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Journal of Human Hypertension (2013) 27, 225–230 & 2013 Macmillan Publishers Limited All rights reserved 0950-9240/13 www.nature.com/jhh

ORIGINAL ARTICLE

High-circulating leptin levels are associated with increased blood pressure in uncontrolled resistant hypertension C de Haro Moraes1, VN Figueiredo1, APC de Faria1, NR Barbaro1, AR Sabbatini1, T Quinaglia1, SE Ferreira-Melo1, LC Martins1, C Demacq1,2 and HM Juńior1 Leptin and aldosterone have been associated with the pathophysiological mechanisms of hypertension. However, despite studies showing the association of leptin with intima-media thickness, arterial distensibility and sympathetic nerve activation, the relationship between leptin and blood pressure (BP) in resistant hypertension (RHTN) is unknown. We aimed to assess the correlation of plasma leptin and aldosterone levels with BP in uncontrolled controlled RHTN (UCRHTN) and CRHTN patients. Plasma leptin and aldosterone levels, office BP, ambulatory BP monitoring and heart rate were measured in 41 UCRHTN, 39 CRHTN and 31 well-controlled HTN patients. No differences were observed between the three groups regarding gender, body mass index and age. The UCRHTN group had increased leptin when compared with CRHTN and well-controlled HTN patients (38.2±21.4, 19.6±8.7 and 20.94±13.9 ng ml 1, respectively; Po0.05). Aldosterone levels values were also statistically different when comparing RHTN, CRHTN and well-controlled HTN patients (9.6±3.8, 8.1±5.0 and 8.0±4.7 ng dl 1, respectively; Po0.05). As expected, UCRHTN patients had higher heart rate values compared with CRHTN and well-controlled HTN patients (86.2±7.2, 83.5±6.7 and 83.4±8.5, respectively; Po0.05). Plasma leptin positively correlated with systolic (SBP) and diastolic BP (DBP), and aldosterone (r ¼ 0.43, 0.35 and 0.47, respectively; all Po0.05) in UCRHTN, but neither in the CRHTN nor in the HTN group. Simple linear regression showed that SBP, DBP and aldosterone may be predicted by leptin (r 2 ¼ 0.16, 0.15 and 0.19, respectively; all Po0.05) only in the UCRHTN subgroup. In conclusion, UCRHTN patients have higher circulating leptin levels associated with increased plasma aldosterone and BP levels when compared with CRHTN and HTN subjects. Journal of Human Hypertension (2013) 27, 225–230; doi:10.1038/jhh.2012.29; published online 19 July 2012 Keywords: resistant hypertension; obesity; leptin; aldosterone

INTRODUCTION Hypertension affects millions of individuals worldwide.1 Despite the adherence to optimized antihypertensive treatment, many patients do not achieve blood pressure (BP) goals, developing resistant hypertension (RHTN). According to the definition provided by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII),2 BP in resistant HTN patients remains above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Ideally, one of the agents should be a diuretic, and all agents should be prescribed at optimal doses.3 This revised definition includes a subgroup of resistant HTN patients whose BP is controlled by using four or more antihypertensive medications and are referred to as having ‘controlled RHTN’ (CRTHN).3 BP goals for this group of resistant HTN patients are the same as established for the general HTN population (140/90 mm Hg) and for HTN individuals with diabetes or chronic kidney disease are 130/80 mm Hg (glomerular filtration rateo60 ml min 1 1.73 m 2; creatinine serum 41.5 mg dl 1 in men or 41.3 mg dl 1 in women; albuminuria 4300 mg per 24 h).2 A definitive diagnosis of RHTN requires ambulatory BP monitoring (ABPM), which allows excluding pseudo-refractory patients (pseudo RTHN).4

