High Plasma Aldosterone Concentration Research Articles

Lack of Renal Tubular Glucocorticoid Receptor Decreases the Thiazide-Sensitive Na+/Cl- Cotransporter NCC and Transiently Affects Sodium Handling.

Chronic glucocorticoid infusion impairs NCC activity and induces a non-dipping profile in mice, suggesting that glucocorticoids are essential for daily blood pressure variations. In this paper, we studied mice lacking the renal tubular glucocorticoid receptor (GR) in adulthood (GR knockouts, Nr3c1Pax8/LC1). Upon standard salt diet, Nr3c1Pax8/LC1 mice grow normally, but show reduced NCC activity despite normal plasma aldosterone levels. Following diet switch to low sodium, Nr3c1Pax8/LC1 mice exhibit a transient but significant reduction in the activity of NCC and expression of NHE3 and NKCC2 accompanied by significant increased Spak activity. This is followed by transiently increased urinary sodium excretion and higher plasma aldosterone concentrations. Plasma corticosterone levels and 11βHSD2 mRNA expression and activity in the whole kidney remain unchanged. High salt diet does not affect whole body Na+ and/or K+ balance and NCC activity is not reduced, but leads to a significant increase in diastolic blood pressure dipping in Nr3c1Pax8/LC1 mice. When high sodium treatment is followed by 48 h of darkness, NCC abundance is reduced in knockout mice although activity is not different. Our data show that upon Na+ restriction renal tubular GR-deficiency transiently affects Na+ handling and transport pathways. Overall, upon standard, low Na+ and high Na+ diet exposure Na+ and K+ balance is maintained as evidenced by normal plasma and urinary Na+ and K+ and aldosterone concentrations.

MODIFIED SEGMENTAL ADRENAL VEIN SAMPLING SUITABLE FOR CARDIOLOGISTS

Objective: The case was a 44-year-old hypertensive male who had a right adrenal mass in the posterior adrenal gland with hypokalemia and a high plasma aldosterone concentration ratio to plasma renin activity. Captopril stress test confirmed the diagnosis of primary aldosteronism (PA). Patient desired partial adrenalectomy. Subsequently, detail localization of aldosterone-producing adenoma is evaluated with preoperative segmental adrenal vein sampling (S-AVS). Design and method: The micro-wire and the micro catheter were advanced to the segmental adrenal vein using a percutaneous coronary intervention - like system consisted of 6.5 French guiding catheter and Y shaped connector. The feature of this system is that we can enhance adrenal vein with contrast agent from the guiding catheter while progressing the wire and micro-catheter. And, we performed S-AVS under guide of the biplane cine angiography. If we performed S-AVS only at frontal view of single plane cine angiography, we hardly find distinction of superior or lateral tributary vein. S-AVS revealed that isolated high plasma aldosterone concentration was detected in right superior tributary adrenal vein which probably flowed from adrenal mass. Results: At a later date, right partial adrenalectomy was conducted. Postoperatively, the blood pressure, aldosterone/renin ratio and result of captopril stress test changed as normalized. Conclusions: Recently, three clinical trials revealed that renal sympathetic denervation (RDN) is effective for reducing the BP, suggesting that catheter intervention will become one of the options for the treatment of hypertension (HT). By screening for secondary HT at the introduction of RDN, cardiologists will encounter many PA patients in near future. Although the opportunity to do AVS will increase, many cardiologists tend to hesitate to do AVS because of its difficulty. However, AVS can be changed easily by using those above methods. Therefore, we report one case where S-AVS was performed by the above methods and partial adrenalectomy was effective.

SUN-144 High Prevalence of Diabetes in Patients with Primary Aldosteronism (PA) Associated with Subclinical Hypercortisolism and Prediabetes More Prevalent in Bilateral Than Unilateral PA

INTRODUCTION: Primary aldosteronism (PA) is characterized by the autonomous production of aldosterone, usually from an aldosterone producing adenoma in one adrenal gland or idiopathic hyperaldosteronism, with bilateral adrenal lesions. It has been suggested that aldosterone overproduction, hypokalemia, or the complication of subclinical hypercortisolism (SH) in patients with PA, are related to impaired glucose homeostasis and insulin resistance. However, the true contributions of these factors to disturbances of carbohydrate metabolism in PA have not been investigated thoroughly from a large-scale epidemiologic viewpoint. In the present study, the true prevalence of glucose intolerance in more than 2000 patients with PA and its association with aldosterone concentration, hypokalemia, and SH were studied in a multicenter collaborative study. METHODS: The prevalence of diabetes was determined in 2210 patients with PA (diagnosed or HbA1c ≥6.5%, NGSP) and compared with that of the Japanese general population from the National Survey of the Ministry of Health, Labour and Welfare in 2016, according to age and sex. In 1386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia (<3.5 mEq/L), suspected SH (serum cortisol ≥1.8 μg/dL after 1-mg dexamethasone suppression test) and PA laterality on the prevalence of diabetes or prediabetes (5.7%≤HbA1c<6.5%) were examined. RESULTS: Of the 2210 patients with PA, 477 (21.6%) had diabetes, this prevalence of being higher than that of the general population (12.1%) or in 10 year cohorts aged 30 to 69 years. According to the χ2 test, diabetes was present significantly more frequently in PA patients with suspected SH (26.8%) than in those with F-1mgDST <1.8 μg/dL (16.9%; p=0.001). When using logistic regression analysis, it was found that age, sex, BMI, and F-1mgDST ≥1.8 μg/dL were significant contributing factors to the presence of diabetes, whereas laterality of PA was not a significant factor. Despite more active PA profiles (e.g. higher PAC, lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA1c values were significantly higher in bilateral PA. PA laterality had no effect on prevalence of diabetes; however, prevalence of prediabetes was significantly higher in bilateral than unilateral PA. CONCLUSIONS: Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA. SUPPORT: This research was supported by the Japan Agency for Medical Research and Development (AMED) for the Practical Research Project for Rare/Intractable Disease.

