Abnormal Aldosterone Physiology and Cardiometabolic Risk Factors

Abstract

Abnormal aldosterone physiology has been implicated in the pathogenesis of cardio-metabolic diseases. Single aldosterone measurements capture only a limited range of aldosterone physiology. New methods of characterizing aldosterone physiology may provide a more comprehensive understanding of its relationship with cardio-metabolic disease. We evaluated whether novel indices of aldosterone responses to dietary sodium modulation, the Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI for serum and SAUSSI for urine), could predict cardio-metabolic risk factors. We performed cross-sectional analyses on 539 subjects studied on liberal (LIB) and restricted (RES) sodium diets with serum and urinary aldosterone measurements. SASSI and SAUSSI were calculated as the ratio of aldosterone on LIB (maximally suppressed aldosterone) to aldosterone on RES (stimulated aldosterone) diets, and associated with risk factors using adjusted regression models. Cardio-metabolic risk factors associated with either impaired suppression of aldosterone on LIB diet, or impaired stimulation on RES diet, or both; in all of these individual cases, these risk factors associated with higher SASSI or SAUSSI. In the context of abnormalities that comprise the metabolic syndrome (MetS), there was a strong positive association between the number of MetS components (0–4) and both SASSI and SAUSSI (P<0.0001) that was independent of known aldosterone secretagogues (angiotensin II, corticotropin, potassium). SASSI and SAUSSI exhibited a high sensitivity in detecting normal individuals with zero MetS components (86% for SASSI and 83% for SAUSSI). Assessing the physiologic range of aldosterone responses may provide greater insights into adrenal pathophysiology. Dysregulated aldosterone physiology may contribute to, and/or result from, early cardio-metabolic abnormalities.

Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variants

“…The marker was tested in relation to components of the metabolic syndrome, where it not only was highly associated with individual risk factors, but also distinguished between severe and moderate metabolic syndrome and between individuals with and without the metabolic syndrome. SASSI-II predictive power was better than any individual ALDO serum or urine level (23). Thus, SASSI-II is a sensitive marker for the risk of CV dysfunction and disease.…”

“…Even when the renin-angiotensin-ALDO system (RAAS) was activated by Na + restriction, AD still have increased ARR compared with ED. More recently, the SASSI-II has been described (23). This index was built on data suggesting that, in CVD -particularly HTN -ALDO responses to physiologic factors that can stimulate or suppress its levels are reduced (29)(30)(31)(32)(33)(34)(35).…”

“…The AngII infusion while on a RES diet is expected to provide maximal adrenal ALDO stimulation. The SASSI-II index correlates with the Framingham Risk Score and the number of components of the metabolic syndrome (23,60). Higher values of SASSI-II are indicative of impaired physiologic regulation of ALDO (23,60).…”

“…Brigham and Women's Hospital's Research Assay Core (BRAC), or BRAC's predecessor, served as the central laboratory for all laboratory processing. All assays used in this study have been extensively reported previously (23,29,61). All subjects had PRA and serum ALDO measured in triplicate at each of the intervention points.…”

“…First, that AD demonstrate dysregulated ALDO secretion compared with ED, assessed by ARR and Sodium-Modulated ALDO Suppression-to-Stimulation Index with AngII infusion (SASSI-II) (23). Second, that genetic variants in ET-1 gene (EDN1) will be associated with inappropriately elevated ALDO.…”