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Abstract Background Increasing evidence suggests the bidirectional interplay between parathyroid hormone and aldosterone as an important mechanism behind the increased risk of cardiovascular damage and bone disease observed in primary hyperparathyroidism. Our primary object is to assess the efficacy of the mineralocorticoid receptor-blocker eplerenone to reduce parathyroid hormone secretion in patients with parathyroid hormone excess. Methods/design Overall, 110 adult male and female patients with primary hyperparathyroidism will be randomly assigned to eplerenone (25 mg once daily for 4 weeks and 4 weeks with 50 mg once daily after dose titration] or placebo, over eight weeks. Each participant will undergo detailed clinical assessment, including anthropometric evaluation, 24-h ambulatory arterial blood pressure monitoring, echocardiography, kidney function and detailed laboratory determination of biomarkers of bone metabolism and cardiovascular disease. The study comprises the following exploratory endpoints: mean change from baseline to week eight in (1) parathyroid hormone(1–84) as the primary endpoint and (2) 24-h systolic and diastolic ambulatory blood pressure levels, NT-pro-BNP, biomarkers of bone metabolism, 24-h urinary protein/albumin excretion and echocardiographic parameters reflecting systolic and diastolic function as well as cardiac dimensions, as secondary endpoints. Discussion In view of the reciprocal interaction between aldosterone and parathyroid hormone and the potentially ensuing target organ damage, the EPATH trial is designed to determine whether eplerenone, compared to placebo, will effectively impact on parathyroid hormone secretion and improve cardiovascular, renal and bone health in patients with primary hyperparathyroidism. Trial registration ISRCTN33941607

Increasing evidence describes a possible interplay between vitamin D insufficiency with increased aldosterone. The authors sought to evaluate the effect of vitamin D supplementation on plasma aldosterone concentration (PAC) in patients with hypertension and 25-hydroxyvitamin D[25(OH)D] insufficiency. The Styrian Vitamin D Hypertension Trial was a single-center, double-blind, placebo-controlled randomized clinical trial conducted from 2011 to 2014. Two hundred patients with arterial hypertension and 25(OH)D levels <30 ng/mL were enrolled. Study participants were randomized to receive either 2800 IU of vitamin D3 or placebo. The present investigation is a post hoc analysis using analysis of covariance adjusting for baseline differences. A total of 188 participants (mean±standard deviation age, 60.1±11.3 years; 47% women; 25(OH)D, 21.2±5.6 ng/mL) completed the trial. Mean differences between baseline and follow-up PAC in the control and intervention arm were +3.3 ng/dL and +0.9 ng/dL, respectively (P=.04). The findings indicate that vitamin D3 supplementation significantly decreases PAC in patients with arterial hypertension and 25(OH)D insufficiency. [ABSTRACT FROM AUTHOR]

Background: The cardiotonic steroid marinobufagenin (MBG) is increasingly suggested to be responsible for some of the cardiovascular injury that has been previously attributed to aldosterone. We examined the clinical correlates of circulating MBG concentrations in hypertensive patients and tested the hypothesis that MBG serves as a reliable diagnostic tool for detecting primary aldosteronism (PA). Methods: Plasma MBG concentrations (mean: 0.51 ± 0.25 nmol/l) were measured in the morning fasting samples in 20 patients with PA and 20 essential hypertensive (EH) controls matched for age, sex, body mass index, renal function, urinary sodium and intake of antihypertensive medication (mean age: 51.6 years; 52.2% women). Results: Overall, plasma MBG was directly correlated with plasma aldosterone, aldosterone to active renin ratio (AARR), diastolic blood pressure, mean carotid intima-media thickness, serum sodium, urinary protein to creatinine ratio and inversely with serum potassium levels. Plasma MBG levels were significantly higher in patients with PA compared to EH (mean: 0.68 ± 0.12 versus 0.35 ± 0.24 nmol/l; p < 0.001). ROC analysis yielded a greater AUC for plasma MBG compared to the AARR, PAC and serum potassium levels for detecting PA. Youden's Index analyses yielded the optimal plasma MBG cut-off score for diagnosing PA at > 0.49 nmol/l with specificity and sensitivity values of 0.85 and 0.95, respectively, which were higher than those at the optimum AARR cut-off at > 3.32 ng/dl/µU/ml. Conclusions: In a well-characterized cohort, values of plasma MBG were significantly related to clinical correlates of cardiovascular and renal disease. Plasma MBG emerged as a valuable alternative to the AARR for screening of PA. [ABSTRACT FROM AUTHOR]