High Prevalence of Diabetes in Patients With Primary Aldosteronism (PA) Associated With Subclinical Hypercortisolism and Prediabetes More Prevalent in Bilateral Than Unilateral PA: A Large, Multicenter Cohort Study in Japan.

To investigate the prevalence and causes of diabetes in patients with primary aldosteronism (PA) in a multi-institutional cohort study in Japan. The prevalence of diabetes was determined in 2,210 patients with PA (diagnosed or glycated hemoglobin [HbA1c] ≥6.5% [≥48 mmol/mol]; NGSP) and compared with that of the Japanese general population according to age and sex. In 1,386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia (<3.5 mEq/L), suspected subclinical hypercortisolism (SH; serum cortisol ≥1.8 µg/dL after 1-mg dexamethasone suppression test), and PA laterality on the prevalence of diabetes or prediabetes (5.7% ≤ HbA1c <6.5% [39 mmol/mol ≤ HbA1c <48 mmol/mol]) were examined. Of the 2,210 patients with PA, 477 (21.6%) had diabetes. This prevalence is higher than that in the general population (12.1%) or in 10-year cohorts aged 30-69 years. Logistic regression or χ2 test revealed a significant contribution of suspected SH to diabetes. Despite more active PA profiles (e.g., higher PAC and lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA1c values were significantly higher in bilateral PA. PA laterality had no effect on the prevalence of diabetes; however, the prevalence of prediabetes was significantly higher in bilateral than unilateral PA. Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA.

Plasma Aldosterone Concentration as a Determinant for Statin Use among Middle-Aged Hypertensive Patients for Atherosclerotic Cardiovascular Disease.

The use of statin therapy on the prevention of atherosclerotic cardiovascular disease (ASCVD) is recommended by the American College of Cardiology (ACC) and the American Heart Association (AHA); nevertheless, its validation on primary aldosteronism (PA) patients has not been reported. We investigated the risk of incident ASCVD in middle-aged patients with PA compared with essential hypertension (EH) based on ACC/AHA recommendations. We enrolled 461 PA patients and 553 EH patients. Even though the ratio of metabolic syndrome in each group was similar, the PA group had higher systolic blood pressures, higher low-density lipoprotein levels, higher plasma aldosterone concentration (PAC), lower high-density lipoprotein levels, and higher 10-year ASCVD compared to the EH group. The discriminative power for predicting ASCVD by the recommended statin use from the ACC/AHA guidelines was proper in the PA group (i.e., under the receiver operating characteristic curve (95% confidence interval; 0.94 (0.91–0.96)). The generalized additive model showed patients with PAC higher than 60 ng/dL accompanying the standard timing of the statin use suggested by the ACC/AHA. The ACC/AHA guidelines have good discriminative power in the prediction of middle-aged high-risk hypertensive patients, while PAC identifies those high-risk individuals who may benefit from early statin therapy.

A prediction model for primary aldosteronism when the salt loading test is inconclusive.

ObjectiveTo develop a prediction model to confirm or exclude primary aldosteronism (PA) in patients with an inconclusive salt loading test (SLT).ContextDiagnosis in patients with a suspicion of PA can be confirmed using an SLT. In case of inconclusive test results the decision about how to manage the patient is usually based on contextual clinical data.DesignWe included a retrospective cohort of 276 patients in the final analysis.MethodsAll patients underwent an SLT between 2005 and 2016 in our university medical center. The SLT was inconclusive (post-infusion aldosterone levels 140–280 pmol/L) in 115 patients. An expert panel then used contextual clinical data to diagnose PA in 45 of them. Together with 101 patients with a positive SLT this resulted in a total of 146 patients with PA. A total of 11 variables were used in a multivariable logistic regression analysis. We assessed internal validity by bootstrapping techniques.ResultsThe following variables were independently associated with PA: more intense potassium supplementation, lower plasma potassium concentration, lower plasma renin concentration before SLT and higher plasma aldosterone concentration after SLT. The resulting prediction model had a sensitivity of 84.4% and a specificity of 94.3% in patients with an inconclusive SLT. The positive and negative predictive values were 90.5 and 90.4%, respectively.ConclusionsWe developed a prediction model for the diagnosis of PA in patients with an inconclusive SLT that results in a diagnosis that was in high agreement with that of an expert panel.

