Fibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system.

Fibrocytes are bone marrow-derived monocytic cells implicated in wound healing. Here, we identify their role in lung cancer progression/ metastasis. Selective manipulation of fibrocytes in mouse lung tumor models documents the central role of fibrocytes in boosting niche features and enhancing metastasis. Importantly, lung cancer patients show increased number of circulating fibrocytes and marked fibrocyte accumulation in the cancer niche. Using double and triple co-culture systems with human lung cancer cells, fibrocytes, macrophages and endothelial cells, we substantiate the central features of cancer-supporting niche: enhanced cancer cell proliferation and migration, macrophage activation, augmented endothelial cell sprouting and fibrocyte maturation. Upregulation of endothelin and its receptors are noted, and dual endothelin receptor blockade suppresses all cancer-supportive phenotypic alterations via acting on fibrocyte interaction with the cancer niche. We thus provide evidence for a crucial role of fibrocytes in lung cancer progression and metastasis, suggesting targets for treatment strategies.

Phosphatidylserine Synthase PTDSS1 Shapes the Tumor Lipidome to Maintain Tumor-Promoting Inflammation.

An altered lipidome in tumors may affect not only tumor cells themselves but also their microenvironment. In this study, a lipidomics screen reveals increased amounts of phosphatidylserine (PS), particularly ether-PS (ePS), in murine mammary tumors compared with normal tissue. PS was produced by phosphatidylserine synthase 1 (PTDSS1), and depletion of Ptdss1 from tumor cells in mice reduced ePS levels accompanied by stunted tumor growth and decreased tumor-associated macrophage (TAM) abundance. Ptdss1-deficient tumor cells exposed less PS during apoptosis, which was recognized by the PS receptor MERTK. Mammary tumors in macrophage-specific Mertk-/- mice showed similarly suppressed growth and reduced TAM infiltration. Transcriptomic profiles of TAMs from Ptdss1-knockdown tumors and Mertk-/- TAMs revealed that macrophage proliferation was reduced when the Ptdss1/Mertk pathway was targeted. Moreover, PTDSS1 expression correlated positively with TAM abundance but negatively with breast carcinoma patient survival. PTDSS1 thus may be a target to modify tumor-promoting inflammation. SIGNIFICANCE: This study shows that inhibiting the production of ether-phosphatidylserine by targeting phosphatidylserine synthase PTDSS1 limits tumor-associated macrophage expansion and breast tumor growth.

Picturing of the Lung Tumor Cellular Composition by Multispectral Flow Cytometry.

The lung tumor microenvironment plays a critical role in the tumorigenesis and metastasis of lung cancer, resulting from the crosstalk between cancer cells and microenvironmental cells. Therefore, comprehensive identification and characterization of cell populations in the complex lung structure is crucial for development of novel targeted anti-cancer therapies. Here, a hierarchical clustering approach with multispectral flow cytometry was established to delineate the cellular landscape of murine lungs under steady-state and cancer conditions. Fluorochromes were used multiple times to be able to measure 24 cell surface markers with only 13 detectors, yielding a broad picture for whole-lung phenotyping. Primary and metastatic murine lung tumor models were included to detect major cell populations in the lung, and to identify alterations to the distribution patterns in these models. In the primary tumor models, major altered populations included CD324+ epithelial cells, alveolar macrophages, dendritic cells, and blood and lymph endothelial cells. The number of fibroblasts, vascular smooth muscle cells, monocytes (Ly6C+ and Ly6C-) and neutrophils were elevated in metastatic models of lung cancer. Thus, the proposed clustering approach is a promising method to resolve cell populations from complex organs in detail even with basic flow cytometers.

Lactate dehydrogenase B regulates macrophage metabolism in the tumor microenvironment.

Background: Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive. Methods: Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging. Results: Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation. Conclusion: Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions.

IL-38 Ablation Reduces Local Inflammation and Disease Severity in Experimental Autoimmune Encephalomyelitis.

