Antihypertensive Research Articles

Epidemiology And Biological Mechanisms Of Cardiovascular Disease And Diabetes

The risk of CVDs in T2DM patients in LMICs is higher than in developed nations. It is essential to make an evaluation of the current situation of CVDs among people with T2DM. These CVDs are easily preventable through intervention especially in T2DM patients and this should be done in a comprehensive manner. The following targets and principles should be considered: individual targets of HbA1c for patients, a rigorous control of cardiovascular risk factors such as blood pressure and lipids, and incorporation of newer anti-diabetic, lipid-lowering and anti-hypertensive agents. It is, therefore, crucial to design a stepped-wedge approach that bundles a patient-level intervention, lifestyle, and pharmacological interventions to reduce the risk of CVD in LMIC T2DM populations. When selecting medications for T2DM patients with cardiovascular conditions, several key considerations must be made: When selecting medications for T2DM patients with cardiovascular conditions, several key considerations must be made: It should be noted that the choice of anti-diabetic drugs should take into consideration cardiovascular safety. SGLT2 inhibitors and GLP-1 agonists are newer agents for managing diabetes and have been found to have cardiorenal benefits. The choice of lipid-lowering should be targeted to lower LDL cholesterol and triglycerides as effectively as possible. If the intensity of statin is high; it is considered first-line therapy, and other optional medication includes ezetimibe and PCSK9 inhibitors. To maintain the best pressure level that is suitable for an individual, and as a result control hypertension, the use of antihypertensive drugs is necessary. This makes ACE inhibitors or ARBs the preferred first-line antihypertensive agents because of their cardiovascular benefits. For the purpose of secondary prevention in individuals who have experienced a cardiovascular event, the antiplatelet drug aspirin in a dosage of between 75 to 150 milligrams per day should be administered. This is to minimize the probability of such difficulties re-emerging by influencing platelet activity. In general, adequate blood pressure management and antiplatelet aggregation therapy are key interventions with specific antiplatelet medication needs in this setting.

Antihypertensive therapy in patients with arterial hypertension and concomitant diseases in real clinical practice (according to the National Registry of Arterial Hypertension, 2019-2022)

Arterial hypertension (AH) remains the leading risk factor associated with cardiovascular diseases (CVDs), cerebrovascular disease and chronic kidney disease. About 70% of patients with AH who are on monotherapy cannot achieve blood pressure (BP) targets, and therefore all quidelines for the management of AH have recently recommended prescribing combination therapy (PCT). In real clinical practice (RCP), there remains significant uncertainty in the effectiveness and rationality of therapy, despite the wide availability of antihypertensive drugs (AHD) and the presence of recommendations for a stepwise approach to prescribing combinations of specific groups of AHD in different clinical situations. Analyze the real ongoing antihypertensive therapy, including the PCT; international nonproprietary names of drugs and their dosages in RCP; compliance of therapy with clinical recommendations; changing trends in the PCT. An analysis was carried out of the data from the register of AH, the compliance of treatment in different clinical groups of patients and the achievement of BP and low-density lipoprotein cholesterol targets in the sample of 2019-2022 (n=5012). The prescription of AHD and achievement of targets values were assessed in accordance with current clinical guidelines for the management of AH and hypercholesterolemia. Data from 2010 (n=7782) and 2020 (n=3061) were analyzed to assess the dynamics of prescription of monotherapy and PCT. The greatest increase in the number of AHD was observed in patients with hypertension in combination with coronary heart disease, heart failure, and atrial fibrillation. In a small group of patients with hypertension without other CVDs, the recommended combinations of AHD were not prescribed; preference was given to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-adrenoblocker (β-AB). PCT mainly differed from the recommended combinations by the wider use of drugs from the β-AB group. The PCT of recommended drugs was highest in patients with hypertension and coronary artery disease - more than 90%, hypertension and heart failure in 56.2%, hypertension and atrial fibrillation - 33.3%, hypertension and chronic kidney desease - 19.6%. Achievement of BP and low-density lipoprotein cholesterol targets was insufficient in all analyzed groups. Among the international nonproprietary names of drugs, the most frequently prescribed are the following: bisoprolol, metoprolol, lisinopril, perindopril, losartan, spironolactone, amlodipine, torasemide, indapamide, hypochlorothiazide, moxonidine. The prescribed daily dosages were closer to the initial recommended ones. By 2020, the prescription of PCT with β-AB and a more uniform prescription of various combinations will come to the fore, while PCT in 2010 is characterized by the presence of one or two leaders combinations. The described features of prescribing AHD partially reproduce clinical recommendations for the management of AH. Differences in therapy provided in RCP may be associated with an attempt to intensify the treatment of hypertension in patients with other concomitant CVDs. At the same time, analysis of combinations and dosages of prescribed drugs suggests the presence of wide opportunities for further escalation of therapy. The presented data can provide insight into current patterns of antihypertensive therapy prescription in patients in RCP and lay the foundation for optimizing therapy in different categories hypertensive patients.