A7140 Layer-specific Strain Analysis of Myocardial Dysfunction by Speckle Tracking Echocardiography in Patients with Primary Aldosteronism

Objectives: Primary aldosteronism may cause subclinical myocardial injury due to plasma aldosterone elevation. We aimed to investigate myocardial dysfunction using layer-specific strain in patients with primary aldosteronism. Methods: Our study included 62 patients with primary aldosteronism (33 with aldosterone-producing adenoma and 29 idiopathic hyperaldosteronism) and 30 patients with primary hypertension. Speckle tracking echocardiography was acquired using GE Vivid E9 equipment. Longitudinal and circumferential layer strains of the endocardium, midmyocardium and epicardium (LSendo, LSmid, LSepi, CSendo, CSmid, CSepi) were then obtained using EchoPAC BT13 workstation. Results: Patients with aldosterone-producing adenoma (369.2 pg/ml and 144), but not those with idiopathic hyperaldosteronism (220.4 pg/ml and 45), had significantly (P ≤ 0.01) higher plasma aldosterone concentration and plasma aldosterone-to-plasma renin activity ratio (ARR) than patients with primary hypertension (183.1 pg/ml and 13). Layer-specific strain showed decreasing gradient from the endocardium to epicardium in all three groups of patients (P ≤ 0.01). LSendo and CSendo were lowest in aldosterone-producing adenoma, intermediate in idiopathic hyperaldosteronism and highest in primary hypertension (P ≤ 0.01 vs both groups of patients with primary aldosteronism). However, LSmid, LSepi, CSmid and CSepi were significantly (P ≤ 0.01) lower only in the presence of aldosterone-producing adenoma than primary hypertension, but not idiopathic hyperaldosteronism ( P ≥ 0.05). Conclusion: Patients with primary aldosteronism show prominent myocardial deformation changes, to a large extent in parallel with the plasma aldosterone elevation, especially those with aldosterone-producing adenoma and at the endocardial layer.

Aldosterone Suppression by Dexamethasone in Patients With KCNJ5-Mutated Aldosterone-Producing Adenoma.

Aldosterone biosynthesis is regulated principally by ACTH and gene mutations as well as by angiotensin II and serum potassium. In addition, previous studies have reported the potential effects of KCNJ5 mutations in aldosterone-producing adenoma (APA) on cardiovascular diseases. However, responsiveness to ACTH in APAs according to potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5) mutations remains unknown. To investigate KCNJ5 genotype-specific differences in aldosterone biosynthesis in response to ACTH stimulation. A cross-sectional study through retrieval of clinical records. One hundred forty-one patients aged ≥20 years with APA were examined. Associations between KCNJ5 mutations and clinical parameters reflecting the renin-angiotensin system [saline infusion test (SIT)] and ACTH pathways [dexamethasone suppression test (DST)]. KCNJ5 mutations were detected in 107 cases. In the crude comparison, patients with mutations in KCNJ5 had higher plasma aldosterone concentrations (PACs) both at baseline and after the SIT. PAC after the DST showed a significant inverse association with KCNJ5 genotypes after controlling for age, sex, tumor size, and PAC after the SIT. Immunohistochemical analysis of 101 cases revealed more abundant immunoreactivity of CYP11B1 and CYP17 in the KCNJ5-mutated group than in the KCNJ5 wild-type group. This report of marked suppression of PAC by dexamethasone in patients with KCNJ5-mutated APAs indicates that such APAs respond to endogenous ACTH more readily than APAs in nonmutated cases. Further molecular and epidemiologic studies are required to validate our results and clarify the clinical effectiveness of the DST for predicting KCNJ5 mutations before adrenalectomy.

