Reducing long-term use of benzodiazepine receptor agonists: In-depth interview study with primary care stakeholders.

AIMS: To increase our understanding of which factors contribute to long-term benzodiazepine receptor agonist (BZRA) use for insomnia in primary care, from a patients', general practitioners' (GP) and pharmacists' perspective. DESIGN: Qualitative research following a grounded theory approach. SETTING: Primary care in Belgium. PARTICIPANTS: Twenty-four participants were interviewed, including nine patients, six GPs and nine pharmacists. MEASUREMENTS: In-depth, semistructured interviews with iterative cycles of data collection and analysis. Transcripts were analysed using the framework method. Thematic findings were interpreted in the context of the Theoretical Domains Framework. FINDINGS: A reflexive relation was identified between views about hypnotic use at the level of society, healthcare and patients. Behaviour change appeared to depend strongly on context and social influence, including a need for supporting relationships by all stakeholders. Six key messages captured factors that contribute to long-term BZRA use for insomnia in primary care: societal beliefs as a game changer, the opportunity of nonpharmacological treatment, collaborative primary care, patient-centred goals, informed consent and self-management. CONCLUSIONS: Long-term BZRA use for insomnia is a complex and multifaceted public health problem that is not adequately addressed in primary care at this time. Although primary care professionals in this study found discontinuation of long-term BZRA use relevant to the patient's health, many organisational and personal barriers were reported. Moreover, the current social and healthcare context is not empowering patients and professionals to reduce long-term BZRA use for insomnia. Specifically, for primary care, all stakeholders reported the need for a nonmedicalised relationship between the patient and GP to lower prescribing rates. PATIENT OR PUBLIC CONTRIBUTION: The Flemish Patient Platform, a patient representative organisation, assisted with recruitment by launching a call for participants in their newsletter and volunteered to disseminate the results. The call for recruitment was also published online in social media groups regarding insomnia and via posters in public pharmacies. Patients or public were not involved in designing or conducting the interview study.

Aldosterone-producing adenoma associated with non-suppressed renin: a case series.

Although the aldosterone/renin ratio (ARR) is the preferred screening test for primary aldosteronism (PA), patients with non-suppressed renin and a falsely negative ARR on non-interfering medications have occasionally been reported. This report describes the clinical characteristics and outcomes of seven patients with proven aldosterone-producing adenoma (APA) and non-suppressed renin.Chart review of seven PA patients with an APA and a non-suppressed plasma renin concentration (PRC > 8.4 mU/L) was undertaken to collect data on anthropometric and biochemical characteristics, diagnostic evaluation and postsurgical outcomes.Seven patients (two women and five men) with a proven APA had median (range) PRC, plasma aldosterone and ARR of 20 (9-43) mU/L, 750 (270-1940) pmol/L and 45 (8-62, normal <70), respectively, on non-interfering medications. Six patients had two consecutive ARR measurements and in five of them both were normal. Renal artery stenosis was carefully excluded in all patients. Further evaluation for PA was pursued because of high clinical suspicion (either hypokalaemia and/or a known adrenal mass lesion on imaging). All underwent adrenal vein sampling confirming unilateral PA which was managed by unilateral adrenalectomy. Postsurgical follow-up data either confirmed or were highly suggestive of cure of PA.Strict control of factors known to influence the ARR is crucial to avoid false-negative results. Other causes that could explain a non-suppressed renin should be excluded. In patients with a consistently non-suppressed renin further diagnostic workup for PA should be considered if clinical suspicion remains high.

Computed Tomography and Adrenal Venous Sampling in the Diagnosis of Unilateral Primary Aldosteronism.

Unilateral primary aldosteronism is the most common surgically correctable form of endocrine hypertension and is usually differentiated from bilateral forms by adrenal venous sampling (AVS) or computed tomography (CT). Our objective was to compare clinical and biochemical postsurgical outcomes of patients with unilateral primary aldosteronism diagnosed by CT or AVS and identify predictors of surgical outcomes. Patient data were obtained from 18 internationally distributed centers and retrospectively analyzed for clinical and biochemical outcomes of adrenalectomy of patients with surgical management based on CT (n=235 patients, diagnosed from 1994-2016) or AVS (526 patients, diagnosed from 1994-2015) using the standardized PASO (Primary Aldosteronism Surgical Outcome) criteria. Biochemical outcomes were highly different according to surgical management approach with a smaller proportion in the CT group achieving complete biochemical success (188 of 235 [80%] patients versus 491 of 526 [93%], P<0.001) and a greater proportion with absent biochemical success (29 of 235 [12%] versus 10 of 526 [2%], P<0.001). A diagnosis by CT was associated with a decreased likelihood of complete biochemical success compared with AVS (odds ratio, 0.28; 0.16-0.50; P<0.001). Clinical outcomes were not significantly different, but the absence of a postsurgical elevated aldosterone-to-renin ratio was a strong marker of complete clinical success (odds ratio, 14.81; 1.76-124.53; P=0.013) in the CT but not in the AVS group. In conclusion, patients diagnosed by CT have a decreased likelihood of achieving complete biochemical success compared with a diagnosis by AVS.