Prophylactic Antihypertensive Effect of Extract of Simarouba glauca on Salt-Load Induced Hypertension in Normotensive Male Wistar Rat

Simarouba glauca has been reported to demonstrate a wide range of medicinal properties; including folklore management of hypertension disorder. The current study focused on the application of aqueous leaf extract of Simarouba glauca (AESG) as a potential prophylactic anti-hypertensive agent in male Wistar rats, following salt-load induced hypertension. A total of 15 experimental adult male Wistar rats weighing between 184 and 244 g were used for the study. The rats were allotted into five (5) groups of 25, 50, and 100 mgkg-1 body weight AESG; group that received 8 % NaCl for one week to induce hypertension; replaced with 0.9 % NaCl daily in drinking water for 4 weeks; the normotensive group, received food and water only ad libitum. Body weights and relevant hemodynamics were obtained weekly for four weeks, using the non-invasive (tail-cuff) MRBP system according to the method described by Bunag and Butterfield. Biochemical evaluation and histopathology investigation were conducted on blood plasma and relevant tissues respectively after 4 weeks according to previously established and reported methods; data were analyzed with GraphPad Prism, version 9 and presented as mean ± Standard Deviation. The results indicated that salt-load elicited significant weight loss; elevated hemodynamics; particularly, systolic and diastolic blood pressures; altered relevant biochemical indicators of hepatic and renal functions. Inversely, groups pre-treated with respective dose of AESG exponentially gained weight, significantly prevented alterations of hemodynamics and mitigated relevant biochemical indicators and pathological changes in relevant organs. Pre-treatment with AESG; particularly at 50 mgkg-1, remarkably demonstrated significant anti-hypertensive potential.

Association of RAAS inhibitors on osteoporosis and fracture risk in the hypertensive population–A prospective population-based cohort study in Lanzhou, China

BackgroundRenin-angiotensin-aldosterone system (RAAS) inhibitors appear to benefit bone tissue in antihypertensive treatment. However, the association between RAAS inhibitors and bone metabolism was inconsistent.Methods and study designBased on the study of Risk Evaluation of Cancers in Chinese Diabetic Individuals(REACTION) conducted in 2011, We followed 6,252 Lanzhou residents aged 40–75 years from 2014 to 2016. Finally, 1,625 hypertension cases with complete data were included in the analysis. The study subjects were divided into four groups according to the type of antihypertensive drugs. We employed logistic or multivariate Cox proportional hazards regression to estimate the association between different antihypertensive drug use and osteoporosis, the risk of fracture, and the change in bone mineral density (BMD) level. The association of osteoporosis or the fracture risk by cumulative duration of use of these medications (< 3 years.) and (> 3 years.) was also estimated.ResultsThe cross-sectional study showed that there was no significant association between baseline antihypertensive drugs (angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB)) use and osteoporosis and fracture. During a mean follow-up of 3.4 years in the longitudinal study, there were 478 new osteoporosis cases and 76 fractures. Compared with patients without antihypertensive drug use, the hazard ratios (HRs) [95% confidence interval (CI)] for the risk of osteoporosis were 1.005(0.651,1.552) and 1.077(0.793,1.462) in ACEI or ARB use (p > 0.05). ACEI or ARB use was also not significantly associated with fracture risk (HR 1.102(0.326,3.726), 0.735(0.251,2.148), p > 0.05). Further analysis showed that the use of ACEI (HR 1.078(0.146,7.950)) or ARB (HR 1.169(0.347,3.939)) was not significantly associated with the improvement of osteoporosis (p > 0.05). In addition, the duration of RAAS inhibitors used showed no apparent correlation with the risk of osteoporosis (≤ 3 years: HR 0.872 (0.516, 1.474), > 3 years: HR 1.151 (0.574, 2.308)), nor with the improvement of osteoporosis and the risk of fracture. Meanwhile, the association mentioned above did not change compared to different RAAS inhibitors.ConclusionsThe use of RAAS inhibitors, including ACEIs and ARBs, was not significantly associated with osteoporosis, risk of fracture, or BMD change.

Antihypertensive Treatment Patterns in CKD Stages 3 and 4: The CKD-REIN Cohort Study

Rationale & ObjectiveBlood pressure (BP) control is essential for preventing cardiorenal complications in chronic kidney disease (CKD), but most patients fail to reach BP target. We assessed longitudinal patterns of antihypertensive drug prescription and systolic BP (SBP). Study DesignProspective observational cohort study Setting & Population2755 hypertensive patients with CKD stages 3–4, receiving care from a nephrologist, from the French CKD-REIN cohort study ExposurePatient factors, including sociodemographic characteristics, medical history, and laboratory data, and provider factors, including number of primary-care physician and specialist encounters. OutcomesChanges in antihypertensive drug class prescription during follow-up: add-on, or withdrawal. Analytical ApproachHierarchical shared-frailty models to estimate hazard ratios (HR) to deal with clustering at the nephrologist level, and linear mixed models to describe Systolic BP trajectory. ResultsAt baseline, median age was 69, mean eGFR, 33 ml/min/1.73m2; 66% of patients were men, 81% had BP ≥130/80 mmHg and 75% were prescribed ≥2 antihypertensive drugs. During a median 5-year follow-up, the rate of changes of antihypertensive prescription was 50 per 100 person-years, 23 per 100 for add-ons and 25 per 100 for withdrawals. After adjusting for risk factors, Systolic BP, and the number of antihypertensive drugs, poor medication adherence was associated with increased HR for add-on, 1.35 (95% confidence interval, 1.01-1.80), while a shorter education level was associated with increased HR for withdrawal, 1.23 (1.02-1.49) for 9-11 years versus ≥12 years. More frequent nephrologist visits (≥4 versus none) were associated with higher HRs of add-on and withdrawal (1.52; 95% CI 1.06-2.18 and 1.57; 1.12-2.19, respectively), while associations with visit frequency to other physicians varied with their specialty. Mean Systolic BPdecreased by 4 mmHg following drug add-on but tended to rise thereafter. LimitationsLack of information on prescriber, and drug dosing. Conclusions: In patients with CKD and poor BP control, changes in antihypertensive drug prescriptions are common and relate to clinician preferences and patients’ tolerability. Sustainable reduction in Systolic BPafter add-on of a drug class is infrequently achieved.