It is well documented the positive relationship between body mass index (BMI) and increased risk of hypertension even in individuals with normal BMI and those overweight.5 In addition, currently it has been thoroughly discussed the influence of obesity on hypertension and resistance to antihypertensive therapy. Moreover, increased activity of the sympathetic nervous system (SNS) and stimulation of the renin-angiotensin–aldosterone system are two important mechanisms associated with obesity. Therefore, taken together, these three conditions (obesity, increased SNS activity and angiotensin–aldosterone system activation) can be involved in the lack of BP control.6 In addition, it is well accomplished that aldosterone excess has a key role in the pathogenesis of obesity and RHTN.7 Adipose tissue, which is known to be a large endocrine organ, has a role in the regulation of diverse biological functions including the secretion of hormones known as adipokines or adipocytokines, such as leptin.8 Leptin crosses the blood–brain barrier and binds to its receptors in different areas of the central nervous system, where it activates neural pathways that increase SNS activity, including the renal SNS system, which will result in angiotensin–aldosterone system stimulation,9 leading to increased plasma aldosterone, sodium retention, volume expansion and increased BP.10 Leptin is also related to metabolic, inflammatory

1 Cardiovascular Pharmacology Laboratory, Faculty of Medical Sciences and Teaching Hospital—University of Campinas (Unicamp), Campinas, Saõ Paulo, Brazil and 2Novartis Biocieˆncias SA, Saõ Paulo, Brazil. Correspondence: C de Haro Moraes, Cardiovascular Pharmacology Laboratory, Faculty of Medical Sciences and Teaching Hospital—University of Campinas, FCM 10 Building, First floor, Campinas, Saõ Paulo 13083-970, Brazil. E-mail: [email protected] Received 5 March 2012; revised 1 June 2012; accepted 18 June 2012; published online 19 July 2012

Circulating leptin in resistant hypertension C de Haro Moraes et al

226 and hemostatic factors involved in the development of hypertension and cardiovascular disease.11 Leptin levels are associated with vascular dysfunction12 and increased common carotid intima-media thickness,13 resulting in decreased arterial compliance.12 Although these emerging data suggest that obesity, high plasma aldosterone and leptin levels and enhanced arterial rigidity may interact with each other and have an important role in the pathophysiology of RHTN,14 some questions are still unanswered. For instance, it is controversial whether there is a ‘cross-talk’ between plasma aldosterone and leptin concentrations. In addition, the involvement of these hormones in the lack of BP control in RHTN subjects needs to be better investigated. Objective This study aimed to evaluate, as demonstrated for aldosterone, whether plasma leptin levels are associated with the lack of BP control in uncontrolled resistant hypertension (UCRHTN). Secondarily, we assessed whether these two plasma hormones are correlated.

MATERIALS AND METHODS This study was approved by the Institutional Research Ethics Committee at the Faculty of Medical Sciences of the University of Campinas (Campinas, Brazil), and all the subjects gave written informed consent (222/2011).

Laboratory assessment Baseline blood samples were collected for the following measurements: glucose, urea and creatinine, total cholesterol, low-density lipoprotein cholesterol fraction,high-density lipoprotein cholesterol fraction, triglycerides, uric acid, creatinine clearance, microalbuminuria, sodium and potassium. Blood samples used for the quantification of plasma leptin, plasma renin activity, and plasma aldosterone concentration were collected at 0800 hours after overnight fasting, during which time the volunteers rested in the supine position for 8 h, followed by 1 h in an upright position in an airconditioned room (22–24 1C). Samples obtained were immediately centrifuged, and serum/plasma was stored at 80 1C until assayed. Leptin levels (R&D Systems, Minneapolis, MN, USA) and plasma aldosterone concentration (DRG International, Mountainside, NJ, USA) were measured by using enzyme-linked immunoabsorbent assay. plasma renin activity (Mayo Clinic Laboratories, Rochester, MN, USA) was measured by radioimmunoassay.

Statistical analysis Data were expressed as mean±s.d. Kolmogorov–Smirnov test was used to assess normal value distribution. The one way analysis of variance and Bonferroni’s multiple comparison tests were used to compare the clinical characteristics and the biochemical variables. Correlation analysis was performed using Pearson’s coefficient. Simple linear regression analysis was used to evaluate leptin association with SBP, DBP and aldosterone. A significance level of the difference between the groups o0.05 was accepted as statistically significant. Analytic statistics was performed using the GraphPad Prism version 5.0 (GraphPad Software, Inc., 1992–2007, San Diego, CA, USA).