Test characteristics of the aldosterone-to-renin ratio as a screening test for primary aldosteronism.

BACKGROUND: The aldosterone-to-renin ratio (ARR) is a widely used screening test for primary aldosteronism. Current guidelines recommend a cut-off value of 91  pmol/mU. Studies on its sensitivity, specificity, reproducibility and the role of medication have been conflicting. We prospectively assessed the test characteristics of the ARR and the effect of combination antihypertensive treatment. METHODS: In 178 patients with persistent hypertension despite the use of at least two antihypertensives, plasma renin and aldosterone were assessed twice within an interval of 4 weeks. All patients underwent an intravenous salt loading test. A posttest plasma aldosterone exceeding 235  pmol/l was considered diagnostic for primary aldosteronism. ARR was repeated after 4 weeks of standardized treatment with a calcium channel blocker and/or α-adrenergic-receptor blocker. RESULTS: The prevalence of primary aldosteronism was 15.2%. The median ARR was 35.0 (interquartile range 16.2-82.0) in primary aldosteronism versus 7.1 (2.2-17.5) pmol/mU in essential hypertensive patients (P < 0.001). Under random medication, the ARR had 22.2% sensitivity and 98.7% specificity. On standardized treatment, the ARR rose from 9.6 (2.5-24.8) to 21.4 (10.8-52.1) (P < 0.001). Multivariate regression showed that angiotensin-converting enzyme (ACE)-inhibitors and angiotensin II-receptor blockers were responsible for the lower ARR during random treatment. The area under the receiver operating characteristic curve was, however, similar under random and standardized treatment (84 vs. 86%, respectively, P = 0.314). Bland-Altman plots showed an almost five-fold difference in ARR values taken under the same conditions. CONCLUSION: ARR sensitivity for primary aldosteronism is low when the recommended cut-off is used. Reproducibility is also poor, stressing the need for alternative screening tests.

Determinants of blood pressure reduction by eplerenone in uncontrolled hypertension.

BACKGROUND: Add-on therapy with aldosterone receptor antagonists has been reported to lower blood pressure (BP) in patients with uncontrolled hypertension. We assessed potential predictors of this response. METHODS: In essential hypertensive patients with uncontrolled BP, despite the use of at least two antihypertensives, plasma renin and aldosterone concentrations and the transtubular potassium gradient (TTKG) were measured. Patients were treated with eplerenone 50 mg daily on top of their own medication. The office and ambulatory BP response and biochemical changes were evaluated after 1 week and 3 months of treatment and 6 weeks after discontinuation. Potential predictors for the change in 24-h ambulatory BP were tested in a multivariate regression model. RESULTS: One hundred and seventeen patients with a mean age of 50.5 ± 6.6 years were included. Office BP decreased from 149/91 to 142/87 mmHg (P < 0.001) and ambulatory BP from 141/87 to 132/83 mmHg after 3 months of treatment (P < 0.001). Six weeks after discontinuation of eplerenone, office and ambulatory BP measurements returned to baseline values. Treatment resulted in a small rise in serum potassium and creatinine, and a small decrease in the TTKG. In a multivariate model, neither renin, aldosterone, or their ratio, nor the TTKG predicted the BP response. Only baseline ambulatory SBP predicted the BP response, whereas the presence of left ventricular hypertrophy was associated with a smaller BP reduction. CONCLUSION: Add-on therapy with eplerenone effectively lowers BP in patients with difficult-to-treat primary hypertension. This effect is unrelated to circulating renin-angiotensin-aldosterone system activity and renal mineralocorticoid receptor activity as assessed by the TTKG.

The phosphorylated sodium chloride cotransporter in urinary exosomes is superior to prostasin as a marker for aldosteronism.

Urinary exosomes are vesicles derived from renal tubular epithelial cells. Exosomes often contain several disease-associated proteins and are thus useful targets for identifying biomarkers of disease. Here, we hypothesized that the phosphorylated (active) form of the sodium chloride cotransporter (pNCC) or prostasin could serve as biomarkers for aldosteronism. We tested this in 2 animal models of aldosteronism (aldosterone infusion or low-sodium diet) and in patients with primary aldosteronism. Urinary exosomes were isolated from 24-hour urine or spot urine using ultracentrifugation. In rats, a normal or a high dose of aldosterone for 2, 3, or 8 days increased pNCC 3-fold in urinary exosomes (P<0.05 for all). A low-sodium diet also increased pNCC in urinary exosomes approximately 1.5-fold after 4 and after 8 days of treatment. The effects of these maneuvers on prostasin in urinary exosomes were less clear, showing a significant 1.5-fold increase only after 2 and 3 days of high-aldosterone infusion. In urinary exosomes of patients with primary aldosteronism, pNCC was 2.6-fold higher (P<0.05) while prostasin was 1.5-fold higher (P=0.07) than in patients with essential hypertension. Urinary exosomal pNCC and, to a lesser extent, prostasin are promising markers for aldosteronism in experimental animals and patients. These markers may be used to assess the biological activity of aldosterone and, potentially, as clinical biomarkers for primary aldosteronism.