Formulation of Felodipine lipid nanoparticle-loaded oral fast-dissolving films

Abstract Felodipine, a calcium channel blocker used to treat hypertension, is a BCS Class II drug characterized by low solubility, high permeability and significant hepatic metabolism, which limits its bioavailability to 15 %. This study focuses on improving the bioavailability of Felodipine by developing oral fast-dissolving films (OFDFs) incorporating lipid nanoparticles. Felodipine loaded lipid nanoparticles were prepared using glyceryl monooleate (GMO) as lipid and Poloxamer 407 as the surfactant, and then incorporated into OFDFs using the solvent casting technique. A Box-Behnken design with Design Expert Stat-Ease® 360 was used to evaluate the impact of GMO, Poloxamer 407 concentration, and sonication time on particle size and entrapment efficiency. The resulting nanoparticle dispersions had particle sizes ranging from 74.92 nm to 112.1 nm and entrapment efficiencies between 80.43 % and 95.23 %. Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) confirmed successful drug encapsulation. The OFDF showed optimal mechanical properties, disintegration within (41.33 ± 3.51) s, and an in-vitro drug release of (89.82 ± 2.75) % in 6 min. Scanning electron microscopy (SEM) revealed a smooth, uniform, porous surface and the films remained stable for three months. The study concludes that Felodipine loaded lipid nanoparticles in fast-dissolving OFDFs improve permeability, dissolution, and onset of action, making them a promising approach for antihypertensive therapy.

Effects of Adopting Preventive Drug Lists on Medication Costs and Disparities by Income Over 2 Years: A Natural Experiment for Translation in Diabetes (NEXT-D) Study.

To examine the association between preventive drug lists (PDLs) and changes in medication costs among patients with diabetes insured in commercial health plans over 2 follow-up years. We conducted a quasiexperimental study using the Optum deidentified Clinformatics Data Mart Database (January 2003 to December 2017). The intervention group included 5,582 patients with diabetes age 12-64 years switched by employers to PDL coverage; the control group included 5,582 matched patients whose employers offered no PDL. Outcomes included out-of-pocket costs, standardized costs, and 30-day fills for all medications because PDL-associated savings could be used to pay for medicines in other classes and for five therapeutic classes covered by the PDLs (oral diabetic medications, insulins, test strips, antihypertensive drugs, and lipid-lowering drugs). Pre- to post-out-of-pocket spending for all medications declined by 29.7% in follow-up year 2 (95% CI -36.0, -23.4%) among PDL members relative to controls. Higher-income and lower-income PDL members experienced significant reductions in out-of-pocket spending for all medications in year 2 (30%) and for key therapeutic classes (range -23 to -67%). We found significant increases in use of key therapeutic classes in the overall population (range 8-15%) and in higher-income and lower-income PDL members (range 9-50%). PDLs offer an effective strategy for employers and insurers to lower member cost sharing and encourage increased use of important medications to prevent or manage chronic illnesses. For patients with diabetes, especially those with lower incomes, PDL coverage resulted in substantial and persistent reductions in out-of-pocket medication costs, medication use increases, and some increased use of more expensive products.

Cardiometabolic factors and vitamin D deficiency in pediatric patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) are at increased risk for cardiovascular disease. Up to 80% of patients with CKD may exhibit inadequate vitamin D (VD) levels, which have been linked to the presence of cardiometabolic factors (CFs) in the adult population. However, research on this association in the pediatric population is limited. To analyze the effects of 25-hydroxyvitamin D3 (25-[OH]D) levels and status on the presence of CFs in children receiving kidney replacement therapy (KRT). This cross-sectional study included pediatric patients receiving KRT, aged 8-17 years, who were receiving hemodialysis or peritoneal dialysis from January 2021 to March 2024. We conducted anthropometric measurements, blood pressure assessments, and glucose, 25-(OH)D, and lipid profiling for all participants. The daily dose of cholecalciferol supplementation, as well as other medications affecting bone and lipid metabolism and antihypertensive drugs, were documented. Statistical analyses were performed using Student's t-tests and chi-square tests to compare the CFs between groups with and without VD deficiency. The study involved 156 patients with an average age of 12.9 years and a mean serum VD level of 22.5 ng/dL. Patients with VD deficiency presented higher levels of total cholesterol and diastolic blood pressure (p < 0.05). No statistically significant differences were found in other biochemical profile variables or in the frequency of cardiometabolic factors. Vitamin D deficiency seems to increase the risk of dyslipidemia and uncontrolled hypertension in children and adolescents with end-stage CKD.

Effectiveness of a fixed combination of empagliflozin with metformin in reduction of cardiovascular risk in patients with uncontrolled arterial hypertension and decompensated type 2 diabetes mellitus

