Gender Differences in Cardiac Organ Damage in Arterial Hypertension: Assessing the Role of Drug Nonadherence.

INTRODUCTION: Cardiac organ damage like left ventricular (LV) hypertrophy and left atrial (LA) enlargement is more prevalent in women than men with hypertension, but the mechanisms underlying this gender difference remain unclear. METHODS: We tested the association of drug nonadherence with the presence of LV hypertrophy and LA enlargement by echocardiography in 186 women and 337 men with uncontrolled hypertension defined as daytime systolic blood pressure (BP) ≥ 135mmHg despite the prescription of at least two antihypertensive drugs. Drug adherence was assessed by measurements of serum drug concentrations interpreted by an experienced pharmacologist. Aldosterone-renin-ratio (ARR) was measured on actual medication. RESULTS: Women had a higher prevalence of LV hypertrophy (46% vs. 33%) and LA enlargement (79% vs 65%, both p < 0.05) than men, while drug nonadherence (8% vs. 9%, p > 0.514) did not differ. Women were older and had lower serum renin concentration and higher ARR than men, while 24-h systolic BP (141 ± 9 mmHg vs. 142 ± 9 mmHg), and the prevalences of obesity (43% vs. 50%) did not differ (all p > 0.10). In multivariable analyses, female gender was independently associated with a two-fold increased risk of LV hypertrophy (OR 2.01[95% CI 1.30-3.10], p = 0.002) and LA enlargement (OR 1.90 [95% CI 1.17-3.10], p = 0.010), while no association with drug nonadherence was found. Higher ARR was independently associated with LV hypertrophy in men only (OR 2.12 [95% CI 1.12-4.00] p = 0.02). CONCLUSIONS: Among patients with uncontrolled hypertension, the higher prevalence of LV hypertrophy and LA enlargement in women was not explained by differences in drug nonadherence. REGISTRATION: URL:  https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03209154.

The improvement of postoperative blood pressure and associated factors in patients with hormone-negative adrenal adenoma and hypertension.

OBJECTIVE: To investigate the effect of adrenal surgery on blood pressure (BP) improvements in patients with hormone-negative adrenal adenoma (HNA) concomitant with hypertension and analyze associated prognostic factors. METHODS: We retrospectively reviewed the clinical data of patients with HNA and hypertension and patients with aldosterone-producing adenoma (APA) and hypertension who underwent adrenal surgery at our center between 2019 and 2022. Hypertension outcomes were evaluated in all patients and subjects were divided into three groups according to follow-up BP and the administration of anti-hypertensive agents: a clinical curation group, an improvement group, and a no-improvement group. Logistic regression analysis was performed to predict factors associated with clinical curation in patients with HNA post-surgery. RESULTS: Of the 182 patients with HNA, clinical curation was achieved in 58 patients (31.9%), improvement in 72 (39.5%), and no improvement in 52 (28.6%). The clinical curation, improvement and no improvement rates in patients with APA were 64.8% (n = 118), 15.9% (n = 29), and 19.2% (n = 35). Multivariate logistic regression analysis indicated that a duration of hypertension ≤6 years and a plasma aldosterone level >160 pg/ml were both independent factors for the clinical curation of hypertension in patients with HNA after adrenal surgery. CONCLUSION: Adrenal surgery can cure or improve hypertension in most patients with HNA, especially in a short duration of hypertension and high plasma levels of aldosterone.

Neurohormonal Activation and Renal Chloride Avidity in Acute Heart Failure: Clinical Evidence Supporting the "Chloride Theory".