Renin and prorenin have no direct effect on aldosterone synthesis in the human adrenocortical cell lines H295R and HAC15.

INTRODUCTION: Transgenic rats expressing the human (pro)renin receptor (h(P)RR) have elevated plasma aldosterone levels despite unaltered levels, in plasma and adrenal, of renin and angiotensin II. MATERIALS AND METHODS: To investigate whether renin/prorenin-(P)RR interaction underlies these elevated aldosterone levels, the effect of (pro)renin on steroidogenesis was compared with that of angiotensin II in two (P)RR-expressing human adrenocortical cell lines, H295R and HAC15. Angiotensin II rapidly induced extracellular signal-regulated kinase (ERK) phosphorylation and increased the expression of STAR, CYP21A2, CYP11B2, and CYP17A1 at 6 and 24 hours, whereas the expression of CYP11A1 and HSD3B2 remained unaltered. Incubation with renin or prorenin at nanomolar concentrations had no effect on the expression of any of the steroidogenic enzymes tested, nor resulted in ERK phosphorylation. Angiotensin II, but not renin or prorenin, induced aldosterone production. CONCLUSION: Although the (P)RR is present in adrenocortical cells, renin and prorenin do not elicit ERK phosphorylation nor directly affect steroid production via this receptor at nanomolar concentrations. Thus, direct (pro)renin-(P)RR interaction is unlikely to contribute to the elevated aldosterone levels in human (P)RR transgenic rats. This conclusion also implies that the aldosterone rise that often occurs during prolonged renin-angiotensin system blockade is rather due to the angiotensin II 'escape' during such blockade.

Angiotensin II-aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase.

AIMS: The aim of this study was to investigate the aldosterone-angiotensin (Ang) II interaction in human coronary microarteries (HCMAs). METHODS AND RESULTS: HCMAs, obtained from 75 heart-beating organ donors, were mounted in myographs and exposed to Ang II, either directly or following a 30-min pre-incubation with aldosterone, 17ß-oestradiol, hydrocortisone, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the extracellular regulated kinase 1/2 (ERK1/2) inhibitor PD98059, the GPR30 antagonist G15, or the epidermal growth factor receptor (EGFR) antagonist AG1478. Ang II constricted HCMAs in a concentration-dependent manner. All steroids, at nanomolar levels, potentiated Ang II and G15 prevented this effect. The potentiation disappeared or was reversed into Ang II antagonism at micromolar steroid levels. NO synthase (NOS) inhibition prevented the latter antagonism in the case of 17ß-oestradiol, whereas both aldosterone and 17ß-oestradiol at micro- (but not nano-) molar levels induced endothelial NOS phosphorylation in human umbilical vein endothelial cells. AG1478, but not SB203580 or PD98059, abolished the Ang II-induced contraction in the presence of aldosterone or 17ß-oestradiol, and none of these drugs affected Ang II alone. CONCLUSION: Steroids including aldosterone affect Ang II-induced vasoconstriction in a biphasic manner. Potentiation occurs at nanomolar steroid levels and depends on GPR30 and EGFR transactivation. At micromolar steroid levels, this potentiation either disappears (aldosterone and hydrocortisone) or is reversed into an inhibition (17ß-oestradiol), and this is due to the endothelial NOS activation that occurs at such concentrations.

Long-term use of aldosterone-receptor antagonists in uncontrolled hypertension: a retrospective analysis.

Background. The long-term efficacy of aldosterone-receptor antagonists (ARAs) as add-on treatment in uncontrolled hypertension has not yet been reported. Methods. Data from 123 patients (21 with primary aldosteronism, 102 with essential hypertension) with difficult-to-treat hypertension who received an ARA between May 2005 and September 2009 were analyzed retrospectively for their blood pressure (BP) and biochemical response at first followup after start with ARA and the last follow-up available. Results. Systolic BP decreased by 22 ± 20 and diastolic BP by 9.4 ± 12 mmHg after a median treatment duration of 25 months. In patients that received treatment >5 years, SBP was 33 ± 20 and DBP was 16 ± 13 mmHg lower than at baseline. Multivariate analysis revealed that baseline BP and follow-up duration were positively correlated with BP response. Conclusion. Add-on ARA treatment in difficult-to-treat hypertension results in a profound and sustained BP reduction.