Subjects A total of 111 HTN patients, regularly followed up in the Outpatient Resistant Hypertension Clinic of the University of Campinas (Campinas, Brazil), were recruited to participate in this observational study. Subjects were divided into three groups: UCRHTN (n ¼ 41), controlled (CRHTN, n ¼ 39) and a control group consisted of well-controlled HTN patients (HTN, n ¼ 31). They were matched for age, gender and BMI. All individuals were regularly followed up during the first 6 months for drug therapy optimization.2 Patients were submitted to investigation including adherence to treatment,15 and secondary forms of hypertension were properly observed and excluded. The diagnosis of RHTN required ABPM (Spacelabs 90207, Spacelabs Inc., Redmon, WA, USA) as an auxiliary method to characterize UCRHTN and CRHTN, as well as to exclude pseudoresistanse to antihypertensive treatment. The exclusion criteria comprised: patients with secondary forms of hypertension, the presence of renal and liver diseases, type 1 or 2 diabetes, obesity (BMI X30 kg m 2), non-complied pharmacological prescription, angina pectoris, primary hyperaldosteronism (aldosterone–renin ratio (ARR)420 ng dl 1 ng 1 ml 1 per hour), stroke, peripheral vascular disease or any other major diseases, pregnancy or oral contraceptive use, smoking, alcohol use and drug abuse. In addition, nonpharmacological therapies were optimized, including salt-restricted diet monitored by measuring urinary sodium. Then, patients with urinary sodium 4100 mEq/24 h were also excluded. Leptin and aldosterone levels, office BP, heart rate and ABPM were evaluated.

BP and heart rate measurements BP (systolic BP (SBP)/diastolic BP (DBP)/pulse pressure (PP)) and heart rate measurements were taken using digital sphygmomanometer (Omron HEM-711DLX, OMRON Healthcare Inc., Bannockburn, IL, USA) three times for each subject, on the right upper arm in the sitting position after a 10-min rest. The average of two consecutive measurements with a variation o5 mmHg in the BP was used for this study.

24-h ABPM The 24-h ABPM was performed using an automated oscillometric device (Spacelabs 90 207, Spacelabs Inc.).16 Patients were engaged in their normal daily activities and BP was taken automatically at intervals of 20 min during an entire 24-h period. The following parameters were measured: average 24 h systolic, diastolic mean and PPs. Journal of Human Hypertension (2013) 225 – 230

RESULTS No differences were observed between UCRHTN, CRHTN and wellcontrolled HTN patients concerning gender, age and BMI (Table 1). All patients were overweight. As expected, UCRHTN patients had higher office and ABPM SBP, DBP, as well as PPs (Table 1). There were no differences in biochemical parameters and hormones between UCRHTN, CRHTN and well-controlled HTN patients, but the UCRHTN group had higher values of leptin compared with CRHTN and well-controlled HTN patients. Aldosterone levels were statistically different when comparing RHTN, CRHTN and well-controlled HTN patients. As expected, UCRHTN patients had higher heart rate values compared with CRHTN and well-controlled HTN patients. ARR were also statistically different when comparing RHTN, CRHTN and with well-controlled HTN

Table 1. General characteristics of UCRHTN, CRHTN and wellcontrolled HTN patients

Gender (F/M) Age (year) BMI (kg m 2) Office SBP (mm Hg) Office DBP (mm Hg) Office PP (mm Hg) ABPM SBP (mm Hg) ABPM DBP (mm Hg) ABPM PP (mm Hg)

UCRHTN (n ¼ 41)

CRHTN (n ¼ 39)

HTN (n ¼ 31)

24/17 56.6±10.9 28.0±2.3 154.5±10.3*, ** 100.5±7.5*, ** 53.9±12.5*, ** 140.1±8.0*, ** 88.2±7.3*, ** 51.9±5.9*, **

21/18 58.9±10.7 27.5±2.1 124.1±5.0 78.0±6.9 45.7±6.9 118.2±8.5 70.3±5.3 47.8±6.7

20/11 55.4±10.6 28.3±2.4 122.7±4.6 79.8±5.4 42.8±7.7 116.3±8.9 69.7±5.6 46.6±11.5

Abbreviations: ABPM, ambulatory BP measurements; BMI, body mass index; CRHTN, controlled resistant hypertension; DBP, diastolic BP; F, female; HTN, well-controlled hypertensive patients; M, male; PP, pulse pressure; SBP, systolic blood pressure; UCRHTN, uncontrolled resistant hypertension. *Po0.05 versus HTN. **Po0.05 versus CRHTN.