Objective is to study the effectiveness of a fixed combination of empagliflozin and metformin in reducing cardiovascular risk in patients with uncontrolled arterial hypertension (AH) and decompensated type 2 diabetes mellitus (DM). Materials and methods. 36 patients with uncontrolled AH and decompensated type 2 diabetes mellitus aged 45 to 60 were examined. Before inclusion in the study, all patients received standard antihypertensive (angiotensin‑converting enzyme (ACE) inhibitor or angiotensin‑II receptor blocker (ARB) in combination with a calcium channel blocker and a thiazide‑like diuretic), glucose‑lowering (metformin) and hypolipidemic (atorvastatin) therapy. However, target levels of blood pressure (BP), glycated haemoglobin (HbA1c) and lipids were not achieved. After the initial examination, all patients were prescribed a fixed combination of empagliflozin and metformin at a dose of 12.5 mg/1000 mg 1—2 times a day, and antihypertensive and hypolipidemic therapy was continued. Re‑examination was carried out after 20 weeks. In the work, a statistical analysis of the obtained data was carried out using standard methods using Microsoft Excel 7.0 and SPSS 19.0 application packages. Results. The transfer of the examined patients from previous ineffective hypoglycemic therapy to a fixed combination of empagliflozin with metformin against the background of standard antihypertensive and hypolipidemic therapy made it possible to achieve the target levels of HbA1c in 69% of patients and target BP levels in 64%. The frequency of reaching target BP levels in the subgroup of patients who received ARB was significantly higher than in the subgroup of patients who received ACE inhibitors. The specified therapy contributed to a significant reduction in body weight, reaching the target levels of low‑density lipoprotein cholesterol (LDL‑C) and non‑high‑density lipoprotein cholesterol (Non‑HDL‑C) in more than a third of patients, and reducing the severity of albuminuria in some patients. The tested therapy, in general, led to reduction in cardiovascular risk and did not cause side effects that could lead to discontinuation of treatment. Conclusions. The fixed combination of empagliflozin with metformin against the background of standard antihypertensive and hypolipidemic therapy in patients with uncontrolled hypertension and decompensated type 2 diabetes mellitus contributed to the achievement in the vast majority of patients of the target levels of HbA1c in the blood and BP levels, reduced body weight, positive changes in lipid metabolism and kidney function, and demonstrated the possibility of a significant reduction in cardiovascular risk. A more pronounced decrease in BP was detected in the case of a fixed combination of empagliflozin and metformin with ARB compared to ACE inhibitors in this category of patients.

Causal relationship between antihypertensive drugs and Hashimoto's thyroiditis: a drug-target Mendelian randomization study.

Recent studies have indicated a potential association of hypertension with Hashimoto's thyroiditis (HT) and other autoimmune diseases, yet the impact of antihypertensive drugs on HT risk is not well understood. We employed a drug-target Mendelian randomization approach to investigate the prolonged impact of 9 classes of antihypertensive medications on HT susceptibility in European and Asian populations. Genetic variants close to or within genes associated with the drug targets and systolic blood pressure (SBP) were utilized to mimic the effects of antihypertensive medications. We focused on drugs linked to a lower risk of coronary artery disease for our main analysis. We gathered genetic data on SBP and HT risk from comprehensive genome-wide association studies available for European and Asian groups. For a supplementary analysis, we used expression quantitative trait loci (eQTLs) related to drug target genes as proxies. Our analysis revealed that the use of calcium channel blockers (CCBs) is linked to a reduced risk of HT in both European (OR [95% CI]: 0.96 [0.95 to 0.98] per 1 mmHg decrease in SBP; p = 3.51×10-5) and Asian populations (OR [95% CI]: 0.28 [0.12, 0.66]; p = 3.54×10-3). Moreover, genetically mimicking the use of loop diuretics (OR [95% CI]: 0.94 [0.91, 0.97]; p = 3.57×10-5) and thiazide diuretics (0.98 [0.96, 0.99]; p = 3.83×10-3) showed a significant association with a decreased risk of HT only in European population. These outcomes were confirmed when eQTLs were employed to represent the effects of antihypertensive medications. The study suggests that CCBs and diuretics could potentially reduce the risk of HT in different populations. Additional research is needed to assess the feasibility of repurposing antihypertensive medications for the prevention of HT.

A newly developed, easy-to-use prehospital drug-derived score compared with three conventional scores: A prospective multicenter study.

The use of medications by emergency medical services (EMS) is increasing. Conventional scores are time-consuming and therefore difficult to use in an emergency setting. For early decision-making, an easy-to-use score based on the medications administered by the EMS may have prognostic value. The primary objective of this study was to develop the prehospital drug-derived score (PDDS) for 2-day mortality. A prospective, multicenter, ambulance-based cohort study was conducted in adults with undifferentiated acute diseases treated by EMS and transferred to the emergency department. Demographic data, prehospital diagnosis data, prehospital medication and variables for the calculation of the National Early Warning Score 2 (NEWS2), Rapid Emergency Medicine Score (REMS), and Rapid Acute Physiology Score (RAPS) were collected. The PDDS was developed and validated, establishing three levels of risk of 2-day mortality. The predictive capability of each score was determined by the area under the curve of the receiver operating characteristic curve (AUROC) and compared using the Delong's test (p-value). A total of 6401 patients were included. The PDDS included age and the use of norepinephrine, analgesics, neuromuscular blocking agents, diuretics, antihypertensive agents, tranexamic acid, and bicarbonate. The AUROC of PDDS was .86 (95% CI: .816-.903) versus NEWS2 .866 (95% CI: .822-.911), p = .828; versus REMS .885 (95% CI: .845-.924), p = .311; versus RAPS .886 (95% CI: .846-.926), p = .335, respectively. The newly developed easy-to-use prehospital drug-derived PDDS score has an excellent predictive value of early mortality. The PDDS score was comparable to the conventional risk scores and therefore might serve as an alternative score in the prehospital emergency setting.

Baseline characteristics of the first 302 patients included for acute malignant hypertension crisis in the prospective multidisciplinary HAMA cohort.

