T3 (0.03mg/mL; HFpEF-T3low, n=8). T3 was supplemented in drinking water from week 13 to 24. The animals were submitted to anthropometric and metabolic evaluation, echocardiography, VO2max evaluation, hemodynamic evaluation, single cardiomyocyte evaluation, and myocardial tissue collection at 24 weeks. Results: HFpEF-Ctrl animals had lower serum and myocardial thyroid hormone levels than Lean-Ctrl. Treatment with low dose and high dose of T3 did not correct serum T3 levels, but increased myocardial T3 levels, with normalization of myocardial T3 levels in the HFpEF-T3high group. In comparison to HFpEF-Ctrl, body weight was significantly decreased in HFpEF-T3low and HFpEF-T3high groups (616±39g, 572±24g and 535±18g respectively, p<0.001). An improvement in glucose metabolism was observed only in HFpEF-T3high, with a decreased AUC of glucose during OGTT and insulin tolerance test. Both treated groups presented an improvement in diastolic function (with decreased isovolumetric relaxation time) and systolic function (with increased peak systolic velocity and decreased ejection time) comparing to HFpEF-Ctrl. These results were supported by enhanced Ca2+ transients during diastole and sarcomere relaxation. Comparing with HFpEF-Ctrl, animals treated with T3 had higher myocardial expression of the calcium transporter RYR2, of the transcriptional coactivator PGC-1α, and of the α-myosin heavy chain (MHC), with a lower expression of β-MHC. VO2max was improved with low-dose and high-dose T3 compared with HFpEF-Ctrl. Comparing with HFpEF-Ctrl, heart rate was increased with high-dose (277.9±30.2 vs 313.5±35.8, p=0.049) but not significantly with low-dose (277.9±30.2 vs 299.8±30.9 bpm, p=0.13). Mortality was increased in the HFpEF-T3high comparing with the other groups (no animals died during the protocol in the Lean-Ctrl, HFpEF-Ctrl and HFpEF-T3low groups; three animals had sudden death in the HFpEF-T3high group). Conclusion: Treatment with T3 improves metabolic function, myocardial calcium handling, diastolic and systolic function, and exercise capacity in this animal model of HFpEF. While the low dose was well tolerated and safe, the high dose was associated with increased heart rate and a higher risk of sudden death. Modulation of thyroid hormones may be a potential therapeutic target in HFpEF; however such approaches must take into account a narrow therapeutic window of T3 in HFpEF.

Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) with Low and High Dose of Triiodothyronine: an Animal Model of Metabolic Syndrome with HFpEF

Thyroid cancer affects ethnic groups at different rates and severity. Despite this, thyroid cancer health disparities are still an understudied area. Our laboratory has shown a differential expression of vitamin D binding protein (DBP) in Filipino Americans (FA) versus European Americans (EA) [1]. Higher DBP levels correlate to a better prognosis. A study has revealed a DBP-dependent vitamin D receptor (VDR) promoter activation. In this study, we investigated whether VDR and DBP are expressed differentially in different ethnic groups, such as African Americans (AA), Hispanic Americans (HA), EA, and FA. We were also able to determine the differential DBP polymorphisms, VDR variant expressions, and DBP-VDR interactions within different ethnicities. By PCR-Restriction Fragment Length Polymorphism (PCR-RFLP), we determined a higher frequency of DBP gene polymorphism in FA versus EA. Analyzing the Cancer Genome Atlas (TCGA) thyroid cancer datasets with the UALCAN assay, we found the differential expressions of DBP and VDR genes based on cancer stages, sample types, race, and histological subtypes. By immunohistochemistry, we detected strong nuclear VDR (nVDR) and very low membranous VDR (mVDR) expression that correlated with low DBP in FA thyroid cancer tissues. In contrast, there was a higher expression of both mVDR and DBP in HA versus the other ethnicities. Co-immunoprecipitation analysis revealed a stronger DBP interaction with mVDR in FA compared to other ethnicities. Our data suggest that low DBP correlates with low mVDR in FA, whereas high DBP correlates with high mVDR in the other ethnicities. In conclusion, the strong interaction of DBP with mVDR in FA may implicate the potential role of DBP-mVDR crosstalk in aggressive thyroid cancer. Future research goals will be aimed at determining pathways involved in BDP-mVDR crosstalk in thyroid cancer health disparities.

B. Mull, R. Davis, I. Munir, M.C. Perez, A.A. Simental, S. Khan, Differential expression of Vitamin D binding protein in thyroid cancer health disparities, Oncotarget 12(7) (2021) 596-607.

