Although aldosterone is known to increase blood pressure. Reversible Sympathetic Overactivity in Hypertensive Patients with Primary Aldosteronism

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1 ORIGINAL Endocrine ARTICLE Research Reversible Sympathetic Overactivity in Hypertensive Patients with Primary Aldosteronism Andrew C. Kontak, Zhongyun Wang, Debbie Arbique, Beverley Adams-Huet, Richard J. Auchus, Shawna D. Nesbitt, Ronald G. Victor, and Wanpen Vongpatanasin Hypertension Section, Cardiology (A.C.K., Z.W., D.A., S.D.N., W.V.) and Endocrinology (R.J.A.) Divisions, and Department of Clinical Sciences (B.A.-H.), University of Texas Southwestern Medical Center, Dallas Texas 75390; and the Heart Institute (R.G.V.), Cedars Sinai Medical Center, Los Angeles California Context: Aldosterone has been shown to exert a central sympathoexcitatory action in multiple animal models, but evidence in humans is still lacking. Objectives: Our objective was to determine whether hyperaldosteronism causes reversible sympathetic activation in humans. Methods: We performed a cross-sectional comparison of muscle sympathetic nerve activity (SNA, intraneural microelectrodes) in 14 hypertensive patients with biochemically proven primary aldosteronism (PA) with 20 patients with essential hypertension (EH) and 18 age-matched normotensive (NT) controls. Seven patients with aldosterone-producing adenoma (APA) were restudied 1 month after unilateral adrenalectomy. Results: Mean blood pressure values in patients with PA and EH and NT controls was 145 4/88 2, 150 4/90 2, and 119 2/76 2 mm Hg, respectively. The major new findings are 2-fold: 1) baseline SNA was significantly higher in the PA than the NT group (40 3 vs bursts/min, P 0.014) but similar to the EH group (41 3 bursts/min) and 2) after unilateral adrenalectomy for APA, SNA decreased significantly from 38 5to27 4 bursts/min (P 0.01), plasma aldosterone levels fell from to ng/dl (P 0.01), and blood pressure decreased from 155 8/94 3to117 4/77 2mmHg(P 0.01). Conclusion: These data provide the first evidence in humans that APA is accompanied by reversible sympathetic overactivity, which may contribute to the accelerated hypertensive target organ disease in this condition. (J Clin Endocrinol Metab 95: , 2010) Although aldosterone is known to increase blood pressure (BP) by promoting renal sodium retention, an increasing body of evidence indicates that aldosterone also acts centrally to stimulate the sympathetic nervous system (1 3). Studies in rats and dogs demonstrated that direct infusion of aldosterone into cerebral ventricles, at the doses that were too small to raise BP when given systemically, caused a sustained increase in sympathetic nerve activity (SNA) and BP (4 7). This central pressor action of aldosterone can be blocked by intracerebroventricular infusion of mineralocorticoid receptor (MR) antagonists (4). Moreover, in mini-pigs, mineralocorticoid-induced hypertension is abrogated by chemical sympathectomy, demonstrating a major sympathetic component (8). The question is whether these experimental animal data have any relevance to clinical hypertension. In a recent study from our lab, SNA measured directly by intraneural microelectrodes was unchanged when patients with essential hypertension (EH) were treated with an MR antagonist but significantly increased by thiazide therapy despite a similar reduction in BP (9). In another recent ISSN Print X ISSN Online Printed in U.S.A. Copyright 2010 by The Endocrine Society doi: /jc Received April 12, Accepted June 25, First Published Online July 21, 2010 Abbreviations: APA, Aldosterone-producing adenoma; AVS, adrenal vein sampling; BMI, body mass index; BP, blood pressure; EH, essential hypertension; MR, mineralocorticoid receptor; NT, normotensive; PA, primary aldosteronism; SNA, sympathetic nerve activity jcem.endojournals.org J Clin Endocrinol Metab, October 2010, 95(10):