Clinical Implications

HomeHypertensionVol. 71, No. 3Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published1 Mar 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.10860Hypertension. 2018;71:367Cardiovascular Disease in Primary Aldosteronism (p 530)Download figureDownload PowerPointAldosterone causes organ damage in animal models, and the prevalence of cardiovascular disease (CVD) among patients with primary aldosteronism (PA) is reportedly high. There have been several clinical studies examining the factors associated with CVD in these people; but the results are controversial. In some studies, the prevalence of CVD was distributed nearly equally across the spectrum of plasma aldosterone or serum potassium levels, whereas other studies reported that hypokalemic patients with PA had an elevated rate of CVD. Of the 2582 patients with PA studied in this study, the prevalence of CVD was higher than in age-, gender-, and blood pressure-matched patients with essential hypertension. Hypokalemia (≤3.5 mEq/L) and the unilateral subtype was associated with significantly higher adjusted odds ratios for CVD. Although plasma aldosterone concentration (PAC) was not linearly related to the adjusted odds ratios for CVD, patients with high PAC (≥125 pg/mL) had significantly higher adjusted odds ratios for CVD than patients with lower PAC (<125 pg/mL). Our result suggests PA patients with PACs higher than the upper limit of normal as well as with hypokalemia or unilateral subtype are at higher risk of developing CVD and, therefore, have a greater need for PA-specific treatment. In contrast, PA patients with normokalemia, the bilateral subtype, and PACs lower than the upper limit of normal are at lower risk of CVD and may not need immediate PA-specific treatment.Left Ventricular Function and Cognitive Impairment (p 429)Download figureDownload PowerPointA growing literature is revealing connections between cardiovascular disease and cognitive impairment/dementia. However, the relationships between subclinical cardiac dysfunction and cognitive performance is not been well established in the general population. In this issue of Hypertension, we investigated longitudinally cardiac magnetic resonance measures of left ventricular structure and function in relation to cognitive performance and incident dementia in a large multiethnic population free of cardiovascular disease at baseline. A total of 4999 participants with cardiac magnetic resonance images at baseline were followed for a median of 12 years. Left ventricular hypertrophy and remodeling were strongly associated with lower cognitive function and a higher risk of future hospitalization with dementia. Additionally, lower left ventricular sphericity (increased conicity) was associated with increased risk of future dementia. These associations were independent of demographic confounders, cardiovascular risk factors, and cardiovascular events. Measures of left ventricular function were not associated with risk of future dementia or cognitive function. This study provides 2 avenues of important insight into the link between cardiac and cerebral involvement in dementia. First, cardiac structural and functional abnormalities may be useful in the identification of individuals at risk of future cognitive impairment. Second, these data suggest that potential common pathophysiological mechanisms could underlie both cardiovascular and cerebrovascular structural remodeling (eg, microvascular disease) leading or contributing to cardiac concentric remodeling and vascular dementia.VEGF Inhibitor–Induced Hypertension and Renal NO (p 473)Download figureDownload PowerPointVEGF (vascular endothelial growth factor) is critically involved in tumor angiogenesis and is therefore an important target in the pharmacological treatment of many cancer diseases. Clinical use of VEGF inhibitors is associated with a preeclampsia-like syndrome characterized by rapid development of hypertension and proteinuria and has revealed an important role of VEGF in blood pressure regulation. The underlying mechanisms of VEGF inhibitor–induced hypertension are only partly understood but may include decreased systemic nitrogen oxide (NO) and increased plasma endothelin-1. Pazopanib is one of the recommended first line treatments in advanced renal cell carcinoma patients and in a prospective, single center observational study in a cohort of pazopanib-treated patients, significant hypertension developed during the first 4 weeks of treatment. Hypertension was accompanied by proteinuria, decreased plasma NO metabolites and increased endothelin-1. In addition, results showed decreased urinary excretion of NO metabolites without change in urine endothelin-1 or renal function. The kidneys are important in long-term regulation of blood pressure, and data support a significant role of reduced renal NO bioavailability in VEGF inhibitor–induced hypertension. Sufficient blood pressure control is necessary in this group of patients to prevent impaired treatment options of cancer targeted therapy. Based on mechanistic evidence, long-acting NO donors or cGMP-based drug interventions seem particularly well suited for organ protection and blood pressure reduction. Previous Back to top Next FiguresReferencesRelatedDetails March 2018Vol 71, Issue 3 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.118.10860PMID: 30543472 Originally publishedMarch 1, 2018 PDF download Advertisement

Renoprotective RAAS inhibition does not affect the association between worse renal function and higher plasma aldosterone levels

BackgroundAldosterone is elevated in chronic kidney disease (CKD) and may be involved in hypertension. Surprisingly, the determinants of the plasma aldosterone concentration (PAC) and its role in hypertension are not well studied in CKD. Therefore, we studied the determinants of aldosterone and its association with blood pressure in CKD patients. We also studied this during renin-angiotensin-aldosterone system inhibition (RAASi) to establish clinical relevance, as RAASi is the treatment of choice in CKD with albuminuria.MethodsWe performed a post-hoc analysis on data from a randomized controlled double blind cross-over trial in non-diabetic CKD patients (n = 33, creatinine clearance (CrCl) 85 (75–95) ml/min, proteinuria 3.2 (2.5–4.0) g/day). Patients were treated with losartan 100 mg (ARB), and ARB + hydrochlorothiazide 25 mg (HCT), during both a regular (200 ± 10 mmol Na+/day) and low (89 ± 8 mmol Na+/day) dietary sodium intake, in 6-week study periods. PAC data at the end of each study period were analyzed. The association between PAC and blood pressure was analyzed continuously, and according to PAC above or below the median.ResultsLower CrCl was correlated with higher PAC during placebo as well as during ARB (β = −1.213, P = 0.008 and β = −1.090, P = 0.010). Higher PAC was not explained by high renin, illustrated by a comparable association between CrCl and the aldosterone-to-renin ratio. The association between lower CrCl and higher PAC was also found in a second study with single RAASi with ACE inhibition (ACEi; lisinopril 40 mg/day), and dual RAASi (lisinopril 40 mg/day + valsartan 320 mg/day). Higher PAC was associated with a higher systolic blood pressure (P = 0.010) during different study periods. Only during maximal treatment with ARB + HCT + dietary sodium restriction, blood pressure was no longer different in subjects with a PAC above and below the median.ConclusionsIn CKD patients with a standardized regular sodium intake, worse renal function is associated with a higher aldosterone, untreated and during RAASi with either ARB, ACEi, or both. Furthermore, higher aldosterone is associated with higher blood pressure, which can be treated with the combination of RAASi, HCT and dietary sodium restriction.The first study was performed before it was standard to register trials and the study was not retrospectively registered. The second study was registered in the Netherlands Trial Register on the 5th of May 2006 (NTR675).

