Aldosterone and Metabolic Dysfunction

Pimenta, Eduardo; Calhoun, David A.

doi:10.1161/hypertensionaha.108.123406

Cited by 15 publications

(15 citation statements)

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“…24 The link between elevated plasma aldosterone levels and the metabolic syndrome and its single components, especially abdominal obesity, although rather extensively evaluated, is still controversial. [25][26][27] In spite of failing to reveal, as another study also did, 8 any correlation between PAC or ARR and spironolactone response, we demonstrated that a higher waist circumference was one of the predictors of a greater SBP reduction after spironolactone use, thus supporting the relationship between obesity and potential aldosterone excess.…”

Section: Discussioncontrasting

confidence: 53%

Efficacy of Spironolactone Therapy in Patients With True Resistant Hypertension

et al. 2010

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Abstract-The role of spironolactone in resistant hypertension management is unclear. The aim of this prospective trial was to evaluate the antihypertensive effect of spironolactone in patients with true resistant hypertension diagnosed by ambulatory blood pressure monitoring. A total of 175 patients had clinical and complementary exams obtained at baseline and received spironolactone in doses of 25 to 100 mg/d. A second ambulatory blood pressure monitoring was performed after a median interval of 7 months. Paired Student t test was used to assess differences in blood pressure before and during spironolactone administration, and multivariate analysis adjusted for age, sex, and number of antihypertensive drugs to assess the predictors of blood pressure fall. There were mean reductions of 16 and 9 mm Hg, respectively, in 24-hour systolic and diastolic blood pressures (95% CIs: 13 to 18 and 7 to 10 mm Hg; PϽ0.001). Office systolic blood pressure and diastolic blood pressure also decreased (14 and 7 mm Hg). Controlled ambulatory blood pressure was reached in 48% of patients. Factors associated with better response were higher waist circumference, lower aortic pulse wave velocity, and lower serum potassium. No association with plasma aldosterone or aldosterone:renin ratio was found. Adverse effects were observed in 13 patients (7.4%). A third ambulatory blood pressure monitoring performed in 78 patients after a median of 15 months confirmed the persistence of the spironolactone effect. In conclusion, spironolactone administration to true resistant hypertensive patients is safe and effective in decreasing blood pressure, especially in those with abdominal obesity and lower arterial stiffness. Its addition to an antihypertensive regimen as the fourth or fifth drug is recommended. (Hypertension. 2010;55:147-152.)Key Words: ambulatory blood pressure monitoring Ⅲ resistant hypertension Ⅲ spironolactone R esistant hypertension (RH) is a common clinical condition defined as the failure to control office blood pressure (BP) despite a treatment with Ն3 different classes of antihypertensive drugs in optimal dosages, ideally including a diuretic. 1 Previous surveys have shown prevalence ranges from 10% to Ϸ30%. 1 Although there is no consensus about the better therapeutic scheme for resistant hypertensive patients, in general, diuretics, angiotensin-blocking agents, calciumchannel blockers, and ␤-blockers are used as the first-line choices. However, there is a lack of evidence about the optimal choice of a fourth-or fifth-line antihypertensive drug, and in this context there has been increasing interest in the role of aldosterone antagonists, particularly spironolactone.The efficacy and safety of spironolactone in reducing BP were demonstrated Ͼ2 decades ago. 2 Over the past 15 years, after many reports had suggested that primary hyperaldosteronism is probably more common than it was regarded previously, 3,4 several studies have been dedicated to evaluate the spironolactone effect in patients with refractoriness to treatment, mo...

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Section: Discussioncontrasting

confidence: 53%

Efficacy of Spironolactone Therapy in Patients With True Resistant Hypertension

et al. 2010

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“…1 Indeed, aldosterone is not only linked to systemic inflammation, endothelial dysfunction, increased vascular stiffness, hypertension, and cardiac hypertrophy, but also to impaired pancreatic β cell function, skeletal muscle insulin sensitivity, liver deficiency, and increased release of proinflammatory cytokines from adipose tissue leading to impaired glucose tolerance and dyslipidemia. [1][2][3] The cause of the apparent hyperaldosteronism induced by obesity is, however, unknown. Neither angiotensin II (AngII), nor plasma potassium (K + ) or adrenocorticotropic hormone, the 3 main regulators of aldosterone secretion, 4 contribute to the inappropriately high aldosterone levels observed in obese patients.…”

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confidence: 99%

Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis

et al. 2015

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Background-In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase (CYP11B2) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms. Methods and Results-Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor α and β adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulinkinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2, in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers. Conclusions-Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting endothelial dysfunction and the expression of profibrotic markers in the heart.

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“…We appreciate the editorial comments by Pimenta and Calhoun 1 and the correspondence by Sechi et al 2 on our work. Attempts to clarify the discrepancies between available studies on the metabolic effects of hyperaldosteronism are welcome.…”

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confidence: 77%

Response to Metabolic Dysfunction in Primary Aldosteronism

Matrozova¹,

Steichen

Médecine³

et al. 2009

Hypertension

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We appreciate the editorial comments by Pimenta and Calhoun 1 and the correspondence by Sechi et al 2 on our work. Attempts to clarify the discrepancies between available studies on the metabolic effects of hyperaldosteronism are welcome. Indeed, our results challenge the prevailing hypothesis that primary aldosteronism (PA) is associated with clinically meaningful metabolic consequences. 3 Pimenta and Calhoun 1 appropriately point out several limitations that may threaten the validity of our study. On the other hand and in keeping with our data, Sechi et al 2 summarize evidence indicating similar levels of insulin resistance in PA and essential hypertension (EH).Pimenta and Calhoun 1 call attention to the retrospective nature of our study. However, it is unlikely to have biased our results, because we analyzed quantitative variables that were objectively and prospectively measured during routine clinical care with very few missing data. As with other studies on the metabolic effects of hyperaldosteronism, however, some issues arise regarding the definition of cases with PA and the choice of controls.In our institution, we waive suppression tests to confirm PA in patients with a high aldosterone:renin ratio and instead rely on high concentrations of plasma or urine aldosterone. The rationale of this approach has been discussed recently. 4 Despite guidelines advocacy, the diagnostic value of suppression tests is not well established, and the best studies only indicate moderate accuracy. 5 Moreover, our results were also negative in the large subgroup of patients with lateralized aldosterone hypersecretion, in whom the diagnosis of PA is well established.The only controls available for our study were patients with EH. Therefore, we cautiously concluded that there was no clinically apparent excess of metabolic disturbances in PA compared with EH. The lack of change in plasma glucose and serum lipids after adrenalectomy in patients with lateralized PA makes an additional point, although the follow-up interval was rather short (median time: 28 weeks).Taken with the evidence mentioned by Sechi et al, 2 our results argue against a clinically significant difference in insulin resistance between patients with PA and otherwise similar patients with EH. We agree that these findings do not definitely preclude metabolic effects of aldosterone. Such effects are still suggested by the different metabolic profile of patients with PA and of normotensive subjects and by some studies showing an association between higher levels of aldosterone and metabolic disturbances in patients with PA or in patients with EH. However, association is not causation, and it remains to be elucidated why large differences in aldosterone levels do not translate into metabolic differences between patients with PA and patients with EH. DisclosuresNone.

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Aldosterone and Metabolic Dysfunction

Cited by 15 publications

References 13 publications

Efficacy of Spironolactone Therapy in Patients With True Resistant Hypertension

Efficacy of Spironolactone Therapy in Patients With True Resistant Hypertension

Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis

Response to Metabolic Dysfunction in Primary Aldosteronism

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