2 J Clin Endocrinol Metab, October 2010, 95(10): jcem.endojournals.org 4757 study, MR blockade with spironolactone was shown to reduce total body norepinephrine spillover in elderly hypertensive patients (10). However, serum aldosterone levels in these patients were normal in both studies. Another approach to this problem is to study SNA in patients with primary aldosteronism (PA), a secondary form of hypertension characterized by adrenal aldosterone overproduction, which is surgically correctable in some cases with unilateral aldosterone-producing adenoma (APA). One group of investigators found that despite very high serum aldosterone levels, PA was accompanied by suppressed SNA, which normalized after surgical resection of the tumor (11, 12). Given the limited clinical studies concerning SNA in PA and the strength of the animal data indicating the opposite, we undertook an independent microneurographic study of SNA in patients with PA before and after curative unilateral adrenalectomy. Patients and Methods Fourteen patients with PA, 20 patients with untreated stage 1 EH, and 18 normotensive (NT) subjects participated in the study after giving written informed consent. The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas. The PA subjects were recruited from the patients referred to our hypertension clinic for evaluation of resistant hypertension or suspected secondary hypertension. The EH and NT groups matched for age, gender, and ethnicity were recruited from the Dallas Heart Study (13). All subjects had no history of heart disease, diabetes mellitus, or chronic kidney diseases or evidence of target organ damage such as left ventricular hypertrophy at least by electrocardiography. Patients had not received any vasoactive medications for at least 24 h before the studies. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics were discontinued for at least 2 wk before biochemical evaluation. During the period of biochemical evaluation, subjects were treated with calcium channel blockers (amlodipine or diltiazem). If BP was not controlled, -adrenergic receptor blockers (labetalol, carvedilol, or metoprolol), and/or -adrenergic receptor blockers (doxazosin) were added to the regimen. None of these subjects had received treatment with spironolactone or central sympatholytic drugs such as clonidine or guanfacine. The diagnosis of PA was established based on the current Endocrine Society guidelines (14). During biochemical evaluation, serum potassium levels were corrected with oral supplementation to 3.5 meq/liter, if necessary. All PA patients had plasma aldosterone levels of more than 15 ng/dl and plasma renin activity of less than 1 ng/ml h during screening evaluation. All subjects with PA demonstrated nonsuppressible aldosterone production after 3 5 d of high dietary sodium ingestion as evidenced by 24-h urinary aldosterone excretion of more than 12 g and urinary sodium excretion higher than 200 meq. All subjects with biochemical confirmation of PA underwent adrenal vein sampling (AVS) to distinguish between unilateral vs. bilateral adrenal overproduction of aldosterone. AVS was performed during iv infusion of 0.25 mg corticotropin (Cortrosyn; Amphastar Pharmaceuticals Inc., Rancho Cucamonga, CA) in 300 ml 5% dextrose in water at a rate of 100 ml/h for the duration of the procedure. Adrenal vein cannulation was considered successful when the cortisol levels in both adrenal veins were three times (or more) higher than the cortisol level in the inferior vena cava, whereas lateralization was considered positive when the adrenal vein aldosterone to cortisol ratio in the dominant side was four times greater than the aldosterone to cortisol ratio in the contralateral side. Microneurographic measurement of SNA All experiments were performed with the subjects in the supine position. BP was measured by the oscillometric technique with the Welch Allyn CE00050 Monitor (Tycos Instruments, Inc., Arden, NC). Heart rate was monitored by the R wave of an electrocardiogram lead. Postganglionic efferent sympathetic nerve discharge, heart rate, and respiratory rate were recorded continuously using a multichannel digital data recorder (MacLab/8S ML780; AD Instruments Inc., Mountain View, CA). Multiunit recordings of postganglionic SNA were obtained with tungsten microelectrodes inserted into muscle nerve fascicles of the peroneal nerves using the microneurographic technique of Valbo et al. (15). The nerve signals were amplified, filtered (bandwidth Hz), rectified, and integrated to obtain a mean voltage display of SNA. A recording of muscle SNA was considered acceptable when the neurograms revealed spontaneous, pulse-synchronous bursts of neural discharge, with the largest bursts showing a minimal signal-to-noise ratio of 3:1. SNA was analyzed by an investigator (Z.W.) without the knowledge of the treatment phase assigned to each subject. The interobserver and intraobserver variations in identifying bursts are less than 10% and less than 5% (16). The intra-subject variability of SNA when measured on repeated occasions without any interventions is less than 15% with the correlation coefficient of reliability in the measurement of SNA of 0.91 (17). Assessment of SNA after adrenalectomy In a subset of seven patients