Effect of weight loss through laparoscopic gastric banding on blood pressure, plasma renin activity and aldosterone levels in morbid obesity

Nutrition, Metabolism & Cardiovascular Diseases (2009) 19, 110e114 available at www.sciencedirect.com

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Effect of weight loss through laparoscopic gastric banding on blood pressure, plasma renin activity and aldosterone levels in morbid obesity C. Dall’Asta a,b,*, P. Vedani c, P. Manunta d, P. Pizzocri c, M. Marchi c, M. Paganelli e, F. Folli f, A.E. Pontiroli a,b a

Dipartimento di Medicina, Chirurgia e Odontoiatria, Universita` degli Studi di Milano, Ospedale San Paolo, Via A. Di Rudinı` 8, 20142 Milano, Italy b  2 Divisione di Medicina Interna, Ospedale San Paolo, Milano, Italy c Divisione di Medicina Interna, IRCCS San Raffaele, Milano, Italy d Divisione di Nefrologia, Dialisi e Trapianti, IRCCS San Raffaele, Milano, Italy e Divisione di Chirurgia, IRCCS San Raffaele, Milano, Italy f Department of Medicine/Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Received 28 September 2007; received in revised form 4 June 2008; accepted 5 June 2008

KEYWORDS Obesity; Weight loss; Bariatric surgery; Arterial hypertension; Renin; Aldosterone

Abstract Background and aims: Several mechanisms are probably involved in obesity-related hypertension. This study was aimed to investigate the effect of significant weight loss on blood pressure and plasma renin activity (PRA) and aldosterone levels, other then on metabolic profile, in normotensive and hypertensive obese subjects. Methods and results: Forty hypertensive and 55 normotensive obese subjects were studied under basal conditions and again 1 year after significant weight loss obtained through laparoscopic adjustable gastric banding (LAGB). Weight, waist circumference, blood glucose, insulin, electrolytes (Na and K), lipids and supine and upright PRA and aldosterone were evaluated. All parameters evaluated improved, except for total cholesterol, and electrolytes that did not change. Blood pressure decreased in hypertensive subjects, with a concordant decrease in PRA and supine aldosterone levels, not observed in normotensive patients. Conclusion: Weight loss is associated with reduction of blood pressure and of PRA and aldosterone levels in obese hypertensive subjects. ª 2008 Elsevier B.V. All rights reserved.

* Corresponding author. Tel.: þ39 02 81844559; fax: þ39 02 81844576. E-mail address: [email protected] (C. Dall’Asta). 0939-4753/$ - see front matter ª 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2008.06.001

PRA and aldosterone in obesity

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Introduction

Methods

It is now accepted that obesity is per se a risk factor for increased morbidity and mortality [1]; weight loss, obtained either through diet alone, or through diet with drugs, or through surgical approaches, improves metabolic features and arterial blood pressure [2e8], and can prevent the appearance of type 2 diabetes and of arterial hypertension at least in short term follow-up studies [7e9]. Several mechanisms are probably involved in obesityrelated hypertension, such as hyperleptinemia and leptin resistance, oxidative stress, inflammation, endothelial dysfunction, sympathetic activation, insulin resistance, the renineangiotensin system (RAAS), and sleep apnea [10]. Most abnormalities improve after weight loss, and there is an evidence that these changes are related to each other and with loss of abdominal fat [11]; in contrast, conflicting data are reported as to the possible role of the RAAS after weight loss: both significant [12e17] and not significant [18,19] modifications in PRA and aldosterone levels have been reported. This study was aimed to investigate the effect of significant weight loss, obtained through laparoscopic adjustable gastric banding (LAGB), on blood pressure and PRA and aldosterone levels, other than on metabolic profile, in hypertensive and normotensive subjects.