IL-38 is an IL-1 family receptor antagonist that restricts IL-17-driven inflammation by limiting cytokine production from macrophages and T cells. In the current study, we aimed to explore its role in experimental autoimmune encephalomyelitis in mice, which is, among others, driven by IL-17. Unexpectedly, IL-38-deficient mice showed strongly reduced clinical scores and histological markers of experimental autoimmune encephalomyelitis. This was accompanied by reduced inflammatory cell infiltrates, including macrophages and T cells, as well as reduced expression of inflammatory markers in the spinal cord. IL-38 was highly expressed by infiltrating macrophages in the spinal cord, and in vitro activated IL-38-deficient bone marrow-derived macrophages showed reduced expression of inflammatory markers, accompanied by altered cellular metabolism. These data suggest an alternative cell-intrinsic role of IL-38 to promote inflammation in the CNS.

Immune Checkpoint Blockade Improves Chemotherapy in the PyMT Mammary Carcinoma Mouse Model.

Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.

Alox12/15 Deficiency Exacerbates, While Lipoxin A4 Ameliorates Hepatic Inflammation in Murine Alcoholic Hepatitis.

Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15-/- mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15-/- mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15-/- mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.

S1PR4 ablation reduces tumor growth and improves chemotherapy via CD8+ T cell expansion.

Tumor immunosuppression is a limiting factor for successful cancer therapy. The lipid sphingosine-1-phosphate (S1P), which signals through 5 distinct G protein-coupled receptors (S1PR1-5), has emerged as an important regulator of carcinogenesis. However, the utility of targeting S1P in tumors is hindered by S1P's impact on immune cell trafficking. Here, we report that ablation of the immune cell-specific receptor S1PR4, which plays a minor role in immune cell trafficking, delayed tumor development and improved therapy success in murine models of mammary and colitis-associated colorectal cancer through increased CD8+ T cell abundance. Transcriptome analysis revealed that S1PR4 affected proliferation and survival of CD8+ T cells in a cell-intrinsic manner via the expression of Pik3ap1 and Lta4h. Accordingly, PIK3AP1 expression was connected to increased CD8+ T cell proliferation and clinical parameters in human breast and colon cancer. Our data indicate a so-far-unappreciated tumor-promoting role of S1P by restricting CD8+ T cell expansion via S1PR4.

S1PR4-dependent CCL2 production promotes macrophage recruitment in a murine psoriasis model.

The sphingolipid sphingosine-1-phosphate (S1P) fulfills distinct functions in immune cell biology via binding to five G protein-coupled receptors. The immune cell-specific sphingosine-1-phosphate receptor 4 (S1pr4) was connected to the generation of IL-17-producing T cells through regulation of cytokine production in innate immune cells. Therefore, we explored whether S1pr4 affected imiquimod-induced murine psoriasis via regulation of IL-17 production. We did not observe altered IL-17 production, although psoriasis severity was reduced in S1pr4-deficient mice. Instead, ablation of S1pr4 attenuated the production of CCL2, IL-6, and CXCL1 and subsequently reduced the number of infiltrating monocytes and granulocytes. A connection between S1pr4, CCL2, and Mϕ infiltration was also observed in Zymosan-A induced peritonitis. Boyden chamber migration assays functionally linked reduced CCL2 production in murine skin and attenuated monocyte migration when S1pr4 was lacking. Mechanistically, S1pr4 signaling synergized with TLR signaling in resident Mϕs to produce CCL2, likely via the NF-κB pathway. We propose that S1pr4 activation enhances TLR response of resident Mϕs to increase CCL2 production, which attracts further Mϕs. Thus, S1pr4 may be a target to reduce perpetuating inflammatory responses.

IL27Rα Deficiency Alters Endothelial Cell Function and Subverts Tumor Angiogenesis in Mammary Carcinoma.