with lateralization of aldosterone production by AVS, measurement of SNA was performed before and 1 month after removal of an aldosteronoma. Pathological evidence of adrenal adenoma was confirmed from the surgical specimens in all subjects. Patients were maintained on the same type and dosage of antihypertensive medications before and after surgery. All vasoactive medications were withheld for at least 24 h before measurement of SNA. Biochemical and hormonal assays Blood samples were collected after fasting for 12 h with the subjects in the seated position for more than 5 min. The plasma samples were then separated and stored at 80 C until analysis. Plasma direct active renin and aldosterone were measured by RIA (Diagnostic Systems Laboratories, Webster, TX). The lower limit of the renin assay was 5 pg/ml with coefficient of variation of 1 2.6%. The lower limit of the aldosterone assay was 8 pg/ml with coefficient of variation of 3 5%. Statistical analysis Statistical analysis was performed with SAS version 9.2 (SAS Institute, Cary, NC). For continuous variables, one-way ANOVA

3 4758 Kontak et al. Sympathetic Overactivity and Primary Aldosteronism J Clin Endocrinol Metab, October 2010, 95(10): TABLE 1. Subject characteristics NT (n 18) EH (n 20) PA (n 14) ANOVA P Age (yr) Sex (male/female) 13/5 14/6 11/3 1 BMI (kg/m 2 ) Ethnicity (AA/H/W) 15/1/2 11/1/8 10/1/ Systolic BP (mm Hg) a a Diastolic BP (mm Hg) a 88 2 a Heart rate (beats/min) Direct renin (pg/ml) a a Aldosterone (ng/dl) a AA, African-American; H, Hispanic; W, White. a P 0.01 vs. NT. models were used to compare means between the PA, ET, and NT groups. Pairwise group differences were tested using the least-squares means contrasts derived from the ANOVA models. Analysis of covariance was used to adjust for age and body mass index (BMI). Comparisons of SNA measured at two occasions in the PA and EH groups were made with two-way ANOVA with repeated measures. Results are expressed as mean and SE unless otherwise indicated. A log transformation was used to reduce the skewness of direct renin and aldosterone levels. Results Baseline characteristics of the study subjects are shown in Table 1. The three groups were well matched on age, BMI, gender, and ethnicity. BP, as expected, was higher in patients wth PA and EH than NTs (Table 1, P ). Also as expected, serum aldosterone levels were significantly higher in patients with PA (Table 1, P ), whereas direct plasma renin levels were lower (P 0.01). SNA, both in bursts per minute and bursts per 100 heartbeats, was significantly higher in the PA patients than NT controls ( vs bursts/min, P 0.014, Figs. 1 and 2) but comparable to the level seen in patients with EH ( bursts/min, P 0.05). Within the PA group, SNA was similar between six subjects with idiopathic or bilateral hyperplasia and eight subjects with APA ( vs bursts/min, P 0.05). Because univariate analysis demonstrates correlation between age and SNA in all three groups and between BMI and SNA in the EH group, we performed SNA analysis of the whole cohort after adjustment for these two variables. Age- and BMI-adjusted analysis of SNA still yielded similar results (Fig. 2), suggesting both age- and obesity-independent sympathetic activation in PA patients. In the subset of seven subjects with surgically confirmed APA, SNA fell significantly after surgical removal of tumor (from to bursts/min, P 0.01, and from to bursts/100 RR intervals, P 0.003, respectively, Figs. 3 and 4). Plasma aldosterone levels and mean BP reduced significantly (from to ng/dl and from 114 5to90 2mm Hg, respectively, P 0.01), whereas plasma direct renin rose after surgery (from to pg/ml, P values 0.01). There were no significant changes in heart rate or body weight after surgery (from 64 4to 61 3 beats/min and from vs kg, respectively, both P values 0.05). In contrast, SNA remained unchanged in a subset of 16 patients with untreated hypertension studied on two different days, separated by a period of 1 month without any changes in medical intervention (Fig. 4), suggesting changes in SNA in the PA group were not due to random variation of SNA measurement over time. Discussion There are two major new findings in our present study. First, we found that SNA was elevated in patients with PA when compared with normal controls and comparable to those with EH. Second, sympathetic activation was normalized by laparoscopic adrenalectomy in those with a FIG. 1. Original recordings of SNA in a 49-yr-old NT subject (top), a 46-yr-old subject with EH (middle), and a hypertensive subject with PA (bottom). HTN, Hypertension.