Role of adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes

Objective: To investigate the role of adrenal vein sampling (AVS) in identifying the subtype of primary aldosteronism (PA). Methods: AVS was performed in 50 patients who were confirmed as PA between September 2010 and September 2016 in Nanjing Drum Tower Hospital. Clinical, biochemical and follow-up data were reviewed retrospectively. Bilaterally simultaneous catheterization without cosyntropin stimulation and contemporaneous cortisol measurement during AVS were used. Selectivity index (SI)≥1.5 suggested that the sample was from the adrenal vein.Lateralization index (LI) ≥2 suggested unilateral disease.Clinical data was further compared and the AVS findings were analyzed. Results: AVS was successful performed in 41 cases of 50 patients, and the success rate was 82%. According to the results of AVS and postoperative pathology, 41 cases were divided into aldosterone-producing adenoma (APA)/unilateral adrenal hyperplasia (UAH) group (24 cases) and idiopathic hyperaldosteronism (IHA) group (17 cases). Compared with IHA group, patients with APA/UAH showed longer duration of hypertension[10.0 (5.0, 13.0) y vs 4.0 (2.0, 8.0) y, P=0.046], higher proportion of hypokalemia (95.8% vs 64.7%, P=0.009). Furthermore, patients with APA/UAH demonstrated lower plasma renin activity (P=0.089), higher plasma aldosterone concentration and aldosterone to renin ratio (ARR) (both P<0.05). The diagnostic concordance between CT and adrenal vein sampling was only 48.8%(20/41). Conclusions: The application of bilaterally simultaneous catheterization and contemporaneous cortisol measurement improves success rate and diagnostic accuracy of AVS. AVS is useful in subtype diagnosis of PA with equivocal imaging findings.

Associations of aldosterone and renin concentrations with inflammation-the Study of Health in Pomerania and the German Conn's Registry.

Chronic inflammation is an age-independent and body mass index-independent contributor to the development of multi-morbidity. Alterations of the renin-angiotensin-aldosterone system are observed within the context of proinflammatory states. We assessed circulating aldosterone, renin, and inflammatory biomarker concentrations in healthy, normotensive subjects and patients with primary aldosteronism. We included 1177 normotensive individuals from the population-based Study of Health in Pomerania (first follow-up, Study of Health in Pomerania-1) and 103 primary aldosteronism patients from the German Conn's Registry. A 1:1 matching for sex, age, body mass index, smoking status, diabetes mellitus, and the estimated glomerular filtration rate was performed to determine whether primary aldosteronism patients exhibit higher inflammatory biomarker concentrations than normotensive controls. The associations of plasma aldosterone concentration or plasma renin concentration with circulating fibrinogen concentrations, white blood cell count, and high sensitive C-reactive protein concentrations in the normotensive sample were determined with multivariable linear and logistic regression analyses. 1:1 matched primary aldosteronism patients demonstrated significantly (p < 0.01) higher plasma aldosterone concentration (198 vs. 47 ng/l), lower plasma renin concentration (3.1 vs. 7.7 ng/l) and higher high sensitive C-reactive protein concentrations (1.5 vs. 1.0 mg/l) than normotensive controls. Within the normotensive cohort, plasma renin concentration but not plasma aldosterone concentration was positively associated with fibrinogen concentrations and white blood cell count. Further, a J-shaped association between plasma renin concentration and high sensitive C-reactive protein concentrations was detected. High plasma aldosterone concentration in a primary aldosteronism cohort and high plasma renin concentration in normotensive subjects are associated with increased concentrations of inflammatory biomarkers. This suggests a link between the renin-angiotensin-aldosterone system and inflammatory processes in patients with primary aldosteronism and even in normotensive subjects.