IL-27 regulates inflammatory diseases by exerting a pleiotropic impact on immune cells. In cancer, IL-27 restricts tumor growth by acting on tumor cells directly, while its role in the tumor microenvironment is still controversially discussed. To explore IL-27 signaling in the tumor stroma, we used a mammary carcinoma syngraft approach in IL27Rα-deficient mice. Tumor growth in animals lacking IL27Rα was markedly reduced. We noticed a decrease in immune cell infiltrates, enhanced tumor cell death, and fibroblast accumulation. However, most striking changes pertain the tumor vasculature. Tumors in IL27Rα-deficient mice were unable to form functional vessels. Blocking IL-27-STAT1 signaling in endothelial cells in vitro provoked an overshooting migration/sprouting of endothelial cells. Apparently, the lack of the IL-27 receptor caused endothelial cell hyper-activation via STAT1 that limited vessel maturation. Our data reveal a so far unappreciated role of IL-27 in endothelial cells with importance in pathological vessel formation.

Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma.

Natural Killer T cells (NKT cells) are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative regulators such as inhibitory immune checkpoints. We observed dominant expression of B- and T-lymphocyte attenuator (BTLA) on type I NKT cells in polyoma middle T oncogene-driven (PyMT) murine autochthonous mammary tumors. Other immune checkpoint receptors, such as programmed cell death 1 (PD-1) were equally distributed among T cell populations. Interference with BTLA using neutralizing antibodies limited tumor growth and pulmonary metastasis in the PyMT model in a therapeutic setting, correlating with an increase in type I NKT cells and expression of cytotoxic marker genes. While therapeutic application of an anti-PD-1 antibody increased the number of CD8+ cytotoxic T cells and elevated IL-12 expression, tumor control was not established. Expression of ZBTB16, the lineage-determining transcription factor of type I NKT cells, was correlated with a favorable patient prognosis in the METABRIC dataset, and BTLA levels were instrumental to further distinguish prognosis in patents with high ZBTB16 expression. Taken together, these data support a role of BTLA on type I NKT cells in limiting anti-tumor immunity.

Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays.

BACKGROUND: As larger numbers of hypertensive patients are screened for primary aldosteronism with the aldosterone-to-renin ratio (ARR), automated analyzers present a practical solution for many laboratories. We report the method-specific ARR cutoff determined with direct, automated chemiluminescence immunoassays allowing the simultaneous measurement of plasma aldosterone concentrations (PACs) and plasma renin concentrations (PRCs). METHODS: Method comparisons to commonly employed assays and tandem mass spectrometry were undertaken. Patients were previously diagnosed based on the local ARR cutoff of 1.2 (ng/dl)/(µIU/ml) in samples collected in upright seated position. Lack of aldosterone suppression in response to salt load to less than 5 ng/dl confirmed primary aldosteronism. For the new assays, the optimal ARR cutoff was established in 152 patients with essential hypertension, 93 with primary aldosteronism and 147 normotensive patients. Aldosterone suppression was assessed in 73 essential hypertensive and 46 primary aldosteronism patients. RESULTS: PAC and PRC were significantly correlated to values determined with currently available methods (P < 0.001). In patients with primary aldosteronism, patients with essential hypertension and controls, mean (95% confidence interval) PAC was 28.4 (25.4-31.8), 6.4 (5.9-6.9) and 6.2 (5.6-6.9) ng/dl, respectively. In the same groups, PRC was 6.6 (5.6-7.7), 12.9 (11.2-14.8) and 26.5 (22.2-31.5) µIU/ml. An ARR cutoff of 1.12 provided 98.9% sensitivity and 78.9% specificity. Employing the new assay aldosterone suppression confirmed the diagnosis of primary aldosteronism and essential hypertension using the cutoff of 5 ng/dl. CONCLUSION: Our data demonstrate that the new assays present a convenient alternative for the measurement of PAC and PRC on a single automated analyzer. Availability of these simultaneous assays should facilitate screening and diagnosis of primary aldosteronism.

Coexisting Prolactinoma and Primary Aldosteronism: Is There a Pathophysiological Link?