Drug mechanisms to help in managing resistant hypertension in obesity.

Obesity is a major risk factor for the development of hypertension. Because the prevalence of obesity is increasing worldwide, the prevalence of obesity hypertension is also increasing. Importantly, hypertension in obesity is commonly complicated by dyslipidemia and type 2 diabetes mellitus and hence imposes a high cardiovascular disease risk. Furthermore, obesity is strongly associated with resistant hypertension. Activation of the sympathetic nervous system and the renin-angiotensin system, leading to renal sodium and water retention, links obesity with hypertension. There is also evidence for the release of factors by visceral adipose tissue promoting excessive aldosterone production, and a more central role of aldosterone in obesity hypertension is emerging. Randomized studies evaluating the effect of different classes of antihypertensive agents in obesity hypertension are scarce, short-lasting, and small. Considering the emerging role of aldosterone in the pathogenesis of obesity hypertension, mineralocorticoid receptor antagonism may play a more central role in the pharmacologic treatment of obesity hypertension in the near future.

Steroidogenesis vs. steroid uptake in the heart: do corticosteroids mediate effects via cardiac mineralocorticoid receptors?

OBJECTIVE: To test whether glucocorticoids act as the endogenous agonist of cardiac mineralocorticoid receptors, we evaluated the cardiac effects of aldosterone and corticosterone and cardiac steroidogenesis vs. steroid uptake from plasma. METHODS AND RESULTS: Both corticosterone and aldosterone increased left ventricular pressure in the rat heart. Aldosterone decreased coronary flow, whereas corticosterone increased it. All corticosterone effects were blocked by the glucocorticoid receptor antagonist, RU486, and unaltered by the mineralocorticoid receptor antagonist, canrenoate, or the 11beta-hydroxysteroid dehydrogenase (HSD11B)2 inhibitor, carbenoxolone. Unlike mineralocorticoid receptor blockade, RU486 did not ameliorate postischemia infarct size and arrhythmias. Corticosterone, when added to the perfusion buffer, rapidly accumulated at cardiac tissue sites, reaching steady-state levels that were identical to those in coronary effluent, independently of the presence of aldosterone, RU486 or canrenoate. After stopping the perfusion, cardiac corticosterone fully washed away with a half-life of less than 1 min. Measurements of steroid-synthesizing enzyme gene expression levels in human ventricular and atrial tissue pieces from heart-beating organ donors, patients with end-stage heart failure and hypertrophic cardiomyopathy patients revealed that under no condition, the human heart was capable of synthesizing aldosterone or cortisol de novo. Yet, expression of HSD11B1, HSD11B2, mineralocorticoid receptors and glucocorticoid receptors was found, and HSD11B2 and mineralocorticoid receptors were upregulated in pathological conditions. Moreover, aldosterone reduced cardiac inotropy in a Na/K/2Cl cotransporter-dependent manner. CONCLUSION: Both cortisol/corticosterone and aldosterone accumulate in the cardiac interstitium. The presence of HSD11B2 and mineralocorticoid receptors/glucocorticoid receptors at cardiac tissue sites allows both steroids to exert their effects via separate mechanisms.

Aldosterone-receptor antagonism in hypertension.

The role of the renin-angiotensin-aldosterone system (RAAS) in hypertension has since long been recognized and aldosterone has been acknowledged as one of the key hormones in the pathophysiology, not only in primary aldosteronism but also in essential hypertension and drug-resistant hypertension. Aldosterone-receptor antagonists (ARAs) are increasingly used in patients with resistant hypertension, often with impressive results. However, definitive evidence for the benefit of ARAs in these patients from randomized, controlled trials is lacking. This review gives an overview of the current data on this topic. Future studies should focus on the identification of factors that are able to predict the response to treatment, as to select patients who will benefit most from treatment with ARAs. On the basis of the current knowledge, we recommend prescription of ARAs to patients with primary aldosteronism, resistant hypertension and patients with hypertension and hypokalemia.

Aldosterone synthase inhibitors: pharmacological and clinical aspects.

Aldosterone plays an important pathophysiological role in cardiovascular disease, and aldosterone (mineralocorticoid) receptor antagonism has been used in the treatment of heart failure and hypertension. However, aldosterone receptor antagonism is associated with an increase in plasma aldosterone levels, which may result in non-mineralocorticoid receptor-mediated (non-genomic) adverse effects. Therefore, the inhibition of aldosterone synthesis may be preferable to blockade at the receptor level. Direct inhibitors of aldosterone synthase are currently under development. However, specificity for aldosterone synthase remains a challenge, and the search for more potent and more selective compounds is ongoing. Experimental animal and human studies are required to establish whether aldosterone synthase inhibitors will be successful as therapeutic agents.