INTRODUCTION: Heart failure (HF) progression according to changes in the serum chloride concentration ([sCl-]) was recently proposed as the "chloride (Cl) theory" for HF pathophysiology. The present study examined the association of neurohormones and renal Cl avidity to determine their contribution to acute HF and their involvement to the "Cl theory." METHODS: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) were analyzed. Blood and urine samples were obtained before decongestive therapy. Clinical tests included peripheral blood, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), and plasma neurohormones. RESULTS: In the 29 patients, urinary Cl concentrations ([uCl-]) inversely correlated with log (plasma renin activity [PRA]) (r = -0.64, p = 0.0002) and log (plasma aldosterone concentration) (r = -0.50, p = 0.006). The [sCl-]‒[uCl-] difference positively correlated with log PRA (r = 0.63, p = 0.0002) and log (plasma aldosterone concentration) (r = 0.49, p = 0.008). Patients were divided into 2 groups according to the [sCl-]‒[uCl-] difference, an excretion (low renal Cl avidity) group and an absorption (high renal Cl avidity) group. Compared with the excretion group (-77 to ‒5 mEq/L; n = 14), the absorption group (1-84 mEq/L; n = 15) exhibited greater renal impairment (serum creatinine; 1.45 ± 0.63 vs. 1.00 ± 0.38 mg/d, p = 0.029) and cardiac burden (log BNP; 2.99 ± 0.3 vs. 2.66 ± 0.32 pg/mL, p = 0.008), higher log PRA (0.20 ± 0.58 vs. -0.25 ± 0.35 ng/mL/h, p = 0.018), and lower fractional urinary Cl excretion (1.34 ± 1.3 vs. 5.33 ± 4.1%, p < 0.001). CONCLUSION: Renal Cl avidity differs in acute HF, i.e., excretion (low renal Cl avidity) versus absorption (high renal Cl avidity) types, involving renin-aldosterone-angiotensin activity as the underlying mechanism, which provides the neurohormonal background for the "Cl theory." A version of this study was presented in part at the annual international scientific assembly (ACC.23) of the American College of Cardiology, March 4-6, 2023.

Adrenal gland response to adrenocorticotropic hormone is intact in patients with postural orthostatic tachycardia syndrome.

BACKGROUND: Many patients with postural orthostatic tachycardia syndrome (POTS) are hypovolemic with plasma volume deficits of 10-30 %. Some also have low levels of aldosterone and diminished aldosterone-renin ratios despite elevations in angiotensin II, pointing to potential adrenal dysfunction. To assess adrenal gland responsiveness in POTS, we measured circulating levels of aldosterone and cortisol following adrenocorticotropin hormone (ACTH) stimulation. METHODS: While on a low Na+ diet (∼10 mEq/day), 8 female patients with POTS and 5 female healthy controls (HC) received a low dose (1 µg) ACTH bolus following a baseline blood sample. After 60 min, a high dose (249 µg) infusion of ACTH was administered to ensure maximal adrenal response. Venous aldosterone and cortisol levels were sampled every 30 min for 2 h. RESULTS: Aldosterone increased in both groups in response to ACTH but was not different between POTS vs. HC at 60 min (53.5 ng/dL [37.8-61.8 ng/dL] vs. 46.1 ng/dL [36.7-84.9 ng/dL]; P = 1.000) or maximally (56.4 ng/dL [49.2-67.1 ng/dL] vs. 49.5 ng/dL [39.1-82.8 ng/dL]; P = 0.524). Cortisol increased in both groups in response to ACTH but was not different in patients with POTS vs. HC at 60 min (39.9 µg/dL [36.1-47.7 µg/dL] vs. 39.3 µg/dL [35.4-46.6 µg/dL]; P = 0.724) or maximally (39.9 µg/dL [33.9-45.4 µg/dL] vs. 42.0 µg/dL [37.6-49.7 µg/dL]; P = 0.354). CONCLUSIONS: ACTH appropriately increased the aldosterone and cortisol levels in patients with POTS. These findings suggest that the response of the adrenal cortex to hormonal stimulation is intact in patients with POTS.

An unusual cause of adrenal insufficiency with elevation of 17-hydroxyprogesterone: case report.

BACKGROUND: We present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease. CASE PRESENTATION: An 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease. CONCLUSIONS: In the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the "healthy" adrenal tissue residue than a direct secretory activity by the adrenal tumor.

Reference intervals for LC-MS /MS measurements of plasma renin activity, aldosterone, angiotensin II, and 24-hour urinary aldosterone in Northern Chinese Han population.