4 J Clin Endocrinol Metab, October 2010, 95(10): jcem.endojournals.org 4759 FIG. 2. Summary data showing SNA and SNA per 100 RR intervals (SNA 100RR) in NT, EH, and PA groups. unilateral APA, further supporting a sympathoexcitatory action of aldosterone. Our study is an important first step forward in the clinical translation of animal data showing a central pressor action of aldosterone. Circulating aldosterone is well known to penetrate the blood-brain barrier at concentrations that are parallel to plasma concentrations (18 20). Studies in conscious dogs demonstrate that closed intracerebroventricular infusion of aldosterone that causes no systemic spillover raises BP in both salt-depleted and saltrepleted conditions (7). The increase in BP was mainly due to an increase in total peripheral resistance rather than an increase in cardiac output or blood volume (7). Studies in NT rats produce similar results and further demonstrate an increase in sympathetic vasoconstrictor activity to the kidneys with central administration of aldosterone (4, 6). FIG. 3. Original recordings of SNA in a 47-yr-old subject with APA before (top) and 4 wk after (bottom) surgical resection of tumor. Our findings are in contrast to those of two previous studies conducted by another group of investigators, who reported that SNA was lower in patients with PA than EH patients and similar to NT controls (11, 12). However, differences in patient population characteristics may have contributed to the divergent results. The study by Miyajima et al. (11) was limited to young subjects younger than 40 yr of age. Matsukawa et al. (12) studied older subjects with similar age to our subjects, but their NT controls had surprisingly high levels of SNA despite being lean with body weight within 10% of ideal range (12). SNA typically increases with both age and BMI. In the same study, the increase in SNA after adrenalectomy was limited to only a few subjects, whereas SNA in other patients displayed only minimal change (12). Circulating levels of aldosterone in PA patients in studies by Miyajima et al. (11) and Matsukawa et al. (12) were also different from our study because they were expressed in nanograms per milliliter instead of nanograms per deciliter. However, these units appear to be incorrectly reported because plasma aldosterone levels in normal controls from both studies would have been more than 300 times higher than upper limit of normal range of 15 ng/dl (14). If the units in these two studies are expressed correctly in picograms per milliliter (rather than nanograms per milliliter), our PA patients would have aldosterone levels more than twice as high as PA patients from previous studies. This is likely to be because our PA subjects were required to demonstrate nonsuppressible aldosterone production despite increased sodium intake and volume expansion according to the current Endocrine Society guidelines (14), whereas the PA subjects in both studies by Miyajima et al. (11) and Matsukawa et al. (12) were identified by only elevated random levels of aldosterone. Furthermore, studies by Miyajima et al. (11) and Matsukawa et al. (12) included only patients with APA that were identified primarily by imaging studies, either the computed tomography or iodomethyl-19-norcholesterol (NP-59) scintigraphy, whereas our study included both patients with APA and bilateral hyperplasia, which was confirmed the gold standard AVS according to the current guidelines (14, 21 23). Thus, our study results are pertinent to both major subtypes of PA patients. Furthermore, we confirmed SNA results in the cross-sectional study with the prospective study in a subset of PA patients after surgical removal of aldosteronomas. Elevated SNA in PA patients remains persistent after adjustment for age and BMI.

