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Salt intake and blood pressure.

To address this, we have now performed a time-group analysis in both datasets (University of Calgary and University of British Columbia) of baseline peripheral aldosterone measures from AVS, stratified according to time of collection where available (n1⁄4 148 and 322, respectively). After grouping data according to collection prior to 10:00 h, between 10:00 h and 12:00 h, and after 12:00 h, we found no difference in basal aldosterone levels between any of the groups (Kruskal–Wallis test, P1⁄4 0.35 and 0.26 for each dataset). Additional analysis in the UBC data cohort showed no significant correlation between time of collection and peripheral, precosyntropin cortisol measured at AVS (0800–1500 h). Thus there is no evidence of a significant circadian rhythm effect upon AVS-measured aldosterone/cortisol results. However, in our published report, we showed that peripheral cortisol levels drawn during AVS were also often very low and these correlated with low aldosterone levels. We therefore believe that this is potentially explained by the profound impact of sedation/narcotic effect upon corticotropin releasing hormone (CRH)/adrenocorticotropin hormone (ACTH)/cortisol secretion [2,3] which over-rides any variation due to circadian CRH/ACTH rhythms. Regarding Dr Tanemoto’s hypothesis that use of calcium channel blockers (CCB) with AVS (but not at diagnosis) could explain the effect, we can confirm that 70.1% of our patients were already using a CCB at the time of their aldosterone-renin-ratio (ARR) measurement; we do not consider CCB as a confounding medication for either ARR or AVS and therefore, this drug would not have been routinely discontinued between ARR and AVS. Therefore, given the high rate of CCB use at primary aldosteronism diagnosis, this does not seem to be a credible explanation for the low aldosterone seen at AVS, especially since the typical effect of CCB on measured, in-vivo aldosterone levels is marginal (<15%), in both essential hypertension and primary aldosteronism [4,5]. We wish to re-emphasize that the main message of our study was not purely speculation on the mechanisms underlying the observation but rather, on the observations themselves: in a large sample of confirmed primary aldosteronism patients, we showed that a substantial majority, under the right conditions, could show surprisingly low aldosterone levels, even in the absence of a traditional suppression test. It is a long-standing assumption (likely based on endocrinology first-principles) that primary aldosteronism should be defined as autonomous aldosterone secretion that cannot be suppressed, as pointed out by Tanemoto and the long history of so-called suppression tests for diagnosis. However, our observation seriously challenges this dogma by showing that aldosterone levels in many primary aldosteronism patients are not always high and may even be surprisingly low at times. Given the numerous contributors to aldosterone secretory dynamics (corticotropin, renin-AII, potassium and other hormones [6,7]), it may be time to re-evaluate the biochemical/ theoretical concept of primary aldosteronism: inappropriate and excessive aldosterone secretion yes, but not necessarily defined as a function of artificial exogenous suppression. ACKNOWLEDGEMENTS