Abstract: Inappropriate aldosterone and parathyroid hormone (PTH) secretion is strongly linked with development and progression of cardiovascular (CV) disease. Accumulating evidence suggests a bidirectional interplay between parathyroid hormone and aldosterone. This interaction may lead to a disproportionally increased risk of CV damage, metabolic and bone diseases. This review focuses on mechanisms underlying the mutual interplay between aldosterone and PTH as well as their potential impact on CV, metabolic and bone health. PTH stimulates aldosterone secretion by increasing the calcium concentration in the cells of the adrenal zona glomerulosa as a result of binding to the PTH/PTH-rP receptor and indirectly by potentiating angiotensin 2 induced effects. This may explain why after parathyroidectomy lower aldosterone levels are seen in parallel with improved cardiovascular outcomes. Aldosterone mediated effects are inappropriately pronounced in conditions such as chronic heart failure, excess dietary salt intake (relative aldosterone excess) and primary aldosteronism. PTH is increased as a result of (1) the MR (mineralocorticoid receptor) mediated calciuretic and magnesiuretic effects with a trend of hypocalcemia and hypomagnesemia; the resulting secondary hyperparathyroidism causes myocardial fibrosis and disturbed bone metabolism; and (2) direct effects of aldosterone on parathyroid cells via binding to the MR. This adverse sequence is interrupted by mineralocorticoid receptor blockade and adrenalectomy. Hyperaldosteronism due to klotho deficiency results in vascular calcification, which can be mitigated by spironolactone treatment. In view of the documented reciprocal interaction between aldosterone and PTH as well as the potentially ensuing target organ damage, studies are needed to evaluate diagnostic and therapeutic strategies to address this increasingly recognized pathophysiological phenomenon. [Copyright &y& Elsevier]

Animal and human studies support a clinically relevant interaction between aldosterone and parathyroid hormone (PTH) levels and suggest an impact of the interaction on cardiovascular (CV) health. This review focuses on mechanisms behind the bidirectional interactions between aldosterone and PTH and their potential impact on the CV system. There is evidence that PTH increases the secretion of aldosterone from the adrenals directly as well as indirectly by activating the renin–angiotensin system. Upregulation of aldosterone synthesis might contribute to the higher risk of arterial hypertension and of CV damage in patients with primary hyperparathyroidism. Furthermore, parathyroidectomy is followed by decreased blood pressure levels and reduced CV morbidity as well as lower renin and aldosterone levels. In chronic heart failure, the aldosterone activity is inappropriately elevated, causing salt retention; it has been argued that the resulting calcium wasting causes secondary hyperparathyroidism. The ensuing intracellular calcium overload and oxidative stress, caused by PTH and amplified by the relative aldosterone excess, may increase the risk of CV events. In the setting of primary aldosteronism, renal and faecal calcium loss triggers increased PTH secretion which in turn aggravates aldosterone secretion and CV damage. This sequence explains why adrenalectomy and blockade of the mineralocorticoid receptor tend to decrease PTH levels in patients with primary aldosteronism. In view of the reciprocal interaction between aldosterone and PTH and the potentially ensuing CV damage, studies are urgently needed to evaluate diagnostic and therapeutic strategies addressing the interaction between the two hormones. [ABSTRACT FROM PUBLISHER]

Background: Primary aldosteronism (PA) affects approximately 5 to 10% of all patients with arterial hypertension and is associated with an excess rate of cardiovascular complications that can be significantly reduced by a targeted treatment. There exists a general consensus that the aldosterone to renin ratio should be used as a screening tool but valid data about the accuracy of the aldosterone to renin ratio in screening for PA are sparse. In the Graz endocrine causes of hypertension (GECOH) study we aim to prospectively evaluate diagnostic procedures for PA. Methods and design: In this single center, diagnostic accuracy study we will enrol 400 patients that are routinely referred to our tertiary care center for screening for endocrine hypertension. We will determine the aldosterone to active renin ratio (AARR) as a screening test. In addition, all study participants will have a second determination of the AARR and will undergo a saline infusion test (SIT) as a confirmatory test. PA will be diagnosed in patients with at least one AARR of ≥ 5.7 ng/dL/ng/L (including an aldosterone concentration of ≥ 9 ng/dL) who have an aldosterone level of ≥ 10 ng/dL after the saline infusion test. As a primary outcome we will calculate the receiver operating characteristic curve of the AARR in diagnosing PA. Secondary outcomes include the test characteristics of the saline infusion test involving a comparison with 24 hours urine aldosterone levels and the accuracy of the aldosterone to renin activity ratio in diagnosing PA. In addition we will evaluate whether the use of beta-blockers significantly alters the accuracy of the AARR and we will validate our laboratory methods for aldosterone and renin. Conclusion: Screening for PA with subsequent targeted treatment is of great potential benefit for hypertensive patients. In the GECOH study we will evaluate a standardised procedure for screening and diagnosing of this disease. [ABSTRACT FROM AUTHOR]