Malignant hypertension has not disappeared and remains the most severe form of hypertension. More than 100 years after its description, many points remain unanswered. Mechanisms, definitions, and optimal treatment are still controversial. In 2019, we decided to launch a prospective multicentre multidisciplinary cohort in France to try to fill these gaps. This study aimed to describe the baseline characteristics of the first 302 included patients and compared these data to already published cohorts. We included patients with severe hypertension associated with severe hypertensive retinopathy and patients filling the HYP MOD (HYPertension MultiOrgan Damage) definition from a broad range of departments (cardiology, nephrology, neurology intensive care unit, emergency department, internal medicine). We collected clinical, biological, imaging, and target organ damage data at admission, along with social and demographic data. We also recorded diagnostic and therapeutic management, adverse events during hospitalization, and characteristics at discharge. We enrolled 302 patients in 32 months (105/year) among 40 centres and different specialties. They mainly included young men (68%, mean age 48.7 ± 14.5 years). Target organ damage involved the eye in 86.7% of patients, kidney in 58.6%, heart in 50%, brain in 32.8%, and Thrombotic Microangiopathy stigmata in 15.6%. Patients with severe retinopathy shared characteristics similar to those included in the most important cohorts already published. We also reported several additional subgroups of interest: one-third of our patients were less than 40 years old, one-third were of non-European origin, 14.3% were included through the multiorgan damage definition, without fundus severe injuries, 22.8% were treated without the use of IV therapy, 40.9% had normal or low renin level, and almost all patients were not on antihypertensive therapy at the time of the enrolment. These preliminary findings already challenge long-standing dogma, raise numerous questions, and provide a solid basis to address them in ancillary studies of the cohort.

Course of arterial hypertension during breast cancer chemotherapy with anthracyclines

Aim. To study the characteristics of the course of arterial hypertension (AH) and subclinical cardiac damage during breast cancer chemotherapy with doxorubicin.Materials and methods. The study included a total of 27 women with breast cancer (BC) and a history of controlled hypertension who were to receive chemotherapy with anthracyclines. Twelve women had stage 1 hypertension; 15 women had stage 2 hypertension. The patients received dual antihypertensive therapy according to clinical guidelines. All patients underwent echocardiography and 24-hour blood pressure monitoring at baseline, after the last course of chemotherapy, and 12 months after the end of chemotherapy. The control group included 35 women with BC without a history of AH, who also were to receive anthracycline chemotherapy.Results. A significant relationship between pre-existing AH and the development of left ventricular systolic dysfunction 12 months after the completion of chemotherapy (p = 0.01) was found. According to 24-hour blood pressure monitoring, 15 women (55.6%) showed deterioration of blood pressure control after the completion of chemotherapy, which required modification of antihypertensive therapy by adding one more drug to the treatment regimen. At 12 months after the end of chemotherapy, in 13 women, hypertension control was reached with triple antihypertensive therapy. In two women, hypertension became resistant, which required prescription of a fourcomponent antihypertensive regimen.Conclusion. Pre-existing AH plays an essential role in the development of anthracycline-induced cardiotoxicity, despite the quality of blood pressure control. Polychemotherapy with anthracyclines may deteriorate blood pressure control in patients with AH, which requires addition of antihypertensive drugs to the treatment regimen.

6636 Primary Hyperaldosteronism Leading to Aldosterone Deficiency

Abstract Disclosure: N.G. Haverstick: None. J.R. Anthony: None. Primary Hyperaldosteronism is a disease process that is often missed, and under checked due to poor screening tools. The disease presents with a common problem, uncontrolled hypertension. It also presents with hypokalemia, fatigue and headaches. It can easily be masked with blood pressure medications, CKD, and pain medications. After treatment there are some rare reports of patients developing hypoaldosteronism. Some risk factors are age &amp;gt;50, duration of hypertension &amp;gt;10 years, pre-existing renal impairment and adrenal adenoma size &amp;gt;2 cm. The patient will present with the opposite: hyperkalemia and hypotension. This is due to the atrophy of the previously healthy gland. Usually this resolves within a year. However in our patient she has continued to require long standing mineralocorticoid replacement therapy. This case highlights the importance of early recognition of hyperaldosteronism. A 63 year-old-female with a medical history of hypertension and diabetes mellitus is being followed for 30+ years of uncontrolled hypertension. Patient has been on multiple agents and blood pressure remained elevated after trying triamterene/hctz, metoprolol, irbesartan, amlodipine. After changing her PCP, there was further investigation into the cause. Leading differentials were Primary Hyperaldosteronism vs Renal Artery Stenosis vs Primary Hypertension. She also had multiple labs with her Potassium below 3 mEq/l. Additional labs were obtained and her Aldosterone level 209 ng/dl and Renin &amp;lt;0.167 ng/mL/hr. The patient was referred to Endocrinology who performed a fludrocortisone suppression test, which did not suppress the levels. A CT scan of the abdomen was performed that showed a 1.3 cm right adrenal mass typical with adrenal adenoma. The patient had an adrenalectomy surgery in February 2022. The patient recovered well, however now developed hypotension off medication, and had consistent hyperkalemia with K &amp;gt; 5.5 mEq/l. The patient had now developed aldosterone deficiency. This was due to the long standing hyperaldosteronism that had caused her left adrenal gland to atrophy after 30 years. The patient was started on Fludrocortisone 0.1 mg daily and a low potassium diet. She has remained off any blood pressure medications since her right adrenalectomy. She has continued to require the mineralocorticoid replacement to date. The diagnostic work-up for primary aldosteronism involves screening, confirmatory testing, and localization studies to distinguish unilateral pathology which may be amenable to adrenalectomy from bilateral adrenal hyperplasia. Through literature review, one theory is that chronic suppression of renin may cause atrophy of the zona glomerulosa cells and hypoaldosteronism. Throughout the case report we emphasize on the importance of early diagnostic screening of secondary hypertension as well as the complications from adrenalectomy. Presentation: 6/2/2024