BACKGROUND: Examination of aldosterone to Renin Ratio (ARR) and plasma aldosterone concentration (PAC) or 24-h urinary aldosterone excretion (24-h UALD) was the necessary tests in confirmatory tests for primary aldosteronism (PA). We developed a combined liquid chromatography-tandem mass spectrometry method (LC-MS/MS) for plasma renin activity (PRA), PAC, and angiotensin II (Ang II) and investigated their reference intervals (RIs) in northern Chinese Han population. The RIs of 24-h UALD excretion were also studied using LC-MS/MS. METHODS: A total of 309 healthy volunteers were recruited in 3 cities in China. PRA, PAC, Ang II, and 24-h UALD were measured using the laboratory-developed LC-MS/MS. Multiple linear regression and the variance component model were applied to determine if the RI needed to be split. The RIs of PRA, PAC, and Ang II were determined using the nonparametric percentile method. RESULTS: The laboratory-developed LC-MS/MS method was verified and showed good performance. Standard deviation ratio (SDR) sex for PAC and SDR region for Ang II are 0.466 and 0.407, respectively, indicating that the RIs of PAC and Ang II must be divided by sex and region, respectively. In addition, the SDR 24hUK for 24-h UALD is 0.579, indicating that the RI of 24-h UALD must be partitioned by urine potassium. CONCLUSION: RIs were established for tests related to the renin-angiotensin-aldosterone system in the apparently healthy northern Chinese Han population by the LC-MS/MS method.

Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.

BACKGROUND: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group. RESULTS: A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug. CONCLUSIONS: Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).

An explorative epigenome-wide association study of plasma renin and aldosterone concentration in a Ghanaian population: the RODAM study.

BACKGROUND: The epigenetic regulation of the renin-angiotensin-aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). Here we report the first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations and the aldosterone-to-renin ratio (ARR). METHODS: Epigenome-wide DNA methylation was measured using the Illumina 450K array on whole blood samples of 68 Ghanaians. Differentially methylated positions (DMPs) were assessed for plasma renin concentration, aldosterone, and ARR using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, hypertension, and technical covariates. Additionally, we extracted methylation loci previously associated with hypertension, kidney function, or that were annotated to RAAS-related genes and associated these with renin and aldosterone concentration. RESULTS: We identified one DMP for renin, ten DMPs for aldosterone, and one DMP associated with ARR. Top DMPs were annotated to the PTPRN2, SKIL, and KCNT1 genes, which have been reported in relation to cardiometabolic risk factors, atherosclerosis, and sodium-potassium handling. Moreover, EWAS loci previously associated with hypertension, kidney function, or RAAS-related genes were also associated with renin, aldosterone, and ARR. CONCLUSION: In this first EWAS on RAAS hormones, we identified DMPs associated with renin, aldosterone, and ARR in a SSA population. These findings are a first step in understanding the role of DNA methylation in regulation of the RAAS in general and in a SSA population specifically. Replication and translational studies are needed to establish the role of these DMPs in the hypertension burden in SSA populations.

Variability of aldosterone, renin and the aldosterone-to-renin ratio in hypertensive patients without primary aldosteronism.

OBJECTIVES: The aldosterone-to-renin ratio (ARR) is commonly used in the screening of primary aldosteronism. However, limited information is available with regard to the intra-patient variability in this ratio. Our objective is to determine whether ARR measurements are reliably consistent over both the short- and long-term. METHODS: We assessed the short-term variability of the aldosterone-to-renin ratio in 116 unmedicated, essential hypertensive participants who had two blood samples taken in the morning of the same day for measurement of aldosterone and active plasma renin concentration. Long-term variability was studied in 22 unmedicated, essential hypertensive participants who had two blood samples taken approximately 1 year apart. All samples were taken under highly standardized conditions. RESULTS: Our data show that renin, aldosterone and the aldosterone-to-renin ratio show marked variations, both when measured on the same day and when assessed at a longer interval. The ARR becomes increasingly variable as its mean value increases. Its degree of variability is similar in both the short-term and the long-term. CONCLUSIONS: Based on our findings, we conclude that the aldosterone-to-renin has acceptable short-term variability in the lower ranges, but increasingly dubious reliability as aldosterone-to-renin values rise. Thus, in a clinical context, great caution should be taken in interpreting point-measurements of moderate to high aldosterone-to-renin ratio values.