& 2013 Macmillan Publishers Limited


227 Table 2.

Biochemical parameters of RHTN subgroups and well-controlled HTN UCRHTN (n ¼ 41) 1

Glucose (mg dl ) Total cholesterol (mg dl 1) LDL cholesterol (mg dl 1) HDL cholesterol (mg dl 1) Triglycerides (mg dl 1) Serum urea (mg dl 1) Serum creatinine (mg dl 1) Creatinine clearance (ml min 1 1.73 m 2) Microalbuminuria (mg g 1) Na þ (mEq l 1) K þ (mEq l 1) PRA (ng ml 1 per hour) Plasma aldosterone (ng dl 1) ARR (ng dl 1 per ng ml 1 per hour) Leptin (ng ml 1) Heart rate (b.p.m.)

CRHTN (n ¼ 39)

HTN (n ¼ 31)

99.3±9.1 193.2±31.8 118.1±23.6 47.1±6.3 148.5±73.2 36.0±10.7 0.96±0.2

98.3±10.9 188.2±29.9 113.7±28.8 46.5±6.8 135.0±41.8 37.8±8.9 0.92±0.2

98.3±5.0 194.7±23.7 109.8±24.6 48.7±8.3 141.8±61.4 35.7±8.2 0.97±0.1

98.5±11.5 43.4±60.1 141.0±2.2 4.2±0.4 3.8±1.9*, ** 9.6±3.8*, ** 3.5±2.6*, ** 38.2±21.4*, ** 86.2±7.2*, **

99.5±11.5 30.8±54.7 140.7±2.4 4.3±0.3 4.9±1.6 8.1±5.0 1.7±1.2 19.6±8.7 83.5±6.7

102.0±13.8 31.1±42.8 140.8±2.2 4.3±0.4 5.3±2.4 8.0±4.7 1.8±1.3 20.94±13.9 83.4±8.5

Abbreviations: ARR, aldosterone–renin ratio; CRHTN, controlled resistant hypertension; HDL, high-density lipoprotein; HTN, well-controlled hypertensive patients; LDL, low-density lipoprotein; PRA, plasma renin activity; UCRHTN, uncontrolled resistant hypertension; *Po0.05 versus HTN. **Po0.05 versus CRHTN.

Table 3.

Antihypertensive (anti-HTN) drug distribution

Total anti-HTN drugs Hidroclorotiazide Spironolactone b-Blockers ACE inhibitors ARB Calcium channel blocker Centrally acting antihypertensive drug

UCRHTN (n ¼ 41)

CRHTN (n ¼ 39)

HTN (n ¼ 31)

5.27±0.63*, ** 100% ( 41) 31.7% (13) 56.1% (23) 29.3% (12) 82.9% (34)*, ** 70.7% (29)** 12.2% (5)

4.2±0.40* 100% (39) 23.1% (9) 61.5% (24) 43.6% (17) 46.1% (18)* 38.5% (15) 5.1% (2)

2.3±0.6 93.5%(29) — 51.6%(16) 54.8%(17) 19.3%(6) — —

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CRHTN, controlled resistant hypertension; TN, well-controlled hypertensive patients; UCRHTN, uncontrolled resistant hypertension. *Po0.05 versus HTN. **Po0.05 versus CRHTN.

Table 4.

Correlation coefficients between plasma leptin levels and numerical variables of RHTN and well-controlled HTN subgroups r (P-value) UCRHTN (n ¼ 41)

Office SBP (mm Hg) Office DBP (mm Hg) Office PP (mm Hg) ABPM SBP (mm Hg) ABPM DBP (mm Hg) ABPM PP (mm Hg) Plasma aldosterone (ng dl 1)

