Hypertension is a common disorder affecting a large heterogeneous patient population. Despite improved understanding of its pathophysiology and availability of effective treatment strategies, hypertension remains a major, potentially modifiable, risk factor for cardiovascular disease. Aldosterone, the principal human mineralocorticoid, is increasingly recognised as playing a significant role in cardiovascular morbidity and its role in hypertension has recently been re-evaluated with studies that suggest that increased aldosterone concentration (as defined by an elevated aldosterone to renin ratio - ARR) is a key phenotype in up to 15 per cent of hypertensive subjects. We have previously reported that polymorphisms of the gene (C to T conversion at position -344 and intron conversion (1C) in intron 2) encoding aldosterone synthase (CYP11B2) are associated with hypertension, particularly in individuals with a high ARR. In normotensives, the T and 1C alleles associate with raised basal and ACTH-stimulated levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for the enzyme 11beta-hydroxylase, encoded by the adjacent and homologous gene CYP11B1. This has led to speculation that the T and 1C alleles of CYP11B2 are in linkage disequilibrium (LD) with functional variants in CYP11B1 resulting in reduced efficiency of this enzyme. In order to maintain cortisol production, positive feedback to the pituitary leads to a subtle but more pronounced adrenocorticotrophic hormone (ACTH) drive to the adrenal cortex and enhanced synthetic capacity of the zona glomerulosa resulting in increased production of aldosterone and suppression of renin. Thus in such individuals, there should be recognisable, genotype dependent, changes in the pattern of adrenal steroid production as well as alteration in the cortisol/ACTH relationship. These data are also consistent with a contribution of ACTH to the production of aldosterone (in - 344T & CYP11B1 -1888T/ -1858G) leading to the eventual phenotype of hypertension with aldosterone excess. (Abstract shortened by ProQuest.).
Summary Objective The significant role of corticosteroids in hypertension and cardiovascular disease highlights the importance of the adrenal gland in these disorders. The ability to correlate corticosteroid production with adrenal volume offers a novel research tool and intermediate phenotype in cardiovascular disease. The aim of this study was to develop and validate the use of magnetic resonance imaging ( MRI ) in adrenal volume assessment and investigate whether this associates with corticosteroid production. Design/Methods Twenty normotensive men underwent noncontrast 1·5 T MRI scanning of adrenals, measurement of blood pressure and plasma corticosteroids. Left adrenal volume was calculated twice using standard segmentation software by four independent observers with differing levels of clinical expertise and segmentation experience. To optimize this process, adrenal ‘phantoms’ with known fixed volumes underwent MRI scanning and analysis by two observers. Results Intra‐observer coefficients of repeatability ( C o R s) in phantoms ranged from 0·23 to 0·43 ml (interobserver C o R 0·48 ml). In the subject group, mean adrenal volumes were 3·99–5·82 ml with intra‐observer C o R s 0·27–1·94 ml. Interobserver variability was 2·73 ml. Segmentation expertise was the main factor affecting variability, with experienced observers having the lowest C o R s; clinical knowledge was a factor when combined with segmentation experience. Mean adrenal volume correlated with plasma glucocorticoids ( r = 0·523, P < 0·05) and aldosterone ( r = 0·515, P < 0·05) for the most experienced observer only. Conclusions Measurement of adrenal volume using MRI is challenging; most accurate volumes are achieved using a single observer with both segmentation experience and anatomical knowledge. The data also provide novel preliminary evidence that adrenal gland volume may be associated with plasma corticosteroid concentrations supporting further study of adrenal volume and steroid production across a range of blood pressures.
BackgroundBlockade of the mineralocorticoid receptor (MR) in patients with chronic kidney disease (CKD) improves surrogate cardiovascular outcomes, such as left ventricular mass. Animal models of renal disease support a pathological role of mineralocorticoids, in the context of a high sodium intake. We aimed to assess the regulation of mineralocorticoid biosynthesis in patients with CKD.
Outcomes are poor for patients with congenital adrenal hyperplasia (CAH), in part due to the supraphysiological glucocorticoid doses required to control adrenal androgen excess. Hydrocortisone (i.e. cortisol) is the recommended glucocorticoid for treatment of CAH. However, the other endogenous glucocorticoid in humans, corticosterone, is actively transported out of metabolic tissues such as adipose tissue and muscle, so we hypothesized that corticosterone could control adrenal androgens while causing fewer metabolic adverse effects than hydrocortisone.
Chloride (Cl-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary Cl- intake increases blood pressure, yet paradoxically, higher serum Cl- appears associated with lower mortality and cardiovascular risk. This implies that serum Cl- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12,968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl- was an independent predictor of mortality. To distinguish the effect of Cl- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+ /HCO3- and Cl- levels. Generalized estimating equation was used to determine the effect of baseline Cl- on follow-up blood pressure. The total time at risk was 19,7101 person-years. The lowest quintile of serum Cl- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+ , and HCO3- levels. The group with Na+ > 135 and Cl- > 100 had the best survival, and compared with this group, the Na+ >135 and Cl- <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.
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