5 4760 Kontak et al. Sympathetic Overactivity and Primary Aldosteronism J Clin Endocrinol Metab, October 2010, 95(10): FIG. 4. Summary and individual data showing SNA and MAP of seven subjects with APA (top) before and after adrenalectomy and 14 subjects with untreated EH studied on two separate occasions separated by 1 month without any medical intervention. HTN, Hypertension. For all these reasons, we believe that our study provides the first valid evidence linking aldosterone excess to sympathetic overactivity in humans. Both studies by Miyajima et al. (11) and Matsukawa et al. (12) were limited to the Japanese population, and therefore, we cannot exclude ethnic differences in SNA responses to aldosterone. Salt consumption in the Japanese population is generally higher than in the United States (24, 25), whereas salt sensitivity in Japanese appears to be comparable to African-Americans but greater than Caucasians (26). Because volume expansion could suppress SNA via activation of cardiopulmonary baroreflexes, the net effects of aldosterone on SNA in a given subject may depend upon relative contributions of a primary central sympathoexcitatory action of aldosterone vs. a secondary sympathoinhibitory reaction of cardiopulmonary baroreflexes to aldosterone-mediated renal sodium retention with plasma volume expansion. Thus, the greater severity of aldosteronism in our patients may have allowed direct central action of aldosterone to dominate. The mechanisms underlying elevated SNA in PA patients remain unknown, but an increasing body of evidence suggests that activation of central MRs may play an important role (5, 27). MRs are abundantly expressed in many brain regions involved in cardiovascular regulation such as the hypothalamus, paraventricular nucleus, and nucleus tractus solitarius (1, 28, 29). Although the brain MR can also be activated by glucocorticoids, which circulate at much higher concentrations than aldosterone, Geerling and Loewy (29) recently demonstrated that coexpression of 11 -hydroxysteroid dehydrogenase enzyme type 2 allows aldosterone to gain access to these neurons by converting glucocorticoids to metabolites with lower binding affinity to MR. The central effects of MR on BP regulation may provide an explanation for the ability of spironolactone to promote natriuresis and reduce BP without causing reflex sympathetic activation in patients with primary hypertension in our recently published study (9). Aside from its direct central action, aldosterone has also been shown to inhibit carotid baroreceptor discharge in dogs, which normally exerts an inhibitory influence on SNA (30). One study in humans, however, provided conflicting evidence because baroreflex control of heart rate indirectly assessed by spectral analysis of heart rate was shown to be augmented in patients with PA (31). Nevertheless, the relative contribution of direct central MR activation vs. secondary sympathetic activation from baroreflex inhibition on augmented SNA in patients with PA and its normalization with surgical treatment of PA remain to be further investigated. Regardless of mechanisms mediating sympathetic activation in PA patients, our study may have potential clinical implications. The sympathetic nervous system is known to contribute to the pathogenesis of hypertension and the poor prognosis in patients with cardiovascular diseases (32 34). Thus, in addition to the effects of aldosterone on renal sodium absorption, aldosterone-induced sympathetic activation may constitute another potential mechanism underlying the high prevalence of resistant hypertension as well as the accelerated cardiovascular complications in PA patients (35 37). Acknowledgments We gratefully acknowledge Dr. Norman Kaplan from the Hypertension Section at the University of Texas Southwestern Medical Center at Dallas for invaluable advice regarding the critical review of the manuscript. Address all correspondence and requests for reprints to: Dr. Vongpatanasin, Hypertension Section, Cardiology Division, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, U9.400, Dallas, Texas wanpen.vongpatanasin@utsouthwestern.edu.

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