Plasma aldosterone level within the normal range is less associated with cardiovascular and cerebrovascular risk in primary aldosteronism

Previous studies showed higher risk of cardiovascular and cerebrovascular (CCV) events in primary aldosteronism compared with essential hypertension, but the patients of these studies were limited to primary aldosteronism patients with high plasma aldosterone concentration (PAC). The introduction of the aldosterone-renin ratio as the screening test for primary aldosteronism led to the recognition of primary aldosteronism patients with normal PAC (nPA). However, there is no information on the risk of primary aldosteronism including nPA. In this retrospectively and cross-sectional study, the clinical features and CCV event risk of primary aldosteronism at diagnosis including nPA were investigated and compared with essential hypertension. The study included 292 consecutive primary aldosteronism patients and 498 essential hypertension outpatients. All primary aldosteronism patients were diagnosed by autonomous aldosterone secretion using confirmatory tests, and then divided into nPA (n = 130) and primary aldosteronism patients with high PAC (hPA: n = 162) using a PAC cutoff level of less than 443 pmol/l (16 ng/dl), representing the normal upper limit of PAC. nPA patients were significantly older at diagnosis of primary aldosteronism and at onset of hypertension compared with hPA patients. They had milder hypokalemia and easier-to-control blood pressure. The results suggested that nPA could be considered a mild type of primary aldosteronism but not an early-stage hPA. Moreover, the risk of all CCV events in nPA was significantly lower than that in hPA (odds ratio 0.42, 95% confidence interval 0.18-0.90, P < 0.05) and not significantly higher than that in essential hypertension (odds ratio 0.95, 95% confidence interval 0.43-1.94, P = 0.899). This study suggests that aggressive diagnostic workout for nPA is less effective to prevent CCV events.

Post-Saline Infusion Plasma Aldosterone Concentrations are Well Correlated with the Lateralized Ratio of Adrenal Venous Sampling in Patients of Primary Aldosteronism

Objective: Adrenal venous sampling (AVS) is the most reliable test to distinguish between unilateral and bilateral primary aldosteronism (PA). However, AVS is invasive, risky, and expensive, and alternative diagnostic methods are desirable. This study aimed to investigate the diagnostic power of saline infusion test (SIT) to distinguish between unilateral and bilateral PA. Design: Retrospective database analysis. Subjects and Methods: We selected 111 patients with PA diagnosed by confirmatory tests who underwent both SIT and successful AVS. Thirty-two patients had lateralized ratio (LR) over 4.0 and 79 patients had LR less than 4.0. Multiple regression analysis and receiver operating characteristic (ROC) analysis were used to examine whether the SIT had good diagnostic power to distinguish between patients with high LR and those with low LR. Results: The patients with high LR had significantly lower serum potassium levels (P<0.0001, Mann-Whitney’s U Test) and higher plasma aldosterone concentrations after SIT (Post-PAC) (P<0.0001). It was revealed that Post-PAC levels were independently associated with the LR by multiple regression analysis (P=0.0112). ROC analysis revealed that the diagnostic accuracy of SIT was very high for distinguishing between patients with high LR and those with low LR. The optimal cut-off value of Post-PAC for the diagnosis of patients with low LR was less than 9.3 ng/dl. Conclusions: SIT is useful for distinguishing between patients with high LR and low LR. It might be possible to omit AVS in patients with a Post-PAC value less than 9.3 ng/dl.Combining the results of serum potassium levels and imaging examinations with SIT might be a potential strategy for PA subtypes.

PS 17-04 SUPER-SELECTIVE ADRENAL VEIN SAMPLING IS USEFUL FOR ALDOSTERONE-PRODUCING ADENOMA UNDIAGNOSABLE BY CONVENTIONAL ADRENAL VEIN SAMPLING

Objective: Although adrenal vein sampling (AVS) is the gold standard for diagnosing subtypes of primary aldosteronism (PA), it is sometimes difficult to make correct diagnosis by conventional AVS in which only adrenal central veins are selected. We recently employed a new approach, super-selective AVS (SS-AVS). We hereby present a case of aldosterone-producing adenoma (APA) diagnosed by SS-AVS and discuss the characteristics of difficult cases. Design and method: Case report: The 36-year-old patient with hypertension was treated with oral medication for five years, but the blood pressure control was poor. Endocrinological examinations were performed and it revealed low plasma renin activity (PRA 0.1 ng/ml/h) and high plasma aldosterone concentration (PAC 190 pg/ml). Imaging examinations showed a 13 mm-sized left adrenal mass. PA was suspected and AVS was performed subsequently to confirmation tests. However, aldosterone/cortisol ratios of both left and right adrenal central veins were lower than that of the inferior vena cava, and he failed to be diagnosed as APA. As we have employed SS-AVS since two years, we performed SS-AVS for the reevaluation for this case, and reviewed such undiagnosable cases. Results: A microcatheter was inserted to the tributaries of the left adrenal vein. Lateralized ratio (LR) using the aldosterone value in the tributary near the mass was 25.8 and contralateral ratio (CR) was 0.50. He was diagnosed as left APA and the surgery was performed. We diagnosed 30 APAs in total, but 8 cases failed to be diagnosed by conventional AVS. Among them, 7 cases were in the left side, and none of them were with tumor size larger than 15 mm. Conclusions: SS-AVS is useful for cases undiagnosable by conventinal AVS because a high plasma aldosterone level can be detected when a microcatheter is inserted closely to APA. It appears that such cases have much in common: a small mass in the left adrenal gland.