Ninety-five obese subjects, 40 hypertensive (31 women 9 men) and 55 normotensive (44 women, 11 men) were studied under basal conditions and 1 year after weight loss, obtained through laparoscopic adjustable gastric banding (LAGB) (Table 1); following the common protocol already described [5] approved by the local Ethics Committee, all subjects gave written informed consent to the study and were studied as in-patients under standardized conditions. All evaluations were performed under basal conditions, i.e. 30e45 days before, and 1 year after LAGB. The diet prescribed has already been described [5]; in particular, the diet contains progressively more calories and greater amounts of Na and K, starting from 500 kcal/ day (214e387 mg/day Na, 940e1462 mg/day K) during the first week, to 740 kcal/day (338 mg/day Na, 1471 mg/day K) during the first month, to 1000 kcal/day (679 mg/day Na, 2468 mg/day K) at 4 months, to 1270 kcal/day (930 mg/day Na, 2487 mg/day K) at 10 months; as a comparison, a normal 2200 kcal/day diet contains 1872 mg/day Na, 3577 mg/day K, and reported diets from obese patients contained 1990e3200 kcal/day (1493e3259 mg/day Na, 2587e3549 mg/day K). Supine (after 2 h in lying position) and upright (2 h after standing) PRA and aldosterone (A), blood glucose, insulin,

Table 1 Clinical and endocrine details of 95 subjects (31 hypertensive and 44 normotensive women, W; 9 hypertensive and 11 normotensive men, M) under basal conditions and after weight loss (1 year) Hypertensive n Z 40 Basal Age (years) BMI (kg/m2) Waist (cm) SBP (mm/Hg) DBP (mm/Hg) Blood glucose (mg/dl) Insulin (mU/ml) HOMA HbA1c (%) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides e mg/dl Supine PRA (ng/ml/h) Upright PRA (ng/ml/h) Supine A (ng/dl) Upright A (ng/dl) A/PRA Serum Na (mEq/L) Serum K (mEq/L)

W M W M

W M

43.3  1.54 44.7  1.14 49.8  2.43 122.3  2.23 139.9  4.28 143.7  1.93x 90.1  1.26x 115.3  5.82** 18.9  1.28 5.23  0.58 6.5  0.19 205.1  5.99 48.3  2.28 42.9  3.25 147.9  13.08 1.84  0.29** 3.24  0.59 3.54  0.50 8.38  0.94 4.72  0.94 139.9  0.31 4.0  0.04

Normotensive n Z 55 After 1 year

Basal

After 1 year

38.4  0.99* 38.9  1.61y 110.1  2.30* 119.2  4.19z 133.6  2.13zx 83.7  1.62** 96.1  2.64y 10.5  0.70* 2.49  0.18* 5.7  0.11* 209.9  8.03 53.4  2.42y 44.9  1.70 116.1  11.20* 1.16  0.20z 2.27  0.44z 2.48  0.30z 7.03  0.69 5.22  0.77 141.2  0.37 4.1  0.05

39.9  1.30 44.0  0.95 46.0  2.14 117.9  1.94 130.7  4.17 125.2  0.91 78.1  0.61 103.2  2.00 19.7  2.02 5.14  0.60 6.2  0.08 194.8  5.63 49.2  1.62 35.2  2.90 143.3  10.62 1.14  0.14 2.22  0.27 3.25  0.28 8.59  0.65 6.2  0.77 140.2  0.33 4.2  0.04

35.8  0.88* 37.1  1.33* 103.1  2.29* 114.9  4.06* 124.7  1.38 78.9  1.14 94.8  1.55* 10.7  0.91* 2.57  0.24* 5.7  0.09* 200.7  5.37 56.0  1.73* 42.1  3.40 103.4  6.78* 0.93  0.12 2.03  0.19 2.73  0.29 8.37  0.59 5.52  0.53 140.8  0.28 4.2  0.04

SBP Z systolic blood pressure; DBP Z diastolic blood pressure; PRA Z plasma renin activity; A Z aldosterone; A/PRA Z upright aldosterone/PRA ratio. *p < 0.001 vs basal; yp < 0.003 vs basal; zp < 0.05 vs basal; xp < 0.003 and **p < 0.05 vs normotensive subjects. Data are expressed as mean  SE.