7025 Acute Psychosis and the Diagnosis of Cushing’s Syndrome: Lessons Learned from a Patient with a Long History of Obesity

Abstract Disclosure: S. Modi: None. L. Belalcazar: None. Background: Although the association of hypercortisolism and psychosis is well established, acute psychosis remains a very rare manifestation of Cushing’s syndrome, especially in the absence of previous psychiatric history. We present lessons learned from a patient in whom the diagnosis of Cushing’s syndrome was missed until the onset of acute psychosis helped identify his underlying endocrine disorder. Clinical Case: A 31-year-old male presented to the Emergency Department after being found down on the street. The patient had superficial lacerations that were suspected to be self-inflicted due to a suicide attempt, but later found to be the result of auditory hallucinations. He had no previous psychiatric history and no history of suicidal ideation. His medical history was positive for obesity since adolescence and a recent diagnosis of hypertension. His family noted that for the past several months he had been experiencing headache, fatigue, muscle weakness and, more recently, insomnia, restlessness, and confusion. Weight gain was noted, but of unknown magnitude. On admission, he was agitated and hallucinating. He was initially sedated with dexmedetomidine and started on quetiapine. Physical examination revealed Cushingoid features with truncal obesity (body mass index of 35 kg/m2), facial plethora, and dorsocervical fat pad; no abdominal striae were present. Labs showed mild hypokalemia. His AM cortisol was markedly elevated at &amp;gt; 123 ug/dL (normal 4.5-23.0 ug/dL) with an ACTH level at 144 pg/mL (normal 7.2-63.3 pg/mL). MRI Brain showed a 1.9 cm pituitary macroadenoma with small suprasellar extension. With a diagnosis of Cushing’s disease, later confirmed by pathology, he underwent transsphenoidal resection. AM cortisol on post-operative day 3 was 3.2 ug/dL (normal 4.5-23.0 ug/dL). Maintenance-dose steroids were started due to evidence of post-surgical corticotroph suppression. Notably, there was marked improvement in his anxiety, paranoia, and confusion post-operatively. Quetiapine and blood pressure medications were discontinued after discharge. Conclusion: In this patient, the diagnosis of Cushing’s syndrome was missed when initially presenting with new onset hypertension in the setting of long-standing obesity. Despite months of symptoms compatible with the diagnosis, it was not until he developed acute psychosis and a careful history was obtained, that the diagnosis of Cushing’s syndrome was entertained. Psychosis is present in only 3-8% of reported cases of Cushing’s syndrome. This case illustrates the importance of including Cushing’s syndrome in the differential diagnosis of acute psychosis, especially in patients without previous psychiatric history. It also highlights the need of excluding secondary causes of hypertension in young adults, with particular attention to Cushing’s syndrome in those who present with obesity, even if long-standing. Presentation: 6/1/2024

12459 Exceptional Response To A Single Dose Of Pembrolizumab As Salvage Therapy In A Patient With Metastatic Adrenocortical Carcinoma (ACC)

Abstract Disclosure: L. Branchaud-Croisetière: None. J. Castilloux: None. E. Turcotte: None. A. Bégin: None. M. St-Jean: Advisory Board Member; Self; GlaxoSmithKline, HRA Pharmaceuticals. Research Investigator; Self; AstraZeneca, Novo Nordisk, Spruce Biosciences. Speaker; Self; GlaxoSmithKline, Recordati Rare Diseases. In advanced ACC, limited effective treatment options are available beyond mitotane and cytotoxic chemotherapy. PD-L1 blockade has shown promising results in small numbers of advanced ACC. In ACC, the reported partial response rate to pembrolizumab is around 25%.[1] Only one case of a significant partial response to a single dose of Pembrolizumab as salvage therapy for metastatic ACC was previously published.[1] In April 2023, a 19-year-old woman presented with severe hypertension, hypokalemia and clinical signs of Cushing syndrome (CS). Thoraco-abdominal scan revealed a left-sided cluster of confluent adrenal masses (7.3 x 14.4 x 11.4 cm), a left cortical renal lesion (2.8x2x2.1cm), a right ovarian teratoma (7.9 x 7.8x7.9 cm) and at least 25 pulmonary micronodules. FDG-PET SCAN revealed a significant hypermetabolism of the left adrenal lesions (SUV 18.6), ovarian teratoma (SUV 5.5) and pulmonary micronodules (SUV 1.1-2). Cortisol and androgens secretion was confirmed biochemically. Initially, she was not candidate for a debulking surgery because the tumor was surrounding the aorta, and mesenteric arteries. Hypertension and hypokalemia were treated with spironolactone, amlodipine, amiloride and irbesartan. Cushing syndrome was treated with metyrapone. In April 2023, Etoposide-Doxorubicine-Cisplatin (EDP) was administered in combination with Mitotane (max: 8g/day). After 6 cycles of EDP-M the disease regressed slightly but was considered stable based on RECIST criteria. After 8 cycles, the follow-up imaging showed a progression of the adrenal lesion (9.2x18.2cm) but stable pulmonary micronodules. A biopsy of the adrenal lesion, for therapeutic purpose, revealed microsatellite stability (MSS). The patient refused germinal genetic testing. It was decided in multidisciplinary tumor board to try Pembrolizumab. In December 2023, she received one cycle of Pembrolizumab (140mg), but the treatment was complicated by grade 4 immune-mediated hepatitis. A few weeks following Pembrolizumab she completely normalized her blood pressure and hypokalemia despite cessation of all her anti-hypertensive drugs. Pembrolizumab and Mitotane were stopped and hepatitis completely resolved after two months of Mycophenolate Mofetil and ongoing decreasing dose of prednisone. In March 2024, CT scan showed a 60% regression of the adrenal mass (4.1 x 7.2 cm), stability of the renal lesion and ovarian teratoma and complete resolution of the pulmonary micronodules. We suspect an ongoing effect of immunotherapy and Mitotane, since Mitotane levels were still in the therapeutic range (15.1 mg/L) six weeks following cessation. Mitotane was resumed in March 2024. The patient will potentially have a resection of the left adrenal lesion in the next month. This is second published case of a significant response to Pembrolizumab as second-line therapy for advanced ACC. [1] Raj Net al. J Clin Oncol. 2020 Presentation: 6/1/2024

