Volume overload is a major characteristic in primary aldosteronism: a 3-year follow-up study.

OBJECTIVES: We examined haemodynamics, focusing on volume balance and forward and backward wave amplitudes, before and after 2.8 years of targeted treatment of primary aldosteronism. Patients with essential hypertension and normotensive individuals were examined for comparison ( n  = 40 in each group). METHODS: Recordings were performed using radial artery pulse wave analysis and whole-body impedance cardiography. Unilateral aldosteronism was treated with adrenalectomy ( n  = 20), bilateral aldosteronism with spironolactone-based medication ( n  = 20), and essential hypertension with standard antihypertensive agents. RESULTS: Aortic SBP and DBP, forward and backward wave amplitudes, and systemic vascular resistance were equally elevated in primary aldosteronism and essential hypertension. All these haemodynamic variables were similarly reduced by the treatments. Primary aldosteronism presented with 1 litre (∼10%) extracellular water excess ( P  < 0.001) versus the other groups, and this excess was normalized by treatment. Initial pulse wave velocity (PWV) was similarly increased in primary aldosteronism and essential hypertension, but final values remained higher in primary aldosteronism ( P  < 0.001). In regression analyses, significant explanatory factors for treatment-induced forward wave amplitude reduction were decreased systemic vascular resistance ( ß â€Š= 0.380) and reduced extracellular water volume ( ß â€Š= 0.183). Explanatory factors for backward wave amplitude reduction were changes in forward wave amplitude ( ß â€Š= 0.599), heart rate ( ß â€Š= -0.427), and PWV ( ß â€Š= 0.252). CONCLUSION: Compared with essential hypertension, the principal haemodynamic difference in primary aldosteronism was higher volume load. Volume excess elevated forward wave amplitude, which was subsequently reduced by targeted treatment of primary aldosteronism, along with normalization of volume load. We propose that incorporating extracellular water evaluation alongside routine diagnostics could enhance the identification and diagnosis of primary aldosteronism.

Pathophysiology of bilateral hyperaldosteronism.

PURPOSE OF REVIEW: Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary hypertension. In this review, we aimed to summarize recent findings regarding pathophysiology of bilateral forms of PA, including sporadic bilateral hyperaldosteronism (BHA) and rare familial hyperaldosteronism. RECENT FINDINGS: The presence of subcapsular aldosterone synthase (CYP11B2)-expressing aldosterone-producing micronodules, also called aldosterone-producing cell clusters, appears to be a common histologic feature of adrenals with sporadic BHA. Aldosterone-producing micronodules frequently harbor aldosterone-driver somatic mutations. Other potential factors leading to sporadic BHA include rare disease-predisposing germline variants, circulating angiotensin II type 1 receptor autoantibodies, and paracrine activation of aldosterone production by adrenal mast cells. The application of whole exome sequencing has also identified new genes that cause inherited familial forms of PA. SUMMARY: Research over the past 10 years has significantly improved our understanding of the molecular pathogenesis of bilateral PA. Based on the improved understanding of BHA, future studies should have the ability to develop more personalized treatment options and advanced diagnostic tools for patients with PA.

Adrenal venous sampling in the diagnostic workup of primary aldosteronism.

Primary aldosteronism (PA) is the primary cause of secondary hypertension. The prevalence of PA has probably been underestimated in the past and recent studies suggest that PA could be present in up to 10% of patients suffering from hypertension. Aldosterone excess in PA can be caused by unilateral adrenal disease, usually adrenal adenoma, or bilateral adrenal hyperplasia. Differentiation between unilateral and bilateral disease is clinically important as the former can effectively be treated by removal of the affected adrenal. CT or MRI cannot reliably distinguish unilateral from bilateral disease. Therefore, adrenal vein sampling (AVS) is an important step of the diagnostic work-up in patients with PA. Current guidelines recommend PA in virtually all patients with biochemically diagnosed PA who would undergo adrenal surgery if unilateral PA was diagnosed. In this narrative review, we give an overview of the current technique used for AVS with a focus on the experience with this technique at the University Hospital Basel, Switzerland.

Alteration of Gut Microbiota Relates to Metabolic Disorders in Primary Aldosteronism Patients.

