Age-Related Autonomous Aldosteronism

Nanba, Kazutaka; Vaidya, Anand; Williams, Gordon H.; Zheng, Isabel; Else, Tobias; Rainey, William E.

doi:10.1161/circulationaha.117.028201

Cited by 125 publications

(133 citation statements)

References 35 publications

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“…APCCs are histopathological findings of large clusters of CYP11B2 (also known as aldosterone synthase) expression that invade the zona fasciculata, harbor pathogenic mutations known to increase aldosterone secretion, and are not suppressed in the face of volume expansion or aldosterone excess(15, 16). Importantly, APCCs have been found in >50% of morphologically normal adrenal glands (with no apparent tumor or hyperplasia) and increase in prevalence with older age(18); consistent with our findings that autonomous aldosterone secretion may be a common pathogenic contributor to incident hypertension.…”

Section: Discussionsupporting

confidence: 91%

“…When compared to participants with higher renin activity, participants with a suppressed renin phenotype were older, more enriched with women and African-Americans, and had higher systolic blood pressure. Notably, although these participants had the lowest serum aldosterone concentrations, they had markedly elevated aldosterone-to-renin ratios (ARR>750 pmol/L per μg/L/h, or >30 ng/dL per ng/mL/h in conventional units), since they also had the lowest PRA(18) (Table 1). …”

Section: Resultsmentioning

confidence: 99%

“…Although PA has classically been typified as a clinical phenotype of severe hypertension and/or hypokalemia caused by adrenal neoplasia, recent evidence points to another potentially prevalent cause of autonomous aldosterone secretion by abnormal cell clusters within morphologically normal adrenal glands: aldosterone producing cell clusters (APCCs) (15–18). …”

Section: Introductionmentioning

confidence: 99%

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The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension

et al. 2017

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Background Primary aldosteronism is recognized as a severe form of “renin-independent aldosteronism” that results in excessive mineralocorticoid receptor (MR) activation. Objective To investigate whether there is a spectrum of subclinical renin-independent aldosteronism among normotensives that increases risk for hypertension. Design Cohort study. Setting National community-based study. Participants 850 untreated normotensive participants in the Multi-Ethnic Study of Atherosclerosis with measurements of serum aldosterone, plasma renin activity (PRA). Measurements Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed: ≤0.50; indeterminate: 0.51–0.99; unsuppressed: ≥1.0 μg/L/h), associated with incident hypertension, defined as SBP≥140, DBP≥90 mmHg, or initiation of anti-hypertensive medications. Cross-sectional analyses investigated associations of aldosterone with MR activity, assessed via serum potassium and urinary fractional excretion of potassium. Results A suppressed renin phenotype was associated with a higher rate of incident hypertension when compared to other PRA phenotypes (85.4 [73.4, 99.3] vs. 53.3 [42.8, 66.4] vs. 54.5 [41.8, 71.0] cases per 1000 person-years of follow-up). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension; whereas no association between aldosterone and hypertension was observed when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed. Limitations Measurements of sodium and potassium occurred several years before renin and aldosterone. Conclusions Suppression of renin, and higher aldosterone concentrations in the context of this renin suppression, associated with an increased risk for developing hypertension and possibly also with increased MR activity. These findings suggest a clinically-relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension. Funding National Institutes of Health

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension

et al. 2017

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“…Clinical correlates indicated that APCCs number and size increase with age, (69) paralleled by a progressive transition towards a discontinuous CYP11B2 expression pattern in older-age adrenal glands which might account for the age-related changes in renin and aldosterone physiology (70).…”

Section: Somatic Mutations In Aldosterone Producing Cell Clustersmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Monticone

Buffolo

Tetti

et al. 2018

European Journal of Endocrinology

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2 AbstractAldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA, and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis has yet to be uncovered.

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“…Among blacks in the Jackson Heart Study,6 aldosterone was positively associated with insulin resistance, while higher levels of aldosterone across the spectrum were associated with a dose‐dependent higher risk of the development of type 2 diabetes mellitus over 8 years. Recent observations demonstrate that aldosterone can be produced autonomously from aldosterone producing cell clusters within morphologically normal adrenal glands with a large spectrum and high prevalence of subclinical aldosteronism 7, 8, 9. Thus, we examined the association of aldosterone and PRA with glucose metabolism and incident diabetes mellitus across the spectrum of aldosterone levels in a multiethnic cohort to determine if there are racial/ethnic differences.…”

Section: Introductionmentioning

confidence: 99%

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

Joseph

Tcheugui

Effoe

et al. 2018

JAHA

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BackgroundMechanistic studies suggest that aldosterone impairs glucose metabolism. We investigated the cross‐sectional associations of aldosterone and plasma renin activity with fasting plasma glucose, insulin resistance (IR), β‐cell function, and longitudinal association with incident diabetes mellitus among adults in MESA (the multiethnic study of atherosclerosis) prospective cohort study.Methods and ResultsHomeostatic model assessment of IR (HOMA2‐IR) and HOMA2‐β were used to estimate IR and β‐cell function, respectively. Incident diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL or anti‐diabetic medication use at follow‐up. Linear regression was used to examine cross‐sectional associations of aldosterone with fasting plasma glucose, HOMA2‐IR and HOMA2‐β; Cox regression was used to estimate hazard ratios (HR) for incident diabetes mellitus with multivariable adjustment. There were 116 cases of incident diabetes mellitus over 10.5 years among 1570 adults (44% non‐Hispanic white, 13% Chinese American, 19% Black, 24% Hispanic American, mean age 64±10 years, 51% female). A 100% increase in log‐aldosterone was associated with a 2.6 mg/dL higher fasting plasma glucose, 15% higher HOMA2‐IR and 6% higher HOMA2‐β (P<0.01). A 1‐SD increase in log‐aldosterone was associated with a 44% higher risk of incident diabetes mellitus (P<0.01) with the greatest increase of 142% (P<0.01) observed in Chinese Americans (P for interaction=0.09 versus other ethnicities). Similar cross‐sectional findings for log‐plasma renin activity existed, but log‐plasma renin activity was not associated with incident diabetes mellitus after full adjustment.ConclusionsAldosterone is associated with glucose homeostasis and diabetes mellitus risk with graded associations among Chinese Americans and blacks, suggesting that pleiotropic effects of aldosterone may represent a modifiable mechanism in diabetes mellitus pathogenesis with potential racial/ethnic variation.

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Age-Related Autonomous Aldosteronism

Cited by 125 publications

References 35 publications

The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension

The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

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