CONTEXT: Coexisting prolactinoma-primary aldosteronism (PA) is infrequently reported. OBJECTIVE: The objective of the study was to identify patients with prolactinoma-PA and test the hypothesis that elevated prolactin (PRL) concentrations play a role in PA pathogenesis. SETTING AND DESIGN: Hyperprolactinemia/prolactinoma was diagnosed in PA patients from two referral centers (Munich, Germany, and Turin, Italy) and in essential hypertensive (EH) patients from one center (Turin). PRL receptor (PRLR) gene expression was determined by microarrays on aldosterone-producing adenomas and normal adrenals and validated by real-time PCR. H295R adrenal cells were incubated with 100 nM PRL, and gene expression levels were determined by real-time PCR and aldosterone production was quantified. RESULTS: Seven patients with prolactinoma-PA were identified: four of 584 and three of 442 patients from the Munich and Turin PA cohorts, respectively. A disproportionate number presented with macroprolactinomas (five of seven). There were five cases of hyperprolactinemia with no cases of macroprolactinoma of 14 790 patients in a general EH cohort. In a population of PA patients case-control matched 1:3 with EH patients there were two cases of hyperprolactinemia of 270 PA patients and no cases in the EH cohort (n = 810). PRLR gene expression was significantly up-regulated in the aldosterone-producing adenomas compared with normal adrenals (1.7-fold and 1.5-fold by microarray and real-time PCR, respectively). In H295R cells, PRL treatment resulted in 1.3-fold increases in CYP11B2 expression and aldosterone production. CONCLUSION: Elevated PRL caused by systemic hyperprolactinemia may contribute to the development of PA in those cases in which the two entities coexist.

CT mapping of the vertebral level of right adrenal vein.

PURPOSE: We aimed to evaluate the accuracy of multidetector computed tomography (MDCT) venous mapping for the localization of the right adrenal veins (RAV) in patients suffering from primary aldosteronism. METHODS: MDCT scans of 75 patients with primary aldosteronism between March 2008 and November 2011 were evaluated by two readers (a junior [R1] and a senior [R2] radiologist) according to the following criteria: quality of RAV depiction (scale, 1-5), localization of the RAV confluence with regard to the inferior vena cava, and depiction of anatomical variants. Results were compared with RAV venograms obtained during adrenal vein sampling and corroborated by laboratory testing of cortisol in selective RAV blood samples. Kappa statistics were calculated for interobserver agreement and for concordance of MDCT mapping with the gold standard. RESULTS: Successful RAV sampling was achieved in 69 of 75 patients (92%). Using MDCT mapping, adrenal veins could be visualized in 78% (R1, 54/69) and 77% (R2, 53/69) of patients. MDCT mapping led to correct identification of RAV in 70% (R1, 48/69) and 88% (R2, 61/69) of patients. Venograms revealed five cases of anatomical variants, which were correctly identified in 60% (R1, R2). MDCT-based localizations were false or misleading in 16% (R1, 11/69) and 7% (R2, 5/69) of cases. CONCLUSION: Preinterventional MDCT mapping may facilitate successful catheterization in adrenal vein sampling.

Aldosterone suppression on contralateral adrenal during adrenal vein sampling does not predict blood pressure response after adrenalectomy.

CONTEXT: Adrenal vein sampling (AVS) is the only reliable means to distinguish between aldosterone-producing adenoma and bilateral adrenal hyperplasia, the two most common subtypes of primary aldosteronism (PA). AVS protocols are not standardized and vary widely between centers. OBJECTIVE: The objective of the study was to retrospectively investigate whether the presence of contralateral adrenal (CL) suppression of aldosterone secretion was associated with improved postoperative outcomes in patients who underwent unilateral adrenalectomy for PA. SETTING: The study was carried out in eight different referral centers in Italy, Germany, and Japan. PATIENTS: From 585 consecutive AVS in patients with confirmed PA, 234 procedures met the inclusion criteria and were used for the subsequent analyses. RESULTS: Overall, 82% of patients displayed contralateral suppression. This percentage was significantly higher in ACTH stimulated compared with basal procedures (90% vs 77%). The CL ratio was inversely correlated with the aldosterone level at diagnosis and, among AVS parameters, with the lateralization index (P = .02 and P = .01, respectively). The absence of contralateral suppression was not associated with a lower rate of response to adrenalectomy in terms of both clinical and biochemical parameters, and patients with CL suppression underwent a significantly larger reduction in the aldosterone levels after adrenalectomy. CONCLUSIONS: For patients with lateralizing indices of greater than 4 (which comprised the great majority of subjects in this study), CL suppression should not be required to refer patients to adrenalectomy because it is not associated with a larger blood pressure reduction after surgery and might exclude patients from curative surgery.

