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Salt-Resistant and Salt-Sensitive Phenotypes www.lejacq.com/CME

Determine the Sensitivity of Blood Pressure

to Weight Loss in Overweight/Obese Patients
1 CME
Irene S. Hoffmann, PhD;1 Anna B. Alfieri, PhD;1 Luigi X. Cubeddu, MD, PhD1,2

1
High blood pressure (BP) is extremely common in formin intervention appears to be determined by the
persons with obesity. However, not all obese indi- SR/SS phenotype. Weight loss and correction of met-
viduals have high BP, nor does weight loss lower BP abolic abnormalities lowers BP in obese SS persons
in all persons. In this study, the authors investigated but not in obese SR persons. Correcting adiposity
whether the salt-sensitive (SS) or salt-resistant (SR) in SS patients lowers BP by making the BP insensi-
phenotype determines the degree of BP lowering tive to dietary salt. The SR phenotype protects from
induced by weight loss in a group of middle-aged obesity-induced increases in BP. J Clin Hypertens
individuals of whom 80% are of Hispanic descent. (Greenwich). 2008;10:355–361. ©2008 Le Jacq
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 exer-
cise, and metformin therapy. Comparable reductions
in obesity (8%–10%), triglycerides (25%), and fast-
O verweight/obesity is a chronic disease that car-
ries an increased risk of hypertension, diabetes
mellitus, and premature death.1,2 The prevalence of
ing insulin concentrations (40%) were observed in obesity in industrialized countries has reached epi-
SR and SS individuals. In SS patients, the interven- demic proportions, with about 1 in 3 persons being
tion lowered systolic BP/diastolic BP by 8.8/6.1 mm obese and another 1 in 3 persons being overweight
Hg, decreased albuminuria by 63%, and decreased and at risk for developing obesity.3–5 Obesity-related
the patient’s salt sensitivity. Neither BP nor albu- metabolic derangements leading to accelerated athero-
minuria was modified in SR persons by the interven- sclerosis include alterations in lipids, increased blood
tion. In obese SS individuals, salt restriction induced pressure (BP), endothelial dysfunction, abnormalities
comparable BP lowering as weight reduction. In in insulin/glucose levels, coagulation, fibrinolysis, and
summary, BP lowering induced by the lifestyle/met- inflammation.1,5–12 Excessive weight gain is a com-
mon predictor of arterial hypertension, although the
reason for this association is unclear. Increased sym-
From the Department of Pharmaceutical Sciences, pathetic activity, hyperinsulinemia, activation of the
College of Pharmacy, Health Professions Division, renin-angiotensin system, impairment of nitric oxide
Nova Southeastern University, Fort Lauderdale, FL;1 bioactivity, and greater reactivity of BP to dietary salt
and the Center for the Detection and Treatment of
Silent Risk Factors for Cardiovascular and Metabolic (salt sensitivity) are some of the mechanisms proposed
Diseases, Division of Clinical Pharmacology Unit, to explain the increased prevalence of elevated BP in
School of Pharmacy, Central University of Venezuela, obese individuals.1,6,7,10–14 Multivariate genetic mod-
Caracas, Venezuela2 eling in twins suggests that the association of obesity
Address for correspondence: and hypertension is influenced by both genetic and
Luigi X. Cubeddu MD, PhD, Nova Southeastern
University, Health Professions Division, 3200 South environmental factors.15 Genetic and environmental
University Drive, Ft Lauderdale, FL 33328 factors have also been shown to determine the sensi-
E-mail: lcubeddu@nova.edu tivity of BP to sodium.16–24
Manuscript received August 22, 2007; Not all obese persons have high BP, and correction
revised January 3, 2008; accepted January 8, 2008 of obesity does not lower BP equally; BP response
to weight loss has been shown to vary among
www.lejacq.com ID: 7609

VOL. 10 NO. 5 may 2008 THE Journal of Clinical Hypertension 355

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 BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
 ®

