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Angiotensin–Aldosterone System Fingerprint in Patients with Primary 1 181 P Wolf and others RAAS activity in adrenal 181:1 39–44 Clinical Study insufficiency Identifying a disease-specific renin– angiotensin–aldosterone system fingerprint in patients with primary adrenal insufficiency Peter Wolf1, Johanna Mayr1, Hannes Beiglböck1, Paul Fellinger1, Yvonne Winhofer1, Marko Poglitsch2, Alois Gessl1, Alexandra Kautzky-Willer1, Anton Luger1 and Correspondence should be addressed Michael Krebs1 to M Krebs 1Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna and Email 2Attoquant Diagnostics, Vienna, Austria michael.krebs@meduniwien. ac.at Abstract Background: In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin–angiotensin–aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity. Methods: Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case–control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry. Results: In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to- European Journal of Endocrinology AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P < 0.01) and plasma renin concentration (r = 0.985; P < 0.001) and was significantly increased in AI patients. Conclusions: AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials. European Journal of Endocrinology (2019) 181, 39–44 Background Primary adrenal insufficiency (AI) is characterized in most affected patients (1). In contrast to the initial by potentially life-threatening glucocorticoid and expectations that regular hormone substitution therapy mineralocorticoid deficiency, requiring daily, life-long might normalize life expectancy, recent evidence glucocorticoid (GC) replacement therapy. Additionally, indicates a more than twofold increase in mortality rates mineralocorticoid (MC) replacement therapy is necessary in affected patients compared to general population, https://eje.bioscientifica.com © 2019 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0086 Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 12:00:39PM via free access -19-0086 Clinical Study P Wolf and others RAAS activity in adrenal 181:1 40 insufficiency despite consequent GC substitution, mainly due to an was approved by the ethical committee of the Medical increased risk of cardiovascular disease (2). University of Vienna, and written informed consent was Whereas the effects of a distinct oversupply of GC obtained from all participating subjects. This study was on cardiovascular risk factors, including body weight, conducted in conformance with the relevant guidelines blood glucose and blood pressure, are well investigated and regulations, i.e. principles of the Declaration of (3), only little knowledge exists on the role of MC Helsinki and the ICH-GCP guidelines. replacement therapy. Secretion of the most important Eight patients with primary autoimmune AI and eight MC aldosterone is mainly regulated by Ang II together healthy controls well matched for age, sex and BMI were with potassium levels in the blood and to less extent by included in this study. History of heart failure, chronic adrenocorticotropic hormone (ACTH) (4). Aldosterone kidney disease or liver disease as well as clinical signs of exerts effects on vasculature, blood pressure and the hypervolemia like peripheral edema was an exclusion myocardium by promotion of sympathetic nervous criterion for all participants. Patients had to be on stable activity, reduction of vascular compliance and the dose of adequate GC and MC therapy for at least 3 months regulation of ion balance. The renin-angiotensin- prior to the study visit. Participants were investigated in the aldosterone system (RAAS) consists of an enzymatic morning following an overnight fast of at least 10 h before cascade with numerous angiotensin metabolites, which taking their daily GC and MC replacement therapy. Since might actively modulate cardiovascular risk factors. all patients were on once daily morning fludrocortisone The most prominent angiotensin metabolite is Ang II, treatment, blood tests were performed approximately which promotes vasoconstriction, cardiac remodeling 24 h after the last intake of MC replacement therapy. Time and regulation of inflammatory responses through direct from last intake of daily GC replacement therapy