Mineralocorticoid interaction with glycated albumin downregulates NRF - 2 signaling pathway in renal cells: Insights into diabetic nephropathy.

In diabetic nephropathy, hyperglycemia elevates albumin glycation and also results in increased plasma aldosterone. Both glycation and aldosterone are reported to cause oxidative stress by downregulating the NRF-2 pathway and thereby resulting in reduced levels of antioxidants and glycation detoxifying enzymes. We hypothesize that an interaction between aldosterone and glycated albumin may be responsible for amplified oxidative stress and concomitant renal cell damage. Hence, human serum albumin was glycated by methylglyoxal (MGO) in presence of aldosterone. Different structural modifications of albumin, functional modifications and aldosterone binding were analyzed. HEK-293 T cells were treated with aldosterone+glycated albumin along with inhibitors of receptors for mineralocorticoid (MR) and advanced glycation endproducts (RAGE). Cellular MGO content, antioxidant markers (nitric oxide, glutathione, catalase, superoxide dismutase, glutathione peroxidase), detoxification enzymes (aldose reductase, Glyoxalase I, II), their expression along with NRF-2 and Keap-1 were measured. Aldosterone binds to albumin with high affinity which is static and spontaneous. Cell treatment by aldosterone+glycated albumin increased intracellular MGO, MR and RAGE expression; hampered antioxidant, detoxification enzyme activities and reduced NRF-2, Keap-1 expression. Thus, the glycated albumin-aldosterone interaction and its adverse effect on renal cells were confirmed. The results will help in developing better pharmacotherapeutic strategies for diabetic nephropathy.

Alleviation of liver cirrhosis and associated portal-hypertension by Astragalus species in relation to their UPLC-MS/MS metabolic profiles: a mechanistic study.

Liver cirrhosis is a late-stage liver disease characterized by excessive fibrous deposition triggering portal-hypertension (PH); the prime restrainer for cirrhosis-related complications. Remedies that can dually oppose hepatic fibrosis and lower PH, may prevent progression into decompensated-cirrhosis. Different Astragalus-species members have shown antifibrotic and diuretic actions with possible subsequent PH reduction. However, A.spinosus and A.trigonus were poorly tested for eliciting these actions. Herein, A.spinosus and A.trigonus roots and aerial parts extracts were subjected to comprehensive metabolic-fingerprinting using UHPLC-MS/MS resulting in 56 identified phytoconstituents, followed by chemometric untargeted analysis that revealed variable metabolic profiles exemplified by different species and organ types. Consequently, tested extracts were in-vivo evaluated for potential antifibrotic/anticirrhotic activity by assessing specific markers. The mechanistic prospective to induce diuresis was investigated by analyzing plasma aldosterone and renal-transporters gene-expression. Serum apelin and dimethylarginine-dimethylaminohydrolase-1 were measured to indicate the overall effect on PH. All extracts amended cirrhosis and PH to varying extents and induced diuresis via different mechanisms. Further, An OPLS model was built to generate a comprehensive metabolic-profiling of A.spinosus and A.trigonus secondary-metabolites providing a chemical-based evidence for their efficacious consistency. In conclusion, A.spinosus and A.trigonus organs comprised myriad pharmacologically-active constituents that act synergistically to ameliorate cirrhosis and associated PH.

Association between Vitamin D Deficiency and Levels of Renin and Angiotensin in Essential Hypertension.