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HbA1c, lipid profile, sodium and potassium were evaluated at 8.0 am under fasting conditions. Height, weight and waist circumference were measured in all subjects. Blood pressure was measured with an appropriate cuff three times in resting conditions in supine position, and the average of the second two readings was recorded. Hypertension was defined as systolic blood pressure (SBP) 140 mmHg and/or diastolic pressure (DBP) 90 mmHg [20]. The upright A/PRA ratio and HOMA-IR index [21] were also calculated. None of the subjects was receiving medications that could influence the present results; in particular, hypertensive subjects were not yet taking any drug to control blood pressure, or the treatment had been withdrawn at least 2 weeks before the clinical work up. Secondary hypertension was excluded on the basis of clinical and instrumental diagnosis, whenever suspected; in particular, subjects with an elevated upright A/PRA ratio [22] underwent further investigation to rule out primary aldosteronism, and were excluded from the study.

Biochemical and hormonal assay Plasma renin activity (ng/ml/h Z mg/l/h) and aldosterone (pmol/l Z ng/dl  27.74) were measured by RIA methods (DiaSorin, Vercelli, Italy, and MedicalSystem SpA, Genova, Italy, respectively). Serum electrolytes, blood glucose, insulin, HbA1c, total and HDL cholesterol, triglycerides were evaluated as already indicated [5,9]. All measurements were carried out in the same laboratory; intra- and inter-assay coefficients of variation (CVs) for insulin, PRA, and aldosterone assay were 3.0%e5.0%, 3.6%e6.1%, and 3.3%e5.6%, respectively.

Statistical analysis Data are presented as mean  SE. Data were compared by paired or unpaired t-test as appropriate. Because of skewness of distribution of values, PRA and aldosterone were log transformed for statistical analyses and then back-transformed for presentation in text and tables. Since a normal distribution of data was not assured, data were also compared by non-parametric tests (Wilcoxon and Manne Whitney). Pairwise correlations between change of blood pressure and of selected variables were also computed. A p value <0.05 was considered statistically significant.

Statistical analysis was performed with a StatView package for MacIntosh.

Results Under basal conditions hypertensive- differed from normotensive subjects for systolic and diastolic blood pressure, for blood glucose and for supine PRA (Table 1). Women and men were not different for all clinical and metabolic variables, except for BMI, waist circumference and HDL-cholesterol levels. BMI decreased during the first year after surgery in a similar way in normotensive- and hypertensive-subjects (Table 1) and was stable for up to 3 years (not shown). Fifteen subjects had hypertension disappearing during the 1 year study period, and hypertension appeared de novo in 5 subjects, so that in the end 65 subjects were normotensive and 30 were hypertensive. In both groups clinical and metabolic parameters ameliorated to a similar extent; cholesterol levels did not change; blood pressure and supine and upright PRA, and supine aldosterone decreased in hypertensive, but not in normotensive subjects, so that in the end there was no difference between the 2 groups in terms of blood pressure and of PRA and aldosterone levels. Changes were not different in hypertensive subjects who became normotensive and in those who remained hypertensive. A direct relationship was observed between basal PRA and aldosterone levels and the extent of their reduction after weight loss (r from 0.259 to 0.747, p from 0.02 to 0.0001); Fig. 1 shows that in hypertensive, but not in normotensive subjects, a direct relationship was observed between decrease of systolic blood pressure and reduction of upright PRA (r Z 0.326, p Z 0.0459); no other relationship was observed. Serum Na and K did not change during the whole period of follow-up (up to 3 years, not shown).

Discussion Previous studies have shown that weight loss improves several metabolic and endocrine variables and reduces blood pressure in a significant proportion of obese subjects [2e9,23]. In this study we evaluated, together with metabolic changes induced by significant weight loss in obese

Δ uprigt PRA (ng/ml/h)

Hypertensive subjects

Normotensive subjects

8

8

4

4

0

0

-4

-4 r = .326

-8 -12

p = 0.0459 -30 -20 -10 0

10 20 30 40 50 60

r = .242

-8 -12

NS -30 -20 -10 0

10 20 30 40 50 60

Δ systolic BP (mmHg)

Figure 1 Relation between delta (D Z difference between systolic blood pressure before and after weight loss) and delta (D Z difference between upright PRA before and after weight loss) in hypertensive (left panel) and in normotensive (right panel) subjects.