0.43 0.35 0.16 0.27 0.23 0.02 0.47

(0.004) (0.02) (0.30) (0.08) (0.14) (0.89) (0.001)

r (P-value) CRHTN (n ¼ 39) 0.14 0.24 0.02 0.02 0.07 0.07 0.21

(0.36) (0.13 ) (0.87) (0.89) (0.63) (0.67) (0.19)

r (P-value) HTN (n ¼ 31) 0.17 0.21 0.03 0.11 0.09 0.05 0.33

(0.22) (0.10 ) (0.65) (0.43) (0.56) (0.61) (0.21)

Abbreviations: ABPM, ambulatory BP measurements; CRHTN, controlled RHTN; DBP, diastolic BP; HTN, well-controlled hypertensive patients; PP, pulse pressure; SBP, systolic blood pressure; UCRHTN, uncontrolled resistant hypertension.

patients. Conversely, UCRHTN had lower plasma renin activity values compared with CRHTN and well-controlled HTN patients (Table 2). The number of antihypertensive classes taken daily by the three groups were significantly different and, as expected, it has been observed that the UCRHTN subjects were taking more classes of antihypertensive drugs than CRHTN and well-controlled HTN patients (Table 3). The most prescribed medications were thiazide diuretics (hidroclorothiazide). Plasma leptin levels positively correlated with SBP, DBP and aldosterone in the UCRHTN but not in CRHTN and in wellcontrolled HTN (Table 4). Simple linear regression showed that & 2013 Macmillan Publishers Limited

SBP, DBP and aldosterone may be predicted by leptin only in the UCRHTN group (Figure 1). DISCUSSION As far as we know, this is the first study to evaluate plasma leptin levels in RHTN patients. Higher leptin levels as well as plasma aldosterone concentration, heart rate and ARR were observed in the UCRHTN group compared with CRHTN and well-controlled HTN patients. In addition, we found a positive correlation between leptin and SBP, DBP and aldosterone only in the UCRHTN group. Finally, leptin was shown to be a predictor factor for SBP, DBP and Journal of Human Hypertension (2013) 225 – 230


228

Figure 1. (a) Simple linear regression between plasma leptin and plasma aldosterone in UCRHTN patients (r 2 ¼ 0.19; P ¼ 0.004); (b) simple linear regression between plasma leptin and plasma aldosterone in CRHTN patients (r 2 ¼ 0.03; P ¼ 0.30); (c) simple linear regression between plasma leptin and SBP in UCRHTN patients (r 2 ¼ 0.16; P ¼ 0.010); (d) simple linear regression between plasma leptin and SBP in CRHTN patients (r 2 ¼ 0.01; P ¼ 0.42); (e) simple linear regression between plasma leptin and DBP in UCRHTN patients (r 2 ¼ 0.15; P ¼ 0.012); (f ) simple linear regression between plasma leptin and DBP in CRHTN patients (r 2 ¼ 0.01; P ¼ 0.50).

aldosterone in the same group of RHTN patients. Taken together, these data strengthen the importance of some different vascular phenotypes and hormonal profile in the pathophysiology of UCRHTN patients whose may be related to difficulty to achieve BP levels control in this group. The higher leptin levels and heart rate we have found in the UCRHTN group is in line with previous publications that point this adipokine as one of the SNS activation mediators, and probably having a crucial role in the obesity and hypertension interaction.6 Nevertheless, SNS overactivity cannot explain alone the relationship between leptin and increased BP. Leptin stimulates the production of endothelin-1,17 promotes vascular smooth muscle cell proliferation18 and stimulates reactive oxygen species formation, increasing tubular Na þ reabsorption and vasoconstriction19 leading to RHTN. In spite of these other mechanisms, based on our results, we can hypothesize that high-circulating leptin levels are, at least in part, responsible for the higher office, ABPM SBP/DBP and PP levels in UCRHTN patients.20 In addition, this group also showed higher values of aldosterone and ARR. In fact, RHTN is frequently associated with high plasma aldosterone concentration and ARR.21 In addition, leptin and angiotensin–aldosterone system seem to be interconnected22 and emerging evidence suggest that adipose tissue by itself can stimulate aldosterone secretion.23 Aldosterone mediates maladaptive changes in the nervous and cardiovascular systems that promote hypertension.21 Recent evidence suggest that elevated levels of aldosterone are involved in the pathophysiology of Journal of Human Hypertension (2013) 225 – 230