PS 05-10 THE CLINICAL CHARACTERISTICS OF MASKED HYPERTENSION

Objective: Background: Masked hypertension, defined as a normal blood pressure (BP) in the clinic or office (<140/90 mmHg) but an elevated BP out of the clinic (ambulatory daytime BP or home BP > 135/85 mmHg), is associated with poor cardiovascular prognosis. Aims: We investigated the clinical characteristics of masked hypertension in patients who were treated with anti-hypertensive drugs. Design and Method: We enrolled 347 patients with essential hypertension and divided them into 2 groups on the basis of the difference between their weekly averaged home BP measured in morning right before hospital visit and office BP: (Group M: home BP > office BP, n = 135, and Group O: home BP Results: There were no differences in age, gender, duration of hypertension, number of BP-lowering medications and comorbidities between the two groups. Home BP was higher and office BP was lower in Group M compared with those in Group O (Home BP: 135.4 ± 11.5 / 75.0 ± 10.1 mmHg in Group M and 125.2 ± 9.2 / 71.3 ± 9.1 mmHg in Group O, p < 0.01, and Office BP: 126.0 ± 10.0 / 72.4 ± 9.6 mmHg in Group M and 136.0 ± 10.3 / 77.0 ± 8.6 mmHg in Group O, p < 0.01). Estimated salt intake assessed by urinary sodium excretion from spot samples was greater in Group M than in Group O (9.1 ± 2.9 g/day and 8.3 ± 2.3 g/day, p < 0.01). While plasma aldosterone concentration (PAC) was greater in Group M than in Group O (11.5 ± 4.9 ng/dl and 10.1 ± 4.6 ng/dl, p < 0.05), plasma renin activity (PRA) and PAC/PRA ratio was similar in the two groups. Conclusions: High salt intake and high PAC are associated with elevated home BP in patients with hypertension despite being well-controlled office BP on medications.

PP.35.03] ALDOSTERONE, RENIN AND THE ALDOSTERONE-TO-RENIN-RATIO

Objective: Renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of human blood pressure. Recent investigations have demonstrated that both a higher aldosterone concentration and a higher aldosterone-to-renin-ratio serve as markers of increased risk for hypertension. However, the distribution of the aldosterone-to-renin-ratio in the general population is largely unknown. We aimed to provide a sex-specific distribution and reference ranges for plasma aldosterone concentration (PAC), plasma renin concentration (PRC) and its ratio in a large population-based sample. Design and method: PAC and PRC were analyzed by chemiluminescent immunoassay (CLIA) (LIAISON®, DiaSorin) in a sample of 7,474 (50.7%) men and 7,266 (49.3%) women from the population-based Gutenberg Health Study in Germany. Multivariable regression analyses for PAC, PRC and the aldosterone-to-direct-renin-ratio (ADRR) were performed under adjustment for age, medication, cardiovascular risk factors (CVRFs) and cardiovascular disease (CVD). Biomarkers and the ratio were log-transformed. Reference subgroups were selected by excluding hypokalemia, CVRFs, CVD, renal insufficiency, and intake of analyte modifying drugs. The reference interval was defined as the central 95% range between the 2.5th and 97.5th percentiles. Results: Results showed sex differences in PAC, PRC and ADRR with lower PRC and higher PAC and ADRR in females than in males. PRC decreased with age in males and females whereas PAC decreased was significant in females only. The ADRR increased with age (ßlog (ADRR) per 5y: 0.08 [95%CI: 0.06/0.09]) and 0.06 [0.05/0.08] for men and women, resp.; p < 0.0001). Thus, age- and sex-specific nomograms for PAC, PRC, and ADRR were created by quantile regression. In multivariable analysis, PAC was positively associated with obesity and dyslipidemia. Both, PAC and PRC were elevated for chronic kidney disease, while the ADRR showed no association. In a fully adjusted multivariable model, the strongest correlation observed was found for hypertension with elevated ADRR in both sexes. Conclusions: Based on a large population-based data set, the present investigation provides a comprehensive characterization of the distribution and reference ranges for PAC, PRC and the ADRR in a predominantly Caucasian sample. Age- and sex-related limits of PAC, PRC, and the ADRR could support clinicians in diagnosis and treatment of hypertension.

Synergic effects of renin and aldosterone on right ventricular function in hypertension: a tissue Doppler study.