PRA and aldosterone in obesity subjects, modifications of both blood pressure and PRA and aldosterone levels. As expected, we observed an amelioration of all clinical parameters considered [5e9,23], except for total cholesterol that was close to normal limits under basal conditions. We also observed a reduced prevalence of arterial hypertension, similar to what we previously reported, so that after 1 year around 25% of the original number of hypertensive subjects became normotensive [6e9]. Under basal conditions, the main findings was that supine PRA levels were higher in hypertensive than in normotensive subjects, in agreement with a previous report [24]; weight loss was accompanied by a significant decrease of PRA levels and of supine aldosterone levels in hypertensive, not in normotensive subjects, so that all differences disappeared at 1 year; a direct relationship was observed between reduction of systolic blood pressure and decrease of upright PRA levels; no difference was observed between subjects becoming normotensive and those remaining hypertensive. We considered together men and women as they showed no baseline differences in PRA and A levels nor in the response to weight loss (data not shown). An abnormal RAAS activity might be a cause as well as a consequence of a dysregulation of blood pressure control mechanisms. The relationships between blood pressure in obesity and PRA/aldosterone levels, as well as their response to weight loss are not unanimous, and this can depend on the small size of studies [13,16,18,24,27] on the fact that patients were not properly defined or properly matched [15,25,27], on selection criteria, i.e. only hypertensives [12] or only normotensives [14]; in addition some studies were cross-sectional with no intervention [24,25]. We should also recall that hypertension is characterized by increased sympathetic activation [11], that is able to stimulate PRA levels [26]; therefore we might hypothesize that obese hypertensive subjects are more sensitive than obese normotensive subjects to the effect of sympathetic activation on RAAS. The RAAS might be influenced by diet, and therefore by current sodium intake. In this respect, different authors found either reduction [14,15,17,27] or increase [12] or no modification [19] of PRA and aldosterone after diets that could be Na-restricted, and of variable duration. Serum Na and K were not different in our subjects before and after LAGB, nor in normotensive- vs hypertensive subjects; in addition, weight loss and metabolic improvements were not different in normotensive- and in hypertensive-subjects. Physical activity was encouraged in all subjects, and we have no data indicating that increase of physical activity was different in normotensive- and in hypertensive-subjects. Therefore, it seems that RAAS can variably adapt to different diets, in particular depending on the Na content and in the short term period; in the long term, when subjects follow a stable regimen and their body weight is steady, the modifications of PRA and A levels might be due to other mechanisms. For instance, the adipose tissue expresses all components of the renineangiotensin axis [28] and secretes a potent mineralocorticoid-releasing factor [29]. A potential explanation is that down-regulation of angiotensinogen (AGT) gene (that does not imply an overall decrease in AGT production, as fat mass is increased in obese people), together with an increase in renin and angiotensin converting enzyme gene expression [30], may

113 influence blood pressure regulation through pathways different from the RAAS. For instance, leptin, which is stimulated by angiotensin II [31], can act on the central nervous system [32], linking adipose tissue with sympathetic activity, which is involved in obesity-related hypertension [6,33,34]. If weight loss is accompanied by decrease of leptin and of sympatethic activation, this might explain the decrease of PRA and aldosterone levels. Moreover, it is known that PRA levels can be low as well as normal or high in essential hypertension [35], and some obese subjects could be affected by essential hypertension, not by obesity-related hypertension. On the other hand, the recent finding of a mineralecorticoidereleasing factor of adipose tissue origin [29] reinforces the hypothesis of several possible pathways; the aldosterone-releasing properties of this factor are not inhibited by an angiotensin type 1 receptor antagonist, and are not related to leptin, adiponectin, IL-6 or TNFalpha actions [29]. This study has limitations; as this study was aimed to evaluate changes in blood pressure and PRA and aldosterone levels in obese subjects after weight loss, we did not address other mechanisms that could be important in obesity-related hypertension, such as oxidative stress, endothelial dysfunction, and sleep apnea. As a consequence, our conclusion could only be one of the many hypothesis to explain the complexity and multifactorial nature of obesity-related hypertension. In conclusion, a hyperactivity of the RAAS is possibly present but it is not the only cause of obesity-related hypertension [36]. Weight loss is accompanied, in hypertensive obese subjects, by reduction of blood pressure and of PRA and aldosterone levels.

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