Differential Interactions of Vitamin D Binding Protein and Vitamin D Receptor in Different Ethnic Groups with Aggressive Thyroid Cancer

Thyroid hormones (THs) thyroxine (T4) and triiodothyronine (T3) are under homeostatic and circadian control by the hypothalamic-pituitary-thyroid axis while their free plasma concentrations are strongly buffered by three TH binding proteins (THBPs): thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB). The THBPs are crucial to the even delivery of THs from the blood to tissues, but their relative contributions and spatial kinetics within tissues are unclear. Many endocrine-disrupting chemicals (EDCs) can interfere with the regulation and actions of THs, some of which are structurally similar to THs with comparable or even higher binding affinities for THBPs. It has been suspected that by disrupting the binding of THs with THBPs, EDCs may alter the plasma TH concentrations and the delivery to tissues. Given that the majority of the binding sites on THBPs are unoccupied—thus available for EDC binding—it is uncertain whether TH homeostasis can be tangibly perturbed by EDC exposure. To answer these questions, we constructed a spatial multi-compartment human physiologically based kinetic (PBK) model of TH production, distribution, and metabolism. The model contains the thyroid, liver, and rest-of-body compartments with explicit descriptions of the reversible binding kinetics between THs and THBPs in the blood. The model was parameterized and validated extensively based on literature data. Here we reported several novel findings: (1) The contribution to TH tissue delivery by each THBP is not spatially constant across a tissue: ALB always contributes more THs to the arterial side of the tissue while TBG contributes more to the venous side.  (2) THBPs are essential for a uniform TH tissue delivery but are cross-compensatory in this role. (3) Contrary to the long-held assumption that ALB is the dominant contributor, TBG contributes more of the THs delivered to a tissue overall than ALB and TTR. (4) Bode plot analysis using control theory suggests that a circadian signal driving T4-to-T3 conversion in the extra-thyroidal tissue is crucial to establish the distinct phase and amplitude profiles of circulating T3 and T4 in humans. (5) Displacement of THs from THBPs by high-affinity EDCs has a negligible effect on free plasma THs even under high exposures. (6) Daily exposure to THBP-binding EDCs does not affect the circadian variations in tissue delivery of THs. The PBK model can be further elaborated in the future to make tissue-specific predictions of TH kinetics.

A Minimal Human Physiologically Based Kinetics Model of Thyroid Hormones and Effects of Endocrine-Disrupting Chemicals

Background: Functional Hypothalamic Amenorrhea (FHA) is characterized by suppression of central GnRH drive with secondary anovulation and hypoestrogenemia, hypercortisolism, and low leptin that results from a combination of psychosocial stress and metabolic imbalance due to excess physical activity and/or weight loss. Cardiovascular disease (CVD) is the leading killer of women at all ages and CVD mortality rates are unchanged or increasing in young women aged 35-44 years. We investigated relations between FHA and preclinical CVD measured by endothelial dysfunction in premenopausal women with and without FHA, and recently menopausal women not on hormone therapy.
Methods: We studied 31 women with FHA, 29 eumenorrheic controls, and 30 recently menopausal women not on hormone therapy. FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, FSH <10 mIU/L, and LH <10 mIU/L, and exclusion of other etiologies including polycystic ovary syndrome, prolactinoma, thyroid dysfunction, and pregnancy. Eumenorrheic controls had self-reported monthly menstrual cycles, were not on hormones, with a day 22-24 progesterone level >3 ng/ml to confirm ovulation. Preclinical CVD testing for eumenorrheic controls took place days 3-5 of menses. Recently menopausal women had natural menopause within 3 years, FSH >30, and not on hormone therapy. Preclinical CVD was measured using Endo PAT 2000 (Itamar® Medical Ltd) to calculate reactive hyperemic index (RHI) stress to rest pulse amplitude. RHI ≤1.67 indicates endothelial dysfunction. Statistical analysis included analysis of variance for normal distributed variables and Kruskal Wallis test for non-parametric variables.
Results: The mean age, BMI and estradiol of FHA, no FHA and recent menopause was 26.4 ± 6.2 y, 30.3 ± 3.7 and 53.3 ± 2.6, respectively (p<0.0001); BMI 21.6 ± 6.2 kg/m2, 21.8 ± 2.0, and 23.5 ± 4.2 (p=0.06); and estradiol 29.7±18.2, 46.4 ± 15.7, and 10.9 ± 14.4 pg/ml (p<0.0001), respectively. The median months of FHA amenorrhea was 10.8 months. There were no differences in testosterone (p=0.48), however FHA women had lower leptin (p=0.012) and higher cortisol (p=0.0005) compared to both no FHA and recently menopausal women. Preclinical CVD measured by RHI was significantly lower in FHA compared to no FHA and recently menopausal women (1.8 + 0.5 vs 2.2 + 0.5 vs 2.2 +0.6;p=0.007, respectively). Further 35% of FHA women had RHI ≤1.67 indicating endothelial dysfunction.
Conclusion: Our results demonstrate endothelial dysfunction in young women with FHA women as compared to eumenorrheic women and older recently menopausal women not on hormone therapy. Our findings suggest that FHA may be an important contributor to CVD mortality in younger women and that preclinical CVD in FHA is not likely due to hypoestrogenemia alone. Future studies will focus on identifying potential treatment targets for CVD prevention.