Objective: The present study aims to investigate the relationship between vitamin D deficiency and renin-angiotensin-aldosterone levels in patients with essential hypertension. Methods: The present study observed two groups of patients from Urumqi, Xinjiang, China, from April 2017 to March 2018. There were two subject groups: the hypertension group (80 patients with essential hypertension selected by random cluster sampling) and the control group (76 healthy adults). The 25-hydroxyvitamin D (25(OH)D or vitamin D) levels were measured through electrolytes; fasting blood glucose, blood lipids, and other biochemical indicators were detected using immune chemiluminescence; and plasma renin activity and angiotensin II concentrations were detected with radio-immunity. Results: Comparison between the hypertension group and control group showed statistically significant differences in the systolic pressure and levels of 25(OH)D, renin, and triglycerides (P < 0.05). The correlation analysis showed that 25(OH)D was negatively correlated with renin (r = -0.185; P=0.021) and positively correlated with systolic pressure (r = -0.105; P=0.035). There were no statistically significant differences in diastolic pressure, fasting blood glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides between the two groups. Conclusions: The results of the present study show that vitamin D deficiency is common in Urumqi, Xinjiang, China and vitamin D levels are negatively correlated with renin levels. Vitamin D plays an important role in regulating blood pressure by affecting renin levels through the renin-angiotensin-aldosterone system.

Aldosterone-to-Renin Ratio Is Associated with Diabetic Nephropathy in Type 2 Diabetic Patients: A Single-Center Retrospective Study.

BACKGROUND It is well established that primary aldosteronism (PA) and aldosterone-to-renin ratio (ARR) are associated with kidney disease. The aim of this study was to retrospectively investigate the relationship between ARR, urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes from a single center. MATERIAL AND METHODS We included 70 patients with type 2 diabetes, UAE ≤100 mg/day, not taking renin-aldosterone system inhibitors, did not meet the diagnostic criteria for PA, and had an ARR <20. The patients were divided into 3 groups: the normal low (NL) group (33 patients) with a UAE <10 mg/day, the normal (N) group (22 patients) with a UAE of 10-29 mg/day, and the microalbuminuria (M) group (15 patients) with a UAE of 30-100 mg/day. The ARR, plasma renin activity (PRA), and plasma aldosterone (PAC) were compared among groups. RESULTS The ARR was highest in group M (10.1±4.6), 6.5±0.3 in group NL, and 7.0±2.7 in group N. The PRA and PAC were significantly lower in group M (P<0.001). The ARR showed a significant positive correlation with log UAE (r=0.37, P<0.001) and a significant negative correlation with eGFR (r=-0.33, P<0.01). CONCLUSIONS High levels of aldosterone relative to renin, which did not fulfill confirmatory criteria for PA, may be one of the risk factors for the development of diabetic nephropathy in patients with diabetes. The present results are supported by previous research showing that an increased ARR without PA was a risk factor for kidney disease.

Kidney-specific KO of the circadian clock protein PER1 alters renal Na+ handling, aldosterone levels, and kidney/adrenal gene expression.

PERIOD 1 (PER1) is a circadian clock transcription factor that is regulated by aldosterone, a hormone that increases blood volume and Na+ retention to increase blood pressure. Male global Per1 knockout (KO) mice develop reduced night/day differences in Na+ excretion in response to a high-salt diet plus desoxycorticosterone pivalate treatment (HS + DOCP), a model of salt-sensitive hypertension. In addition, global Per1 KO mice exhibit higher aldosterone levels on a normal-salt diet. To determine the role of Per1 in the kidney, male kidney-specific Per1 KO (KS-Per1 KO) mice were generated using Ksp-cadherin Cre recombinase to remove exons 2-8 of Per1 in the distal nephron and collecting duct. Male KS-Per1 KO mice have increased Na+ retention but have normal diurnal differences in Na+ excretion in response to HS + DOCP. The increased Na+ retention is associated with altered expression of glucocorticoid and mineralocorticoid receptors, increased serum aldosterone, and increased medullary endothelin-1 compared with control mice. Adrenal gland gene expression analysis revealed that circadian clock and aldosterone synthesis genes have altered expression in KS-Per1 KO mice compared with control mice. These results emphasize the importance of the circadian clock not only in maintaining rhythms of physiological functions but also for adaptability in response to environmental cues, such as HS + DOCP, to maintain overall homeostasis. Given the prevalence of salt-sensitive hypertension in the general population, these findings have important implications for our understanding of how circadian clock proteins regulate homeostasis.NEW & NOTEWORTHY For the first time, we show that knockout of the circadian clock transcription factor PERIOD 1 using kidney-specific cadherin Cre results in increased renal Na+ reabsorption, increased aldosterone levels, and changes in gene expression in both the kidney and adrenal gland. Diurnal changes in renal Na+ excretion were not observed, demonstrating that the clock protein PER1 in the kidney is important for maintaining homeostasis and that this effect may be independent of time of day.

