The Role of Aldosteronism in Causing Obesity-Related Cardiovascular Risk

Calhoun, David A.; Sharma, Kumar

doi:10.1016/j.ccl.2010.04.001

Cited by 62 publications

(67 citation statements)

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“…Indeed, data from the Framingham Heart Study suggest that about 78% of the risk for hypertension in men and approximately 65% in women can be directly related to excess body weight (Calhoun & Sharma 2010). This relationship has been further supported by experimental studies showing an increase in blood pressure after weight gain, as well as the therapeutic value of weight loss in reducing blood pressure (Kawarazaki & Fujita 2016).…”

Section: :1mentioning

confidence: 92%

“…Additional data from the Framingham Offspring Study indicate that high levels of plasma aldosterone, albeit in the normal range, predict the development of hypertension (Garrison et al 1987). In addition to hypertension, aldosterone is thought to mediate various other processes that contribute to cardiorenal disease, such as cardiac fibrosis, proteinuria and endothelial dysfunction, through its interaction with and activation of MR (Calhoun & Sharma 2010). On the other hand, the glucocorticoid cortisol, perhaps acting through the MR, has also been proposed to contribute to obesity-associated hypertension (Varughese et al 2014).…”

Section: :1mentioning

confidence: 99%

“…On the other hand, accumulating evidence suggests a potential link between obesity-related hypertension and the 230:1 mineralocorticoid aldosterone (Briet & Schiffrin 2011), a steroid hormone involved in maintaining fluid and electrolyte balance in the human body. Thus, aldosterone levels are elevated in obesity, and weight loss in obese individuals is accompanied by reductions in both blood pressure and aldosterone levels (Calhoun & Sharma 2010, Briet & Schiffrin 2011. Furthermore, in several studies, aldosterone levels have been correlated with body mass index, waist circumference and/or visceral adiposity (Calhoun & Sharma 2010).…”

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confidence: 99%

“…Thus, aldosterone levels are elevated in obesity, and weight loss in obese individuals is accompanied by reductions in both blood pressure and aldosterone levels (Calhoun & Sharma 2010, Briet & Schiffrin 2011. Furthermore, in several studies, aldosterone levels have been correlated with body mass index, waist circumference and/or visceral adiposity (Calhoun & Sharma 2010). Based on this link between obesity and aldosterone levels, it has been proposed that adipose tissue produces a factor or factors that can stimulate aldosterone secretion from the adrenal gland independently of the traditional aldosterone secretagogues, angiotensin II (AngII), elevated serum potassium levels and adrenocorticotrophic hormone (ACTH).…”

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Obesity, hypertension and aldosterone: is leptin the link?

Xie

Bollag

2016

Journal of Endocrinology

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Obesity is a serious health hazard with rapidly increasing prevalence in the United States. In 2014, the World Health Organization estimated that nearly 2 billion people worldwide were overweight with an estimated 600 million of these obese. Obesity is associated with many chronic diseases, including cardiovascular disease and hypertension. Data from the Framingham Heart study suggest that approximately 78% of the risk for hypertension in men and 65% in women is related to excess body weight, a relationship that is further supported by studies showing increases in blood pressure with weight gain and decreases with weight loss. However, the exact mechanism by which excess body fat induces hypertension remains poorly understood. Several clinical studies have demonstrated elevated plasma aldosterone levels in obese individuals, especially those with visceral adiposity, with decreased aldosterone levels measured in concert with reduced blood pressure following weight loss. Since aldosterone is a mineralocorticoid hormone that regulates blood volume and pressure, serum aldosterone levels may link obesity and hypertension. Nevertheless, the mechanism by which obesity induces aldosterone production is unclear. A recent study by Belin de Chantemele and coworkers suggests that one adipose-released factor, leptin, is a direct agonist for aldosterone secretion; other adipose-related factors may also contribute to elevated aldosterone levels in obesity, such as very low-density lipoprotein (VLDL), the levels of which are elevated in obesity and which also directly stimulates aldosterone biosynthesis. This focused review explores the possible roles of leptin and VLDL in modulating aldosterone secretion to underlie obesity-associated hypertension.

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confidence: 92%

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confidence: 99%

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Obesity, hypertension and aldosterone: is leptin the link?

Xie

Bollag

2016

Journal of Endocrinology

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“…Aldosterone, the mineralocorticoid hormone synthesized by the zona glomerulosa cells of the adrenal cortex, is produced in excess in obesity and has been reported to be a major contributor to both cardiovascular and metabolic dysfunctions associated with obesity. 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.…”

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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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Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension

Laffin,

Rodman,

Luther

et al. 2023

JAMA

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ImportanceExcess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure.ObjectiveTo compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials.Design, Setting, and ParticipantsRandomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h.InterventionsParticipants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.Main Outcomes and MeasuresThe primary end point was change in automated office systolic blood pressure from baseline to study week 8.ResultsBetween July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of −14.1, −13.2, −6.9, and −4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was −9.6 mm Hg (90% CI, −15.8 to −3.4 mm Hg; P = .01) for the 50-mg once-daily dose and −7.8 mm Hg (90% CI, −14.1 to −1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred.Conclusions and RelevanceAmong individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies.Trial RegistrationClinicalTrials.gov Identifier: NCT05001945

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The Role of Aldosteronism in Causing Obesity-Related Cardiovascular Risk

Cited by 62 publications

References 65 publications

Obesity, hypertension and aldosterone: is leptin the link?

Obesity, hypertension and aldosterone: is leptin the link?

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

Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension

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