Background Inappropriate aldosterone and parathyroid hormone (PTH) secretion is associated with increased cardiovascular risk. Accumulating evidence suggests bidirectional interplay between aldosterone and PTH. Methods We evaluated the cross-sectional relationship between plasma aldosterone concentration (PAC), aldosterone to renin ratio (ARR) and PTH and subsequently tested whether the interaction between PAC and PTH modified the risk of cardiovascular death. PAC [78.0 (48.0-123.0) pg/mL], ARR [6.4 (2.9-12.9) pg/mL/pg/mL] and PTH concentration [median: 29.0 (22.0-40.0) pg/mL] were measured in 3074 patients (mean age: 62.5 ± 10.6 years; 30.3% women) referred to coronary angiography in a tertiary care center in Southwest Germany. Results Using multiple linear regression analysis, PAC and ARR emerged as an independent predictor of higher PTH concentrations (β = 0.12 and 0.21, P < 0.001 for both) irrespective of intake of antihypertensive treatment, 25(OH)D, kidney function, serum calcium, phosphate, magnesium, cortisol, NT-pro-BNP, soluble α-klotho and FGF-23 concentration. After a median follow-up of 9.9 years, 512 (16.7%) participants had died due to fatal cardiovascular events. Multivariate Cox proportional hazard analysis revealed that both PAC and PTH were independently associated with cardiovascular mortality, with a potential synergistic interaction (P = 0.028). PAC and PTH are exclusively associated with cardiovascular death in subjects with PTH and PAC concentrations above the median, respectively (PAC: HR per log SD: 1.14; 95% CI 1.02-1.29; P = 0.026; PTH: HR per log SD: 1.18; 95% CI 1.02-1.37; P = 0.031). Conclusions Higher PAC and ARR were independently associated with PTH. PAC was independently related to incident cardiovascular mortality exclusively in patients with elevated PTH and vice versa. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To date studies evaluating the relation between circulating aldosterone levels and mortality in elderly female individuals are lacking. We therefore aimed to assess the relationship between circulating aldosterone levels and mortality in a population-based cohort study of female nursing home residents. Methods: Individuals aged 70years and older were recruited from 95 nursing homes in Austria. Participants were enrolled and followed up by mobile study teams. All participants underwent an extensive health examination and were followed until death or end of the study. Serum aldosterone concentration (SAC) was measured at baseline after exclusion of twenty seven patients taking mineralocorticoid-receptor (MR) blockers. Results: Median SAC was 171.1 (IQR: 103.2–303.4) pg/mL (normal range: 30–400) in 471 female individuals (mean age: 83.7±6.2years). After a median follow-up of 27±8months, a total of 121 (25.7%) participants died. In multivariable Cox proportional hazard analysis, SAC levels stratified in quartiles were significantly associated with all-cause mortality. Compared with the reference (first) SAC quartile, the Cox proportional hazard ratio (confidence interval 95%) for the fourth SAC quartiles was 1.94, 95% CI=1.08–3.46, p=0.026. We found statistically significant interaction terms between SAC-related mortality and the presence of advanced heart failure (NYHA functional class III; p=0.038), HbA1c (p=0.043) and eGFR levels (p=0.030). Conclusions: Higher circulating aldosterone levels are related to an increased mortality risk in elderly female nursing home residents. Interventional studies are needed to assess the potential influence of MR blockade on “hard” clinical outcomes in individuals aged 70years and older. [Copyright &y& Elsevier]

Objectives: With the present analysis we intended to investigate the magnitude of the effect of relative aldosterone excess in predicting peripheral as well as aortic blood pressure levels in a well-characterized cohort of patients undergoing coronary angiography. Background: The discussion on the relationship between aldosterone concentration and blood pressure has recently gone beyond the role of primary aldosteronism in the genesis of arterial hypertension. Methods: Plasma aldosterone (pg/ml) and plasma renin concentration (pg/ml) were determined in 3,056 Caucasian patients (age 62.5 ± 11 years; 31.9% women) scheduled for coronary angiography in a single tertiary care center. We formed sex-specific deciles (D) according to plasma aldosterone/renin concentration ratio (ARR) (pg/ml/pg/ml). Results: Mean peripheral systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the entire cohort were 141 ± 24 mm Hg and 81 ± 11 mm Hg, respectively. Mean ARR was 10.2 ± 15.7 in men and 14.4 ± 19.9 in women (p < 0.0001). Median SBP and aortic SBP increased steadily and significantly from ARR D1 (126.8 mm Hg and 130.0 mm Hg, respectively) to D10 (151.0 mm Hg and 149.6 mm Hg, respectively; p < 0.0001 for both) after multivariate adjustment for age, sex, body mass index, renal function, antihypertensive medications, and various parameters potentially influencing BP. Adjusted median DBP and aortic DBP also increased significantly from 74.3 mm Hg and 66.5 mm Hg (D1) to 86.9 mm Hg and 76.7 mm Hg, respectively (D10) (p < 0.001 for both). In a multivariate stepwise regression model, ARR emerged as the second most significant independent predictor (after age) of mean SBP and as the most important predictor of mean DBP in this patient cohort. Conclusions: Our results: 1) underline that the ARR affects BP well below a cutoff used for screening for primary aldosteronism; and 2) illustrate the importance of the ARR in modulating BP over a much wider range than is currently appreciated. [Copyright &y& Elsevier]