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1 CME CREDIT Salt-Resistant and Salt-Sensitive Phenotypes Determine the Sensitivity of Blood Pressure to Weight Loss in Overweight/Obese Patients 1 CME
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Irene S. Hoffmann, PhD;1 Anna B. Alfieri, PhD;1 Luigi X. Cubeddu, MD, PhD1,2
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High blood pressure (BP) is extremely common in persons with obesity. However, not all obese individuals have high BP, nor does weight loss lower BP in all persons. In this study, the authors investigated whether the salt-sensitive (SS) or salt-resistant (SR) phenotype determines the degree of BP lowering induced by weight loss in a group of middle-aged individuals of whom 80% are of Hispanic descent. Overweight/obese participants classified as SS or SR (N=45; body mass index, 27–35 kg/m2) entered a 1-year program of dietary restriction, aerobic exercise, and metformin therapy. Comparable reductions in obesity (8%–10%), triglycerides (25%), and fasting insulin concentrations (40%) were observed in SR and SS individuals. In SS patients, the intervention lowered systolic BP/diastolic BP by 8.8/6.1 mm Hg, decreased albuminuria by 63%, and decreased the patient’s salt sensitivity. Neither BP nor albuminuria was modified in SR persons by the intervention. In obese SS individuals, salt restriction induced comparable BP lowering as weight reduction. In summary, BP lowering induced by the lifestyle/met-
From the Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, Fort Lauderdale, FL;1 and the Center for the Detection and Treatment of Silent Risk Factors for Cardiovascular and Metabolic Diseases, Division of Clinical Pharmacology Unit, School of Pharmacy, Central University of Venezuela, Caracas, Venezuela2 Address for correspondence: Luigi X. Cubeddu MD, PhD, Nova Southeastern University, Health Professions Division, 3200 South University Drive, Ft Lauderdale, FL 33328 E-mail:
[email protected] Manuscript received August 22, 2007; revised January 3, 2008; accepted January 8, 2008
www.lejacq.com VOL. 10 NO. 5 may 2008
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formin intervention appears to be determined by the SR/SS phenotype. Weight loss and correction of metabolic abnormalities lowers BP in obese SS persons but not in obese SR persons. Correcting adiposity in SS patients lowers BP by making the BP insensitive to dietary salt. The SR phenotype protects from obesity-induced increases in BP. J Clin Hypertens (Greenwich). 2008;10:355–361. ©2008 Le Jacq
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verweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death.1,2 The prevalence of obesity in industrialized countries has reached epidemic proportions, with about 1 in 3 persons being obese and another 1 in 3 persons being overweight and at risk for developing obesity.3–5 Obesity-related metabolic derangements leading to accelerated atherosclerosis include alterations in lipids, increased blood pressure (BP), endothelial dysfunction, abnormalities in insulin/glucose levels, coagulation, fibrinolysis, and inflammation.1,5–12 Excessive weight gain is a common predictor of arterial hypertension, although the reason for this association is unclear. Increased sympathetic activity, hyperinsulinemia, activation of the renin-angiotensin system, impairment of nitric oxide bioactivity, and greater reactivity of BP to dietary salt (salt sensitivity) are some of the mechanisms proposed to explain the increased prevalence of elevated BP in obese individuals.1,6,7,10–14 Multivariate genetic modeling in twins suggests that the association of obesity and hypertension is influenced by both genetic and environmental factors.15 Genetic and environmental factors have also been shown to determine the sensitivity of BP to sodium.16–24 Not all obese persons have high BP, and correction of obesity does not lower BP equally; BP response to weight loss has been shown to vary among
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The Journal of Clinical Hypertension® (ISSN 1524-6175) is published monthly by Le Jacq, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Le Jacq is an imprint of Blackwell Publishing, which was acquired by John Wiley & Sons in February 2007. Blackwell’s programme has been merged with Wiley’s global Scientific, Technical, and Medical business to form Wiley-Blackwell. Copyright ©2008 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Ben Harkinson at
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individuals.15 The determinants of BP sensitivity to weight reduction are poorly understood. Salt sensitivity has been shown to be associated with obesity, and correction of adiposity has been shown to decrease salt sensitivity.23,25,26 Thus, we hypothesized that the salt-sensitive (SS) phenotype is an important determinant of the BP increase associated with obesity and of the extent of BP lowering induced by correction of adiposity. The salt-resistant (SR) phenotype, on the other hand, would be characterized by resistance of BP to changes in body weight. To test our hypothesis, dietary restriction combined with regular aerobic exercise and metformin therapy was employed to evaluate the comparative BP lowering in obese SS and SR individuals. Caloric restriction, exercise, and metformin therapy are individually known to induce weight loss; reduce central adiposity; lower BP; improve the lipid profile, insulin sensitivity, and endothelial function; and decrease the development of diabetes mellitus.15,27–29 Methods Study Participants A total of 45 (15 SR and 30 SS) otherwise healthy adult overweight/obese patients were enrolled in a combined program of diet, exercise, and metformin therapy for weight reduction and correction of metabolic abnormalities. Patients were included if they had a body mass index (BMI) between 27 and 35 kg/m2 and a waist circumference >102 cm for men and >92 cm for women (according to the National Cholesterol Education Program Adult Treatment Panel III guidelines for abdominal obesity) and completed salt sensitivity testing.25 The main objective was to investigate whether the SS and SR phenotype played a role in determining the BP-lowering effect of weight loss in obese persons. Participants were excluded if they were older than 70 or had a history of coronary artery disease, heart failure, valvular heart disease, stroke, transient ischemic attacks, arteriosclerosis obliterans, renal or hepatic dysfunction, active disease states, oral contraceptive use, polycystic ovary syndrome, or serum creatinine concentration >1.5 mg/dL. The research protocol was approved by the Central University Hospital of the City of Caracas, Venezuela, and by the Nova Southeastern University review boards. All participants gave written informed consent. Procedures Complete history, physical examination, and laboratory investigations, including hematology, chemistry, fasting lipid panel, fasting and postload (75 g D-glucose) glucose and insulin levels, liver function
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tests, urinalysis, and microalbuminuria and urinary sodium in 24-hour urine samples, were obtained at baseline and at 12±1 months after the program began. Antihypertensive drugs were withheld for 8 weeks before the salt sensitivity testing. BP was monitored on a weekly basis after antihypertensive drug withdrawal and on a monthly basis once the intervention was begun (only 4 patients were on antihypertensive medication [3 in SS groups] after washout; all 4 had systolic BP values between 140 and 150 mm Hg). The goals of the lifestyle program were to achieve and maintain a weight reduction of at least 7% of body weight through a nutritionist-designed, healthy low-calorie diet (1800–2000 calories for men and 1600–1800 calories for women), in which carbohydrates composed 50% to 60%, fat