Chronic hypertension and superimposed preeclampsia: screening and diagnosis.

Superimposed preeclampsia complicates about 20% of pregnancies in women with chronic hypertension and is associated with increased maternal and perinatal morbidity compared with preeclampsia alone. Distinguishing superimposed preeclampsia from chronic hypertension can be challenging because, in chronic hypertension, the traditional criteria for the diagnosis of preeclampsia, hypertension, and significant proteinuria can often predate the pregnancy. Furthermore, the prevalence of superimposed preeclampsia is unlikely to be uniformly distributed across this high-risk group but is related to the severity of preexisting endothelial dysfunction. This has led to interest in identifying biomarkers that could help in screening and diagnosis of superimposed preeclampsia and in the stratification of risk in women with chronic hypertension. Elevated levels of uric acid and suppression of other renal biomarkers, such as the renin-angiotensin aldosterone system, have been demonstrated in women with superimposed preeclampsia but perform only modestly in its prediction. In addition, central to the pathogenesis of preeclampsia is a tendency toward an antiangiogenic state thought to be triggered by an impaired placenta and, ultimately, contributing to the endothelial dysfunction pathognomonic of the disease. In the general obstetrical population, angiogenic factors, such as soluble fms-like tyrosine kinase-1 and placental growth factor, have shown promise in the prediction of preeclampsia. However, soluble fms-like tyrosine kinase-1 and placental growth factor are impaired in women with chronic hypertension irrespective of whether they develop superimposed preeclampsia. Therefore, the differences in levels are less discriminatory in the prediction of superimposed preeclampsia compared with the general obstetrical population. Alternative biomarkers to the angiogenic and renal factors include those of endothelial dysfunction. A characteristic of both preeclampsia and chronic hypertension is an exaggerated systemic inflammatory response causing or augmenting endothelial dysfunction. Thus, proinflammatory mediators, such as tumor necrosis factor-α, interleukin-6, cell adhesion molecules, and endothelin, have been investigated for their role in the screening and diagnosis of superimposed preeclampsia in women with chronic hypertension. To date, the existing limited evidence suggests that the differences between those who develop superimposed preeclampsia and those who do not are, as with angiogenic factors, also modest and not clinically useful for the stratification of women with chronic hypertension. Finally, pro-B-type natriuretic peptide is regarded as a sensitive marker of early cardiac dysfunction that, in women with chronic hypertension, may predate the pregnancy. Thus, it has been proposed that pro-B-type natriuretic peptide could give insight as to the ability of women with chronic hypertension to adapt to the hemodynamic requirements of pregnancy and, subsequently, their risk of developing superimposed preeclampsia. Although higher levels of pro-B-type natriuretic peptide have been demonstrated in women with superimposed preeclampsia compared with those without, current evidence suggests that pro-B-type natriuretic peptide is not a predictor for the disease. The objectives of this review are to, first, discuss the current criteria for the diagnosis of superimposed preeclampsia and, second, to summarize the evidence for these potential biomarkers that may assist in the diagnosis of superimposed preeclampsia.

Blood and adipose tissue steroid metabolomics and mRNA expression of steroidogenic enzymes in periparturient dairy cows differing in body condition.

In high-yielding dairy cows, the rapidly increasing milk production after parturition can result in a negative nutrient balance, since feed intake is insufficient to cover the needs for lactation. Mobilizing body reserves, mainly adipose tissue (AT), might affect steroid metabolism. We hypothesized, that cows differing in the extent of periparturient lipomobilization, will have divergent steroid profiles measured in serum and subcutaneous (sc)AT by a targeted metabolomics approach and steroidogenic enzyme profiles in scAT and liver. Fifteen weeks antepartum, 38 multiparous Holstein cows were allocated to a high (HBCS) or normal body condition (NBCS) group fed differently until week 7 antepartum to either increase (HBCS BCS: 3.8 ± 0.1 and BFT: 2.0 ± 0.1 cm; mean ± SEM) or maintain BCS (NBCS BCS: 3.0 ± 0.1 and BFT: 0.9 ± 0.1 cm). Blood samples, liver, and scAT biopsies were collected at week -7, 1, 3, and 12 relative to parturition. Greater serum concentrations of progesterone, androsterone, and aldosterone in HBCS compared to NBCS cows after parturition, might be attributed to the increased mobilization of AT. Greater glucocorticoid concentrations in scAT after parturition in NBCS cows might either influence local lipogenesis by differentiation of preadipocytes into mature adipocytes and/or inflammatory response.