to blood binding to Ang II type I receptors (AT1R) in target tissues sampling was about 16 h. and might contribute to the development of cardiovascular After the measurement of blood pressure and heart disease (5, 6). Binding of Ang II to adrenocortical AT1R rate blood was drawn after at least 15 min of rest in sitting results in aldosterone secretion under normal conditions, position to assess serum electrolytes, cortisol, ACTH, stimulating sodium retention and potassium excretion renin, aldosterone and angiotensin metabolites (RAS in the kidneys, which constitutes a well-balanced system fingerprint). via a negative feedback on renin. An impaired negative All parameters but the RAS fingerprint (equilibrium feedback due to the lack of aldosterone might result in angiotensin levels) and aldosterone levels were measured excessive renin secretion and elevated levels of vasoactive at the central laboratory of the Medical University of European Journal of Endocrinology and detrimental angiotensin metabolites like Ang II in Vienna according to current standards (www.kimcl.at). patients suffering from AI (7). Equilibrium concentrations of Ang I, Ang II, Ang Inadequate MC replacement therapy might contribute III, Ang IV, Ang 1-7 and Ang 1-5 and aldosterone were to the observed increase in cardiovascular mortality (8). measured following ex vivo equilibration and subsequent The thorough assessment of the status of the RAAS might stabilization of conditioned plasma samples as described thus represent a potential clinical advantage to optimize previously (9, 10). Samples were spiked with stable isotope- treatment regimens and to individualize MC substitution labeled internal standards for individual angiotensins therapy. Therefore, this study aims to investigate, if (200 pg) and aldosterone (500 pg). Following C18-based the peptide branch of the RAAS might be stimulated in solid-phase extraction, samples were subjected to liquid primary AI despite MC replacement therapy and if there chromatotraphy tandem mass spectrometry (LC-MS/MS) is a disease-specific RAAS profile that might be suitable analysis using a reversed-phase analytical column (Acquity for diagnosis or therapeutic monitoring of AI patients in UPLC® C18, Waters) operating in line with a XEVO TQ-S order to reduce AI-associated cardiovascular risks. triple quadrupole mass spectrometer (Waters Xevo TQ/S, Milford, MA, USA) in multiple reaction monitoring mode. Internal standards were used to correct for analyte recovery Methods across the sample preparation procedure in each individual sample. Analyte concentrations were calculated from To address our aims we performed a cross-sectional, single- integrated chromatograms considering the corresponding center, case–control pilot study at the Medical University response factors determined in appropriate calibration of Vienna, Department of Internal Medicine III, Division curves in serum matrix, on condition that integrated of Endocrinology and Metabolism. The study protocol signals exceeded a signal-to-noise ratio of 10. Equilibrium https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/29/2021 12:00:39PM via free access Clinical Study P Wolf and others RAAS activity in adrenal 181:1 41 insufficiency Table 1 Baseline characteristics in patients suffering from ABAng I Ang I adrenal insufficiency and controls; data are given as 20.2 102.6 means ± standard deviation or as median (minimum–maximum). AC AC E E Adrenal insufficiency Controls P value Ang II Ang II 62.8 373.9 Age (years) 55 ± 21 51 ± 21 n.s. Sex (female/male) 5/3 5/3 n.s. Ang 1-7 AT1RT Ang III Ang 1-7 Ang III BMI (kg/m2) 22.8 ± 3 25.2 ± 4 n.s. <2.5 1.9 3.9 AT1R 4.4 AC GC dose (mg/day) 21.9 ± 5 AC AP AP E MC dose (mg/day) 0.061 ± 0.03 E Systolic RR (mmHg) 140 ± 16 134 ± 13 n.s. Aldo Ang 1-5 Aldo Ang IV Ang 1-5 <20.0 Ang IV Diastolic RR (mmHg) 83 ± 10 84 ± 7 n.s. <2.0 158.1 2.4 6.3 8.3 Heart rate (bpm) 79 ± 16 76 ± 14 n.s. Sodium (mmol/L) 140 ± 1.2 142 ± 2.4 n.s. Potassium (mmol/L) 4.5 ± 0.3 4.4 ± 0.4 n.s. Figure 1 Chloride (mmol/L) 100 ± 1.7 101 ± 2.7 n.s. RAS fingerprint in healthy controls (A) and patients with Calcium (mmol/L) 2.3 ± 0.9 2.3 ± 0.1 n.s. primary adrenal insufficiency (B). The sizes of spheres and the Phosphate (mmol/L) 1.1 0.1 1.1 0.1 n.s.
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