Long-term air pollution exposure and diabetes in a population-based Swiss cohort.

Air pollution is an important risk factor for global burden of disease. There has been recent interest in its possible role in the etiology of diabetes mellitus. Experimental evidence is suggestive, but epidemiological evidence is limited and mixed. We therefore explored the association between air pollution and prevalent diabetes, in a population-based Swiss cohort. We did cross-sectional analyses of 6392 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults [SAPALDIA], aged between 29 and 73 years. We used estimates of average individual home outdoor PM10 [particulate matter <10µm in diameter] and NO2 [nitrogen dioxide] exposure over the 10 years preceding the survey. Their association with diabetes was modeled using mixed logistic regression models, including participants' study area as random effect, with incremental adjustment for confounders. There were 315 cases of diabetes (prevalence: 5.5% [95% confidence interval (CI): 2.8, 7.2%]). Both PM10 and NO2 were associated with prevalent diabetes with respective odds ratios of 1.40 [95% CI: 1.17, 1.67] and 1.19 [95% CI: 1.03, 1.38] per 10µg/m(3) increase in the average home outdoor level. Associations with PM10 were generally stronger than with NO2, even in the two-pollutant model. There was some indication that beta blockers mitigated the effect of PM10. The associations remained stable across different sensitivity analyses. Our study adds to the evidence that long term air pollution exposure is associated with diabetes mellitus. PM10 appears to be a useful marker of aspects of air pollution relevant for diabetes. This association can be observed at concentrations below air quality guidelines.

Novel genes in primary aldosteronism.

PURPOSE OF REVIEW: Novel high-throughput genetic techniques have increased the pace of discoveries in the field of primary aldosteronism. Mutations in the potassium channel gene KCNJ5 are a cause of familial and sporadic forms of primary aldosteronism with around 30-40% of aldosterone-producing adenomas being affected by somatic mutations. RECENT FINDINGS: Exome sequencing of tumors without KCNJ5 mutations revealed genetic alterations in the ATPases ATP1A1 and ATP2B3, with a combined prevalence of 5-7%. Mutations in the gene encoding a subunit of the Ca channel Cav1.3 (CACNA1D) were described with a prevalence of 5-8%. In addition, a new syndrome consisting of primary aldosteronism, seizures, and neuromuscular disease with germline CACNA1D mutations could be identified. All these genetic variants enhance Ca-mediated signalling and steroidogenesis in affected glomerulosa cells and provide the molecular basis for autonomous aldosterone secretion. Furthermore, the pattern of genetic alterations allows for subgrouping of patient cohorts with potentially distinct clinical features including sex and age distribution as well as endocrine and cardiovascular endpoints. SUMMARY: Altogether in around 50% of aldosterone-producing adenomas, a somatic point mutation can be identified as the underlying genetic cause. These findings will provide the framework for potential identification of new biomarkers and therapeutic targets of this most common form of secondary hypertension.

Sleep quality in patients with primary aldosteronism.