Right ventricular dysfunction (RVD) is associated with poor cardiovascular outcome. The renin-angiotensin-aldosterone system is involved in alterations of the left ventricular geometry and function. Detrimental effects of the renin-angiotensin-aldosterone system on the right ventricular function are being postulated, but data supporting this assumption are still lacking. The aim of the study was to assess the impact of hyperreninemia, hyperaldosteronism or their combination on right ventricular function in hypertensive individuals. Plasma renin activity (PRA) and plasma aldosterone concentrations (PACs) were measured in 116 hypertensive patients, divided as follows: normal PRA and PAC (n = 38); high PRA and normal PAC (hypereninemia) (n = 26); normal PRA and high PAC (hyperaldosternism) (n = 27); high PRA and PAC (HRA) (n = 25). Echocardiographic evaluation of the left and right ventricles (RV), including tissue Doppler imaging, was performed. RVD was identified by tissue Doppler Imaging-derived Myocardial Performance Index, calculated with a multisegmental approach. Indices of the right ventricular structure and function, as well as the prevalence of RVD, were higher in hyperreninemia and hyperaldosternism groups as compared with the normal group, and a further increase was observed in the HRA patients. Regression models showed a similar risk of RVD in the hyperreninemia and hyperaldosternism patients, regardless of systemic and pulmonary pressure, as well as left ventricular dysfunction. Notably, patients with both hyperreninemia and hyperaldosternism exhibited the strongest association with RVD as compared with patients with only hyperreninemia or hyperaldosternism. Isolated hyperreninemia or hyperaldosternism determines a similar impairment of the right ventricular function, whereas their combination is further detrimental. Renin and aldosterone may represent early biomarkers of right ventricular dysfunction in hypertension.

The Ratio of Plasma Aldosterone Concentration to Potassium in Adrenocorticotropin Stimulation Test is a Possible New Index for Diagnosis of Aldosterone-producing Adenoma in Patients with Primary Aldosteronism

Primary aldosteronism (PA)is the most common form of secondary hypertension,and is characterized by high plasma aldosterone concentration (PAC)and low plasma renin activity(PRA),refractory hypertension, and occasional hypokalemia. Reliable parameters are required to identify aldosterone-producing adenoma (APA)in patients with PA,because APA is treatable with surgical resection if localization of aldosterone hypersecretion can be determined by adrenal venous sampling (AVS).The purpose of this study is to summarize the results of AVS in our institute and to evaluate the diagnostic accuracy of various parameters with adrenocorticotropic hormone(ACTH)stimulation test in identifying probable APA among patients with PA. Eighty-one patients with PA were admitted to Shinshu University Hospital from April 2009 to March 2013,and 59 patients who underwent AVS were included in the study.PAC and aldosterone to potassium ratio (APR) in ACTH stimulation tests were examined in 28 patients. Receiver operating characteristic (ROC) curve analysis was used to evaluate diagnostic accuracy.The response of PAC to ACTH in the probable APA group was stronger than that in the others.In ROC curve analysis,the area under the curve(AUC)of APR (PAC / potassium)for diagnosis of probable APA was 0.9840 with an optimal cutoffvalue>102.6 corresponding to sensitivity and specificity of 94.1% and 90.9 % for diagnosis of APA,respectively.This study indicated that APR after the ACTH stimulation test may be a useful and accurate parameter in cases of PA.In cases with APR 100 after ACTH stimulation,AVS is strongly recommended for localization of aldosterone hypersecretion.Shinshu Med J 63 : 145―156, 2015 (Received for publication December 8,2014;accepted in revised form January 28,2015)

Plasma aldosterone concentration is positively associated with pulse pressure in patients with primary hypertension.

Increasing evidence showed a link between arterial elasticity and stiffness and pulse pressure (PP), in which plasma aldosterone may play a role. The observational study aimed to explore the potential relations between plasma aldosterone concentration (PAC) and PP in patients with hypertension.We evaluated the relation between PP and PAC in supine, seated, and upright positions in 195 patients with primary hypertension who underwent postural stimulation test. They were divided into 3 groups by tertiles of PP: PP ≤ 44 mm Hg (n = 70), 44 mm Hg < PP ≤ 51 mm Hg (n = 63), and PP ≥ 51 mm Hg (n = 62). The PAC in different postures was compared, respectively.The results showed the following. First, segregated by tertiles of PP, serum K+, 24-hour systolic blood pressure, 24-hour diastolic blood pressure, sex, upright PAC, and seated PAC showed statistically significant differences in groups. Second, the PAC were significantly different in 3 levels of PP regardless of postures, the individuals with PP ≥ 51 mm Hg had the highest PAC. On contrast, the patients with PAC > 12 ng/dL showed greater PP than those with PAC ≤ 12 ng/dL. Third, weak associations between PP and upright (r = 0.288, P < 0.001), seated (r = 0.265, P < 0.001), and supine postures (r = 0.191, P = 0.008) were detected by simple correlation analysis. After corrected serum K+, age, and sex, the partial correlation coefficients did not change greatly. Fourth, the logistic regression model was constructed with PP ≥ 40 mm Hg or PP < 40 mm Hg as the dependent variable; the serum K+[OR = 0.043, 95% CI: 1.09(1.00–1.12)] and PAC [OR = 0.025, 95%CI: 0.35(0.13–0.88)] were included as significant contributing factors.The results showed that higher PAC was weakly, but significantly, correlated to greater PP regardless of different postures, suggesting that higher PAC may be a risk factor of reduced arterial elasticity in patients with hypertension.