Purpose: This study aimed to determine the relationships among gut microbiota, primary aldosteronism (PA), and related metabolic disorders. Methods: The study enrolled 13 PA patients, 26 sex-matched primary hypertension patients, and 26 sex-matched healthy controls. Demographic and clinical characteristics such as age, body mass index (BMI), blood aldosterone-renin ratio, blood potassium, blood glucose, blood lipid parameters, and history of diabetes mellitus (DM) were compared between the three groups. The gut microbiota of each participant was examined by 16S rRNA gene sequencing. Spearman correlation analysis was performed to demonstrate the relationship between gut microbiota and clinical characteristics. Results: BMI and the percentage of DM in PA patients were higher than those in healthy controls (p < 0.05), but not higher than those in primary hypertension patients (p > 0.05). The gut microbiota of healthy controls and primary hypertension patients had a higher alpha diversity level than that of PA patients. PA patients had fewer short-chain fatty acid (SCFA)-producing genera (Prevotella, Blautia, Coprococcus, Anaerostipes, and Ruminococcus) and more inflammation-associated genera (Megamonas, Sutterella, and Streptococcus) than healthy controls (p < 0.05). The gut microbiota of PA patients was more inclined to encode microbial pathways involved in sugar metabolism, such as starch and sucrose metabolism and fructose and mannose metabolism. Blood potassium was negatively correlated with the relative abundance of Romboutsia (R = -0.364, q = 0.023). Diastolic blood pressure (DBP) was positively correlated with Romboutsia (R = 0.386, q = 0.015). Systolic blood pressure (SBP) was negatively correlated with Blautia (R = -0.349, q = 0.030). Conclusions: The alteration of gut microbiota in PA patients, especially bacteria and pathways involved in inflammation, SCFAs, and sugar metabolism, may be associated with chronic metabolic disorders.

Re-evaluating absent clinical success after adrenalectomy in unilateral primary aldosteronism.

BACKGROUND: Adrenalectomy cures unilateral primary aldosteronism, and it improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success postsurgery, suggesting that surgery was ineffective. METHODS: We assessed all patients 6 to 12 months post-surgery for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2, and CONNsortium criteria. We estimated blood pressure changes after adjustment for changes in defined daily dosages of antihypertensive medications. We also reassessed all patients using PASO at their recent clinical visit. RESULTS: A total of 104 patients with unilateral primary aldosteronism underwent adrenalectomy at 2 tertiary centers from 2000 to 2019; 24 (23%), 31 (30%), and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2, and CONNsortium criteria, respectively. Among 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariable analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus, and lower defined daily dosages at baseline. After adjustment for changes in defined daily dosages, 7 of 24 patients showed blood pressure improvement ≥20/10 mm Hg post-surgery. After a follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show clinical improvement post-surgery using any of the 3 mentioned criteria or using PASO criteria at their recent clinical visit. CONCLUSION: Although some patients may be classified with absent clinical success post-surgery, the assessment of clinical outcomes remains subject to many variables. In patients with unilateral primary aldosteronism, evidenced by lateralization on AVS, unilateral adrenalectomy should remain the recommended treatment.

CMR-Verified Myocardial Fibrosis Is Associated With Subclinical Diastolic Dysfunction in Primary Aldosteronism Patients.

Objectives: The main cardiac features of primary aldosteronism (PA) are impaired left ventricular (LV) diastolic function, and some articles also reported more cardiac fibrosis in PA patients. However, the correlation between LV dysfunction and diffuse myocardial fibrosis in PA remains unknown. Methods: We enrolled 84 PA patients and 28 essential hypertension (EH) patients in West China Hospital. Cardiac magnetic resonance imaging (CMR) contrast enhancement was arranged for all subjects. Postcontrast T1 time and left ventricular myocardial strains and strain rates were measured. Results: 76 PA patients and 27 essential hypertension (EH) patients were included in the final analysis. Blood pressure, LV mass indexes, and LV ejection fractions were comparable in both groups, while the global circumferential peak diastolic strain rate (PDSR) was lower (0.9 ± 0.3 vs. 1.1 ± 0.4, p <0.01) and the postcontrast T1 time was shorter (520 ± 38 vs. 538 ± 27, p = 0.01) in PA patients than those in EH patients. Postcontrast T1 time (p = 0.01) was independently related to global circumferential PDSR after adjusting for age and duration of hypertension in PA patients. Furthermore, plasma aldosterone concentration was negatively associated with postcontrast T1 time (R = -0.253, p = 0.028) in PA patients. Conclusions: The global circumferential PDSR derived by CMR is decreased, and the diffuse myocardial fibrosis is increased in PA patients compared to those in blood pressure matched EH patients. The severity of cardiac diastolic dysfunction independently relates to the degree of diffuse myocardial fibrosis in PA patients, and the diffuse myocardial fibrosis may be caused by high PAC level. Clinical Trial Registration: http://www.chictr.org.cn/listbycreater.asp, identifier ChiCTR2000031792.

Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+ ).

Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel CaV3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1hM1560V/+ knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h-/- ). Adrenal morphology of both Cacna1hM1560V/+ and Cacna1h-/- mice was normal. Cacna1hM1560V/+ mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal Cyp11b2 (aldosterone synthase) expression was increased and remained elevated on a high-salt diet (relative autonomy, characteristic of primary aldosteronism), but plasma aldosterone was only elevated in male animals. The systolic blood pressure of Cacna1hM1560V/+ mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. Cacna1h-/- mice had elevated renal Ren1 (renin-1) expression but normal adrenal Cyp11b2 levels, suggesting that in the absence of CaV3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1hM1560V/+ adrenal slices showed increased baseline and peak intracellular calcium concentrations in the zona glomerulosa compared to controls, but the frequency of calcium spikes did not rise. We conclude that FH-IV, on a molecular level, is caused by elevated intracellular Ca2+ concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline Cacna1h gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of CaV3.2 channel function can be compensated for in a chronic setting.

Comparison of biomarkers of endothelial dysfunction and microvascular endothelial function in patients with primary aldosteronism and essential hypertension.

INTRODUCTION: Studies have shown that primary aldosteronism (PA) has a higher risk of cardiovascular events than essential hypertension (EH). Endothelial dysfunction is an independent predictor of cardiovascular events. Whether PA and EH differ in the endothelial dysfunction is uncertain. Our study was designed to investigate the levels of biomarkers of endothelial dysfunction (Asymmetric dimethylarginine, ADMA; E-selectin, and Plasminogen activator inhibitor-1, PAI-1) and assess the microvascular endothelial function in patients with PA and EH, respectively. METHODS: The biomarkers of endothelial dysfunction were measured by enzyme-linked immunosorbent assay (ELISA). Microvascular endothelial function was evaluated by Pulse amplitude tonometry (PAT). RESULTS: Thirty-one subjects with EH and 36 subjects with PA including 22 with aldosterone-producing adenoma (APA) and 14 with idiopathic hyperaldosteronism (IHA) were enrolled in our study. The ADMA levels among the three groups were different (APA 47.83 (27.50, 87.74) ng/ml vs EH 25.08 (22.44, 39.79) ng/ml vs IHA 26.00 (22.23, 33.75) ng/ml; p = 0.04), however, when the APA group was compared with EH and IHA group, there was no statistical significance (47.83 (27.50, 87.74) ng/ml vs 25.08 (22.44, 39.79) ng/ml for EH, p = 0.11; 47.83 (27.50, 87.74) ng/ml vs IHA 26.00 (33.75) ng/ml, p = 0.07). The results of ADMA levels are presented as Median (p25, p75). Whereas, levels of PAI-1 and E-selectin, microvascular endothelial function were not significantly different between PA and EH subjects. CONCLUSIONS: Our study shows no significant differences between PA and EH in terms of biomarkers of endothelial dysfunction and microvascular endothelial function. The microvascular endothelial function of PA and EH patients is comparable.

Volumetric evaluation of CT images of adrenal glands in primary aldosteronism.