insulin resistance, metabolic signaling and endothelial function, which contribute in promoting inflammation and oxidative stress that advance RHTN development.7 In addition, SNS overactivity, leptin can also influence the hypothalamic–pituitary–adrenal axis24 increasing the levels of corticotropin-releasing hormone.25 Consequently, adreno-corticotropic hormone would be an obvious suspect to stimulate aldosterone liberation by adrenal gland26 indirectly by higher leptin levels. In this study, to avoid the inclusion of patients with primary hyperaldosteronism, the exclusion criteria included the cutoff value of ARR 420 ng dl 1 ng 1 ml 1 per hour. Probably, the higher ARR founded in UCRHTN patients reflects both aldosterone excess and lower renin concentration, in spite of the facts that spironolactone and diuretics increase plasma renin activity plasma levels. However, all resistant groups (uncontrolled and controlled patients) are under pharmacological treatment including at least four drugs combination. Thus, this measurement may be result of the combination with other drugs. Furthermore, RHTN patients are exposed to high cardiovascular risk,3 which precludes safe withdrawal of medications. Aldosterone is known to cause vascular injury, change in collagen synthesis and fibrosis, which increase arterial stiffness and may contribute to changes in cardiac remodeling, including fibrosis and inflammation.27 Therefore, our results demonstrate that UCRHTN individuals may be exposed to a greater risk of structural, vascular and myocardial damage. & 2013 Macmillan Publishers Limited


229 Our findings reinforce some therapeutic strategies. For example, combined with pharmacological treatment or not, especial attention should always be paid to weight loss,28 mainly because, dietary changes and physical exercises can lower plasma inflammatory cytokines, BP and enhance insulin sensitivity.29 Pimenta et al.30 have shown extreme salt sensibility by RHTN patients, who manifested a mean reduction in office BP in response to a low-salt diet. Excessive dietary sodium ingestion contributes significantly to resistance to antihypertensive treatment.30 Conversely, mineralocorticoid receptor antagonists have been a therapeutic target for RHTN treatment in several studies.31 Mineralocorticoid receptor blockade has been shown to improve expression of anti-inflammatory adipokines and reverses obesity-related changes in proinflammatory adipokines.32 In addition, mineralocorticoid receptor blockade, angiotensinconverting enzyme inhibitors and angiotensin receptor blockers improve renal and cardiovascular outcomes.33 Most subjects who exhibit hyperleptinemia have an increase in adipocyte mass, but remain obese, indicating leptin resistance.34 As resistance to this hormone is at least in part responsible for the increased sympathetic activation and enhanced BP levels observed in obese HTN subjects, leptin receptor should be considered not only a potential target for therapeutic intervention,28 but also to specifically determine how leptin is involved in high BP levels, which is a huge challenge. Probably, it will require the development of new pharmacological tools targeting only this adipokine.35 In conclusion, all of these results reinforce that, in addition to phenotypic and vascular differences previously described by our group,14 there are also relevant hormonal differences between individuals classified as UCRHTN and CRHTN. Moreover, as UCRHTN patients have greater plasma leptin concentration positively correlated with increased aldosterone and BP levels when compared with CRHTN and well-controlled HTN subjects, these findings clearly suggest that this adipokine probably also contributes to the difficulty in obtaining BP control in patients in this subset of RHTN individuals. It remains unclear whether aldosterone and leptin production/releasing are intrinsically and directly interconnected in this syndrome.

What is known about this topic Hypertension is a major cause of morbidity and mortality worldwide. Leptin and aldosterone have been associated with the pathophysiological mechanisms of hypertension. The relationship between leptin and BP in RHTN is unknown. What this study adds A possible contribution of leptin for the lack of BP control in resistant HTN patients. UCRHTN patients have higher circulating leptin levels associated with increased plasma aldosterone and BP levels when compared with UCRHTN and well-controlled HTN subjects.

ACKNOWLEDGEMENTS This study was supported by the State of Saõ Paulo Research Foundation (FAPESP) Brazil, National Council for Scientific and Technological Development (CNPq) and Coordination for the Improvement of Higher Education Personnel (Capes), Brazil.

Caroline Demacq is an employee of Novartis Biocieˆncias SA (Brazil).

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