Functional Hypothalamic Amenorrhea and Preclinical Cardiovascular Disease

Background: The subtyping of primary aldosteronism (PA) requires interpretation of aldosterone and cortisol concentrations measured during adrenal vein sampling (AVS). The use of intravenous sedation during AVS is not standardized but may affect AVS outcomes.
Purpose: To characterize the impact of sedation on the outcomes of AVS, including cortisol and aldosterone concentrations, cannulation success and rates of lateralisation.
Materials and Methods: This is a retrospective cohort study based at a tertiary health centre. Consecutive patients who underwent AVS both before and after ACTH stimulation between June 2018 and July 2020 were included. AVS was performed without IV sedation in patient cohort 1 (n = 70), with sedation (midazolam and fentanyl) in cohort 2 (n = 34) and both before and after sedation in cohort 3 (n = 14). Comparisons were performed using the nonparametric (Mann Whitney U) test for continuous variables and the Chi square test for categorical variables.
Results. Overall, 118 patients (median age, 53 years; 67 men) were evaluated with no significant demographic differences between the three cohorts. Compared to cohort 1, patients in cohort 2 displayed significantly lower cortisol concentrations in the peripheral vein (median of 141 nmol/L vs 218 nmol/L), left adrenal vein (522 nmol/L vs 1284 nmol/L) and right adrenal vein (577 nmol/L vs 1578 nmol/L) in unstimulated AVS. Fewer patients were assessed to have successful right sided cannulation in cohort 2 (79% vs 93% in cohort 1, p = 0.047).  In cohort 3, cortisol concentrations were markedly lower after sedation, with the decrease being more marked in the adrenal veins compared to peripheral veins, hence leading to lower selectivity indices.  There were no clinically significant changes in aldosterone concentration or rates of lateralisation after sedation.
Conclusions. IV sedation reduces cortisol concentrations during unstimulated-AVS, leading to lower selectivity indices and fewer cannulations judged as successful. Importantly, radiologists are turning to point-of-care rapid cortisol tests to determine if the catheter is 'in' the adrenal vein in real-time.  Adrenal vein samples collected after sedation are more likely to be considered "unsuccessful" using these semi-quantitative assays. The need for IV sedation during AVS should be carefully assessed.

Impact of Intra-Procedural Sedation on Outcomes of Adrenal Vein Sampling

Background: Primary aldosteronism (PA) is broadly divided into unilateral and bilateral forms, and the most reliable subtyping tool available is adrenal vein sampling (AVS). Unilateral PA is generally diagnosed based on AVS lateralization indices (LI=[aldosterone/cortisol] ratio between the dominant and contralateral adrenal vein) ≥4, or even ≥2 when AVS is performed without cosyntopin stimulation. Long-term follow-up data from patients with PA treated with unilateral adrenalectomy have been minimal.
Objective: To assess the rates of residual and recurrent PA after AVS-guided unilateral adrenalectomy.
Methods: We enrolled patients with PA who underwent unilateral adrenalectomy between 09/2017 and 08/2021 in a single tertiary referral center and followed them longitudinally. Demographics, laboratory, imaging, and pathology data were collected. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue blocks.
Results: During the study period, 80 patients (52 men) with median age 53 (range, 19-76) years underwent unilateral adenectomy, and were followed for a median 80 days (range, 6-653 days). In total 14 (17.5%) patients had evidence of residual PA following surgery, including 3 who had complete biochemical failure, and 1 who had apparent cure of PA immediately post-operatively. All 14 patients had severe PA, with baseline plasma aldosterone concentrations between 23.4 and 496 ng/dL and suppressed renin. Baseline and post-cosyntropin stimulation LIs ranged from 2.7- 187.5 and 1.3-53.7. The LI was >4 only at baseline in 3 cases, and only after cosyntropin stimulation in 2 cases. Histology showed single adenomas, ranging from 0.7-5.3 cm in 7 (50%) patients, and multiple adenomas and/or nodular hyperplasia in 7 (50%) patients. Of the 7 cases analyzed for aldosterone-driver mutations so far, 4 harbored CACNA1D mutations, 2 ATP1A1 mutations, and 1 a KCNJ5 mutation.
Conclusions: Patients with severe PA and frank AVS aldosterone lateralization might have multifocal, bilateral disease. Long-term follow up and targeted medical therapy should be pursued after unilateral adrenalectomy for presumed unilateral PA.

A Prospective Clinical Trial of Vosoritide in Selected Genetic Causes of Short Stature

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