OBJECTIVES: To investigate whether adrenal volumetry provides better agreement with adrenal vein sampling (AVS) than conventional CT for subtyping PA. Furthermore, we evaluated whether the size of this contralateral adrenal was a prognostic factor for clinical outcome after unilateral adrenalectomy. METHODS: We retrospectively analyzed volumes of both adrenal glands of the 180 CT-scans (88/180 with unilateral and 92/180 with bilateral disease) of the patients with PA included in the SPARTACUS trial of which 85 also had undergone an AVS. In addition, we examined CT-scans of 20 healthy individuals to compare adrenal volumes with published normal values. RESULTS: Adrenal volume was higher for the left than the right adrenal (mean and SD: 6.49 ± 2.77 ml versus 5.25 ± 1.87 ml for the right adrenal; p < 0.001). Concordance between volumetry and AVS in subtyping was 58.8%, versus 51.8% between conventional CT results and AVS (p = NS). The volumes of the contralateral adrenals in the patients with unilateral disease (right 4.78 ± 1.37 ml; left 6.00 ± 2.73 ml) were higher than those of healthy controls reported in the literature (right 3.62 ± 1.23 ml p < 0.001; left 4.84 ± 1.67 ml p = 0.02). In a multivariable analysis the contralateral volume was not associated with biochemical or clinical success, nor with the defined daily doses of antihypertensive agents at 1 year follow-up. CONCLUSIONS: Volumetry of the adrenal glands is not superior to current assessment of adrenal size by CT for subtyping patients with PA. Furthermore, in patients with unilateral disease the size of the contralateral adrenal is enlarged but its size is not associated with outcome.

Altered Taste Perception for Sodium Chloride in Patients With Primary Aldosteronism: A Prospective Cohort Study.

[Figure: see text].

Normotensive presentation in primary aldosteronism: A report of two cases.

Normotensive patients with primary aldosteronism (PA) are relatively rare. Herein, we report two patients with normotensive PA and present a literature review to improve an understanding of the disease. Patient 1, a 56-year-old man, presented with recurrent hypokalemia that lasted for more than 2 years. Patient 2 was a 33-year-old man who presented with sexual dysfunction and was diagnosed with a prolactinoma combined with adrenal insufficiency and hypogonadism. Neither of these patients had hypertension that was detectable on repeated manual measurements. In both patients, a typical biological profile of PA was demonstrated that included hypokalemia with kaliuresis, elevated plasma aldosterone concentration (PAC), suppressed plasma renin concentration, and a high aldosterone-to-renin ratio. Both patients did not have sufficiently suppressed PAC on the saline infusion test, confirming the diagnosis of PA. Computed tomography of the adrenal gland and adrenal venous sampling suggested an aldosteronoma, which was confirmed by lateralized hypersecretion of aldosterone. After removal of the benign adenoma, the biochemical abnormalities were corrected. As hypertension is not necessarily a sign of PA, we propose that all patients with hypokalemia should be screened for PA in order to prevent cardiovascular complications while balancing economics and effectiveness.

Familial hyperaldosteronism type 1 and pregnancy: successful treatment with low dose dexamethasone.

PURPOSE: Familial hyperaldosteronism type 1 (FH-1) is an autosomal dominant form of primary aldosteronism (PA), featuring a marked phenotypic heterogeneity, ranging from mild forms of PA and arterial hypertension (HT) to severe forms complicated by stroke at a young age. Affected patients usually reach the fertile age; hence, transmission of the disease to offspring is common. Notwithstanding this, only anecdotal reports of FH-1 in pregnancy exist and recommendations for treatment remain vague. MATERIALS AND METHODS AND RESULTS: We herein report on a novel FH-1 pedigree featuring very severe HT, fatal aortic dissection, and high rate of early stroke, where a young FH-1 woman was successfully managed throughout pregnancy with low-dose dexamethasone. CONCLUSIONS: Based on this experience and on available information on pathophysiology of FH-1 in pregnancy, the pros and cons of dexamethasone administration in the treatment of FH-1 in pregnancy are also discussed.

Quadriplegia and rhabdomyolysis as a presenting feature of Conn's syndrome.

Conn's syndrome is an important endocrine cause for secondary hypertension. Hypokalaemia paralysis and rhabdomyolysis with accelerated hypertension may be the presenting symptoms of Conn's syndrome. Here, we present one such case of a 38-year-old woman presenting with accelerated hypertension and acute onset quadriplegia. On biochemical evaluation, she was found to have severe hypokalaemia, metabolic alkalosis and elevated creatinine phosphokinase. Further evaluation revealed an elevated aldosterone renin ratio suggestive of primary hyperaldosteronism which was localised to left adrenal adenoma on contrast-enhanced CT. Patient's blood pressure and serum potassium levels normalised after resection of the adrenal adenoma.