The circulating renin-angiotensin-aldosterone system is down-regulated in dogs with glomerular diseases compared to other chronic kidney diseases with low-grade proteinuria.

Glomerular diseases (GD) lead to a variety of disorders of the vascular and the total body water volumes. Various pathomechanisms, including vascular underfill and overfill, have been suggested to explain these disturbances. Accordingly, the circulating renin-angiotensin-aldosterone system (cRAAS) is expected to be activated as either a cause or a result of these fluid disorders. The aim of this study was to characterize the activity of the cRAAS in dogs with GD and to evaluate its relationship with the vascular volume status. In a prospective study, we evaluated the plasma renin activity and the serum aldosterone concentration in 15 dogs with GD. Their fluid volume status was estimated with clinical variables reflecting volemia and hydration, echocardiographic volume assessment, N-terminal pro B-type natriuretic peptide, blood urea nitrogen:creatinine ratio, and the urinary fractional excretion of sodium. Ten dogs with chronic kidney disease (CKD) with matching degree of azotemia were recruited as controls. The activity of the cRAAS was low in 10 dogs, normal in 3 dogs, high in 1 dog and equivocal (high renin-low aldosterone) in 1 dog with GD. These dogs had a lower cRAAS activity than dogs with CKD (p = 0.01). The clinical evaluation showed 8 hypovolemic and 7 non-hypovolemic dogs; 3 dehydrated, 9 euhydrated and 3 overhydrated dogs. The cRAAS activity was not different between hypovolemic and non-hypovolemic dogs. The down-regulated cRAAS without obvious association with the clinical volume status of these dogs with GD, suggests different mechanisms of fluid volume dysregulation in dogs with GD than previously assumed. This finding however should be confirmed in a focused larger scale study, as it may influence the use of cRAAS blockers as part of the standard therapy of GD in dogs.

Enhanced performance of a modified diagnostic test of primary aldosteronism in patients with adrenal adenomas.

OBJECTIVE: Primary aldosteronism (PA) is the commonest cause of endocrine hypertension ranging from 4.6 to 16.6% according to the diagnostic tests employed. The aim of this study was to compare the traditional saline infusion test (SIT) with the modified post-dexamethasone saline infusion test (DSIT) by applying both tests on the same subjects. METHODS: We studied 68 patients (72% hypertensives) with single adrenal adenoma and 55 normotensive controls with normal adrenal imaging. Serum cortisol, aldosterone, and plasma renin concentration (PRC) were measured and the aldosterone-to-renin ratio (ARR) was calculated. Using the mean ± 2 s.d. values from the controls, we defined the upper normal limits for cortisol, aldosterone, and PRC for both the SIT and DSIT. RESULTS: In the controls, the post-DSIT aldosterone levels and the ARR were approximately two-fold and three-fold lower, respectively, than the corresponding post-SIT values (all P = 0.001) leading to lower cut-offs of aldosterone suppression. Applying these cut-offs to patients with adrenal adenomas, the prevalence of PA was 13.2% following the SIT and 29.4% following the DSIT, respectively. In addition, 54.5% of patients with PA had concomitant autonomous cortisol secretion (ACS). Targeted treatment of PA resulted in resolution of hypertension and restoration of normal secretory aldosterone dynamics. CONCLUSIONS: The DSIT improves the diagnostic accuracy of PA, allowing for the detection of milder forms of PA in patients with adrenal adenomas. This is of particular importance as such patients may be at an increased risk of developing cardiovascular and renal morbidity that could be enhanced in the presence of concomitant ACS.