Prolonged Time-to-antihypertensive Therapy Worsens Organ Damage and Blood Pressure Control in Arterial Hypertension.

Delay in arterial hypertension (AH) diagnosis and late therapy initiation may affect progression towards hypertensive-mediated organ damage (HMOD) and blood pressure (BP) control. We aimed to assess the impact of time-to-therapy on BP control and HMOD in patients receiving AH diagnosis. We analysed data from the Campania Salute Network, a prospective registry of hypertensive patients (NCT02211365). At baseline visit, time-to-therapy was defined as the interval between the first occurrence of BP values exceeding guidelines-directed thresholds and therapy initiation; HMOD included left ventricular hypertrophy (LVH), carotid plaque, or chronic kidney disease. Optimal BP control was considered for average values < 140/90 mmHg. Low-risk profile was defined as grade I AH without additional cardiovascular risk factors. From 14,161 hypertensive patients, we selected 1,627 participants who were not on antihypertensive therapy. This population was divided into two groups based on the median time-to-therapy (≤ 2 years n = 1,009, > 2 years n = 618). Patients with a time-to-therapy > 2 years had higher risk of HMOD (adjusted odds ratio, aOR:1.51, 95%, CI:1.19-1.93, p < 0.001) due to increased risks of LVH (aOR:1.43, CI:1.12-1.82, p = 0.004), carotid plaques (aOR:1.29, CI:1.00-1.65, p = 0.047), and chronic kidney disease (aOR:1.68, CI:1.08-2.62, p = 0.022). Time-to-therapy > 2 years was significantly associated with uncontrolled BP values (aOR:1.49, CI:1.18-1.88, p < 0.001) and higher number of antihypertensive drugs (aOR:1.68, CI:1.36-2.08, p < 0.001) during follow-up. In low-risk subgroup, time-to-therapy > 2 years did not impact on BP control and number of drugs. In hypertensive patients, a time-to-therapy > 2 years is associated with HMOD and uncontrolled BP.

9330 Atumelnant (crn04894) Induces Rapid And Sustained Reductions In Serum And Urine Cortisol In Patients With Acth-Dependent Cushing Syndrome During A Phase 1b/2a, Single Center, 10-day, Inpatient, Open-Label Study

Abstract Disclosure: H. Elenius: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. R. McGlotten: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. C. Moore: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. Y.B. Omotosho: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. L.K. Nieman: Grant Recipient; Self; Crinetics Pharmaceuticals, Inc.. Atumelnant is a potent, once-daily oral, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R) antagonist that blocks ACTH-mediated G-protein activation and subsequent signaling. It is being developed for the treatment of ACTH-dependent Cushing Syndrome (ADCS) and classic congenital adrenal hyperplasia. We report preliminary data from the first-in-disease, dose-finding study of atumelnant in patients with ADCS (NCT05804669). Inpatient participants with active ADCS (24h urine free cortisol (UFC) &amp;gt;1.3xULN, ACTH &amp;gt;10 pg/mL) received atumelnant 80 mg once daily at 08.00 for 10 days (D1-10) followed by a 4-day washout. Endpoints included changes in UFC (upper limit of normal (ULN) 45 ug/d), early morning cortisol (EMC), and early morning ACTH (EMA, ULN 46 pg/mL). Daily questionnaires assessed adverse events (AEs) and signs and symptoms of adrenal insufficiency (AI) and ADCS. Data are shown as median (range). We report 5 participants (4 men; 4 Cushing disease, 1 ectopic ACTH; age 47 years (34-55)); each completed the study. All participants developed biochemical evidence of AI (EMC &amp;lt;5 mcg/dL) after 2 days (1-10) of atumelnant administration and then commenced physiologic hydrocortisone (HC) add-back. Compared to D1, biochemical disease control (normal UFC plus EMC &amp;lt;5 mcg/dL) was shown on D11 in all participants, while receiving HC replacement: UFC 252 mcg (99-293) vs 24 mcg (3.9-51); EMC 14 mcg/dL (10.7-18.1) vs 1.4 (1.0-4.7). This was associated with an increase in EMA: 52.1 pg/mL (33-1088) vs 78 pg/mL (48.8-4045). HC was discontinued when EMC was ≥7 mcg/dL, on D13 (D12-18). Many pre-existing features of ADCS improved during atumelnant administration, including poor concentration, insomnia (n=3 each); brain fog, anxiety, irritability (n=2 each); fatigue, poor memory, low libido, depression, edema and bloating (n=1 each). Low testosterone, neutrophilia (n=3 each) and leukocytosis (n=2) observed at baseline resolved during atumelnant administration. Anti-hypertensive therapy was paused or reduced in 3 subjects. New fatigue, headache, nausea, anorexia, edema (n=2 for each) all coincided with development of biochemical AI; most symptoms improved with HC add-back. Serious adverse events included AI and one non-treatment related transient GI bleed 19 days after the last dose. All other AEs were mild or moderate: transient increases of creatinine (n=2), and ALT (&amp;lt;3xULN, n=2). In conclusion, the first 5 patients with ADCS to receive once daily, oral atumelnant experienced rapid lowering of serum and urine cortisol and improvement or resolution of some signs and symptoms of ADCS. Atumelnant was generally well-tolerated. The observed compensatory increase in ACTH was not associated with loss of efficacy or clinical sequelae. This ongoing study will further explore the relationship between atumelnant dose, including lower doses, and therapeutic response. Presentation: 6/3/2024