OBJECTIVE: In subjects at high risk for sleep apnea (SA), aldosterone concentrations correlate with severity of SA and primary aldosteronism (PA) is very often diagnosed. Patients with PA show a high prevalence of SA. Treatment of PA either by adrenalectomy (ADX) or mineralocorticoid receptor (MR) blockade is thought to abolish the increased comorbidities. However, no data are available regarding effectiveness of different PA treatments on quality of sleep. DESIGN: This prospective multi-center study included 15 patients with newly diagnosed PA evaluated before and 0.7 ± 0.2 years after treatment initiation, and a second cohort including 81 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Biochemical parameters, 24h blood pressure and three validated self-assessment questionnaires (Giessen Complaint List (GBB-24), Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality-Index (PSQI)) were analyzed. RESULTS: Z-scores of exhaustion tendency of GBB significantly improved in newly diagnosed PA patients after treatment initiation (1.8 ± 1.4 vs. 1.0 ± 1.2, p=0.034). In the second cohort no differences were found in GBB-24, ESS and PSQI. No differences were found in all three questionnaires independently of type of PA therapy. However, female patients scored significantly higher than males in the PSQI (8.7 ± 3.6 vs 5.7 ± 4.2, p<0.005), indicating lower sleep quality, independently of the type of therapy. CONCLUSIONS: For the first time, we analyzed quality of sleep in patients with PA, demonstrating that therapy initiation improves exhaustion tendency. Surprisingly, female PA patients showed significantly more sleep disturbances than male PA patients several years after treatment initiation.

Age below 40 or a recently proposed clinical prediction score cannot bypass adrenal venous sampling in primary aldosteronism.

CONTEXT: Adrenal venous sampling (AVS) is used to distinguish bilateral from unilateral primary aldosteronism (PA). Due to its limited availability, clinical prediction scores have been proposed to diagnose unilateral disease without AVS. OBJECTIVE: Our goal was to test 2 recently proposed predictors of unilateral PA: 1) a clinical prediction score using imaging, serum potassium, and glomerular filtration rate and 2) the combination of visible unilateral adenoma on imaging and age <40 years. DESIGN AND SETTING: We used the data of all patients with PA of the prospective German Conn's Registry treated in Munich and Berlin since 2008. PATIENTS AND INTERVENTION: Of 205 patients with PA, 194 had a successful AVS and were included. MAIN OUTCOME MEASURES: Parameters were compared between patients with lateralized and nonlateralized AVS. Specificity and sensitivity of the proposed predictors were calculated. RESULTS: A total of 130 patients (67%) had unilateral PA according to AVS. Patients with unilateral PA showed a significantly lower estimated glomerular filtration rate compared with patients with bilateral disease (P < .05). The cohorts differed significantly in potassium supplementation, serum potassium, baseline and post-saline plasma aldosterone, baseline aldosterone to renin ratio, and adenoma in imaging. The proposed prediction score had a sensitivity of 46% (58 of 127) and a specificity of 80% (53 of 66). In patients below 40 years (n = 28), the prediction score achieved a specificity of 100%; however, relying only on imaging in this young cohort, the specificity dropped to 83%. CONCLUSIONS: The suggested prediction score has high accuracy only in young patients but cannot substitute for AVS in the elderly.

A high aldosterone to renin ratio is associated with high serum parathyroid hormone concentrations in the general population.

CONTEXT: Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with high serum PTH concentrations and vice versa. OBJECTIVE: The aim of this study was to analyze the associations of the plasma aldosterone concentration (PAC), the plasma renin concentration (PRC), or the aldosterone to renin ratio (ARR) with serum PTH concentrations in a sample from the general population of northeast Germany. DESIGN: We selected 3105 subjects (25-88 y) from the first 5-year follow-up examination of the Study of Health in Pomerania. The associations of PAC, PRC, or ARR with serum PTH concentrations were examined with multivariable linear regression analyses. We further calculated adjusted mean serum PTH concentrations according to PAC, PRC, and ARR categories (≥90th and < 90th sex specific percentiles and sex specific quartiles). The models were adjusted for age, sex, estimated glomerular filtration rate, serum 25-hydroxy vitamin D concentration, waist circumference, body mass index, hypertension, diabetes mellitus, liver disease, and intake of drugs that affect the RAAS or bone metabolism. RESULTS: We found no associations between PAC or PRC and serum PTH concentrations in fully adjusted linear regression models. However, fully adjusted linear regression and ANOVA models revealed higher serum PTH concentrations in subjects with an ARR 90th percentile or greater than in subjects with a lower ARR. CONCLUSIONS: Our data show that a high ARR is associated with high serum PTH concentrations in the general population and thus add to the increasing evidence of a relation between the RAAS and PTH.