Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk

Abstract

Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal vascular and cardiovascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1124 visits) in the General Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression to stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics and the renal vascular responses to dietary sodium manipulation and angiotensin II infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (β=-4.60; P<0.0001) and higher SASSI (β=-58.63; P=0.001) predicted lower RPF and a blunted RPF response to sodium loading and angiotensin II infusion. We observed a continuous, independent, multivariate-adjusted interaction between age and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (P<0.05). Higher SASSI and lower RPF independently predicted higher Framingham Risk Score (P<0.0001) and together displayed an additive effect. Aldosterone regulation and age may interact to mediate renal vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease.

Keywords: aging; aldosterone; renal plasma flow; renin-angiotensin system.

Figure 1. Interaction between age and SASSI predicts renal plasma flow (RPF)

For every quartile of aldosterone dysregulation (SASSI), we observe an inverse relationship between age and renal-vascular function. In contrast, in the younger age quartiles (Q1-Q2), RPF is relatively independent of SASSI, whereas with older age (Q3-Q4), there is an increasingly apparent negative relationship between SASSI and renal-vascular function. In an adjusted, continuous, interaction model, there was a significant interaction between age and SASSI in predicting RPF (p-interaction<0.027), suggesting that aldosterone dysregulation may modify the effect of age on renal-vascular function.

Figure 2. Aldosterone dysregulation and impaired renal-vascular hemodynamics may additively contribute to CVD risk

Higher SASSI and lower Renal Plasma Flow (RPF) appear to display an additive effect in predicting Framingham Risk Score (FRS), such that higher SASSI in combination with lower RPF correspond to the highest FRS. Q1-Q4 indicate quartiles 1-4 of RPF and of SASSI.