6602 Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort

Abstract Disclosure: M.D. Ettleson: None. G.C. Penna: Consulting Fee; Self; Ipsen, Bayer, Inc.. W. Wan: None. I.M. Bensenor: None. N. Laiteerapong: None. A.C. Bianco: Consulting Fee; Self; Abbvie. Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort Introduction: Hypothyroidism is a common endocrine disorder for which levothyroxine (LT4) serves as the primary treatment. Periods during which thyroid stimulating hormone (TSH) levels are outside the normal range have been associated with adverse cardiovascular outcomes, including mortality. In practice, serial TSH levels are measured over time to ensure therapeutic LT4 treatment is maintained. However, there is no measure of the quality of treatment maintenance over time. TSH trajectory classification represents a novel approach to define the adequacy of LT4 treatment for hypothyroidism over time utilizing multiple observation points. Methods: With longitudinal clinical data, including thyroid function from a large prospective study, we aimed to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over a 9 year study period with three observation points. Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to measure within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. Results: From the 621 LT4-treated study participants, the best-fit GMM approach identified four TSH trajectory classes, as defined by their relationship to the normal TSH range: 1) High-high normal TSH, 2) Normal TSH, 3) Normal-to-low TSH, and 4) Low-to-normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 mcg, p &amp;lt;0.001). There were no significant differences in CV health markers between the classes at baseline. At least one significant difference in CV markers occurred in all classes, highlighted by the low-to-normal class, in which total and HDL cholesterol, triglycerides, and A1c all increased significantly (p = 0.049, p &amp;lt;0.001, p &amp;lt;0.001, and p = 0.001, respectively). Medication utilization increased in all classes over the study period. Conclusion: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. In the future, more comprehensive datasets will allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes. Defining the adequacy of LT4 treatment using a longitudinal scope could allow clinicians to more accurately communicate treatment progress and identify patients at risk for adverse CV outcomes. Presentation: 6/3/2024

6457 You Are Never Too Old For Pheo

Abstract Disclosure: M. Masumy: None. B. McAdams: None. P. Mikkilineni: None. Introduction: Pheochromocytomas (PCC) are a rare neuroendocrine tumor derived from chromaffin cells. The incidence is estimated at 8 in 1 million individuals with no sex or ethnic predilection. It is estimated that 0.05-0.2% of hypertensives may have PCC. Its incidence generally peaks between the third and fifth decades of life. The classic PCC symptoms are headaches, hypertension, palpitations, pallor and tachycardia. However, most patients may not present with these symptoms, and may go undiagnosed. Untreated PCC can have significant morbidity and mortality such as MI, CVA, and hypertensive crises. The current standard of evaluation for PCC includes obtaining serum metanephrines, then if significantly elevated, obtaining CT imaging. Oftentimes, surgical resection is the treatment of choice, but PCC may recur, thus regular follow up is needed. We present a case of PCC in an elderly patient who developed symptoms over a year. Case presentation: A 72-year-old Caucasian female with diabetes presented to the emergency department with palpitations, severe headache, flushing and hypertension. She began experiencing these spells several months earlier with increasingly difficult to manage hypertension. She also had a CVA and NSTEMI earlier in the year. Her blood pressure regimen included amlodipine 20 mg, valsartan 160 mg, and carvedilol 12.5 mg bid. Despite this her blood pressure was uncontrolled. She also had palpitations and unease up to an hour after taking valsartan. Due to her symptoms; PCC was suspected. Serum metanephrines were obtained with her normetanephrines measured at 3334.7 pg/ml and metanephrines were 475.6 pg/ml, these were significantly elevated and thus an abdominal CT scan was done. On CT, she was found to have a 4.9 cm x 4.4 cm left adrenal mass with a density of 31 Hounsfield units. Her symptoms, labs and imaging were strongly indicative of PCC and she was referred to surgery. Her previous blood pressure medications were discontinued, and doxazosin was titrated to a goal SBP of 120 mmHg. Then metoprolol was added to attain a goal heart rate below 70 bpm. She then underwent a successful laparoscopic left adrenalectomy. She is now on 5mg of amlodipine for her blood pressure and metformin for her diabetes. She will be having regular follow ups to monitor for pheochromocytoma recurrence. Conclusion: Though pheochromocytoma is a rare entity that affects individuals primarily in the third and fourth decade of life, it may also occur in elderly patients. In patients with difficult hypertension, screening with metanephrines may be indicated if these are significantly elevated CT imaging should be obtained. When obtaining CT imaging, Hounsfield units are important in characterizing PCC. Achieving adequate alpha blockade before beta blockade is also essential pre-surgery for the best outcome. Even after surgery, patients will require lifelong follow up to monitor for recurrence. Presentation: 6/1/2024