individuals.15 The determinants of BP sensitivity to tests, urinalysis, and microalbuminuria and urinary
weight reduction are poorly understood. Salt sensitiv- sodium in 24-hour urine samples, were obtained
ity has been shown to be associated with obesity, and at baseline and at 12±1 months after the program
correction of adiposity has been shown to decrease began. Antihypertensive drugs were withheld for
salt sensitivity.23,25,26 Thus, we hypothesized that the 8 weeks before the salt sensitivity testing. BP was
salt-sensitive (SS) phenotype is an important determi- monitored on a weekly basis after antihypertensive
nant of the BP increase associated with obesity and drug withdrawal and on a monthly basis once the
of the extent of BP lowering induced by correction of intervention was begun (only 4 patients were on
adiposity. The salt-resistant (SR) phenotype, on the antihypertensive medication [3 in SS groups] after
other hand, would be characterized by resistance of washout; all 4 had systolic BP values between 140
BP to changes in body weight. To test our hypothesis, and 150 mm Hg).
dietary restriction combined with regular aerobic The goals of the lifestyle program were to achieve
exercise and metformin therapy was employed to and maintain a weight reduction of at least 7%
evaluate the comparative BP lowering in obese SS of body weight through a nutritionist-designed,
and SR individuals. Caloric restriction, exercise, healthy low-calorie diet (1800–2000 calories for
and metformin therapy are individually known to men and 1600–1800 calories for women), in which
induce weight loss; reduce central adiposity; lower carbohydrates composed 50% to 60%, fat <30%,
BP; improve the lipid profile, insulin sensitivity, and and protein 20% to 30%. In addition, participants
endothelial function; and decrease the development were asked to engage in aerobic physical activity of
of diabetes mellitus.15,27–29 moderate intensity, such as brisk walking, for about
150 min/wk. Exercise was to start slow and build up
Methods over the first 2 months. Metformin was started at a
Study Participants daily dose of 500 mg for one week and increased to
A total of 45 (15 SR and 30 SS) otherwise healthy 500 mg twice daily for an additional week, reach-
adult overweight/obese patients were enrolled in a ing a maximum dosage of 500 mg 3 times daily by
combined program of diet, exercise, and metformin the third week. Individualized adjustments in dose
therapy for weight reduction and correction of met- escalation were made based on drug tolerability.
abolic abnormalities. Patients were included if they Participants were seen on a monthly basis. Body
had a body mass index (BMI) between 27 and 35 weight, BP, heart rate, patient’s general health, and
kg/m2 and a waist circumference >102 cm for men program compliance were assessed, and benefits
and >92 cm for women (according to the National associated with the program were discussed and
Cholesterol Education Program Adult Treatment reinforced (behavior modification).
Panel III guidelines for abdominal obesity) and com- Salt sensitivity testing was conducted twice in all
pleted salt sensitivity testing.25 The main objective participants, once at the beginning of the study and
was to investigate whether the SS and SR pheno- again 12 months into the program. For the high-salt
type played a role in determining the BP-lowering diet, participants were instructed to continue with
effect of weight loss in obese persons. Participants their dietary habits and to take ten 1-g tablets of
were excluded if they were older than 70 or had sodium chloride daily for 1 week (≈17 g/d of salt).
a history of coronary artery disease, heart failure, The high-salt period was followed by a 1-week
valvular heart disease, stroke, transient ischemic period of a low-salt diet designed to provide 2.5 g/d.
attacks, arteriosclerosis obliterans, renal or hepatic The low-salt diet was formulated to contain the same
dysfunction, active disease states, oral contraceptive caloric intake as the high-salt diet. BP readings were
use, polycystic ovary syndrome, or serum creatinine obtained before and at the end of each of the salt
concentration >1.5 mg/dL. The research protocol periods. If the difference in mean BP between high-
was approved by the Central University Hospital and low-sodium weeks was ≥5 mm Hg, the patient
of the City of Caracas, Venezuela, and by the Nova was deemed SS. Salt resistance was defined either as
Southeastern University review boards. All partici- increases of <3 mm Hg, no changes, or decreases in
pants gave written informed consent. mean BP. Twenty-four–hour urinary sodium excre-
tion values were obtained for assessing levels of salt
Procedures intake and compliance with sodium diets. All partici-
Complete history, physical examination, and labo- pants were exposed to the same order of salt diets:
ratory investigations, including hematology, chem- first usual, next high, and last low salt intake. This
istry, fasting lipid panel, fasting and postload (75 g order was chosen because it is more accurate in test-
D-glucose) glucose and insulin levels, liver function ing for the BP effects of salt restriction than for the

356 THE Journal of Clinical Hypertension VOL. 10 NO. 5 May 2008

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 BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
 ®

effects of high salt. Although unlikely, the design does measures) was employed for the statistical analysis
not rule out an order effect of diets. of the data, followed by Bonferroni posttests to
BP was measured with a standard mercury sphyg- compare replicate means by salt sensitivity status.
momanometer with the cuff size optimized for arm cir- Triglyceride, insulin, and albuminuria concentrations
cumference. The same cuff, sphygmomanometer, and were log-transformed for statistical analysis and
arm were used to measure the BP in a specific patient. back-transformed for reporting. Differences were
Because BP was the main variable of the study, resting considered significant at values of P<.01.
BP was attained with patients lying comfortably rather
than sitting for 30 minutes. The average of 3 consecu- Results
tive BP readings not >4 mm Hg apart was employed. Salt sensitivity testing was conducted to determine
During the salt sensitivity testing, the investigators the BP reactivity to dietary salt of the study par-
obtaining the BP readings were not aware of the salt ticipants and to establish the comparative effects of
intake period of the study participants, of the partici- the lifestyle/metformin intervention in SR and SS
pants’ BP at baseline, or of the participants’ SS phe- patients. Of the study patients, 33.3% (n=15) were
notype. Results obtained were provided to the study SR, and the remaining 66.6% (n=30) were classi-
assistant, who entered the BP data in the participants’ fied as SS (Table). At baseline, most individuals were
data collection forms. Heart rate was estimated from moderately obese; had an increased waist circumfer-
a 1-minute pulse assessed after the last BP measure- ence; were mostly sedentary; and had fasting insulin,
ment. Overall adiposity was assessed by body weight low-density lipoprotein cholesterol, and triglyceride
and BMI. BMI was calculated as the ratio of body levels either within the upper normal range or slightly
weight in kilograms to height in meters squared (kg/ above normal levels. SR and SS individuals had com-
m2). Waist circumference was measured in the stand- parable weight; waist circumference; and fasting and
ing position midway between the highest point of the postload glucose, insulin, triglyceride, high-density
iliac crest and the lowest point of the costal margin in lipoprotein cholesterol, and low-density lipoprotein
the midaxillary line. All anthropometric measurements cholesterol concentrations. SS individuals were, how-
reflected the average of 2 measurements. Physical ever, an average of 8 years older and had significantly
activity was quantified employing the following 0-to-4 higher BP and urinary albumin excretion levels than
score: 0, completely sedentary; 1, only job-related the SR group (Table). BMI and urinary sodium were
activity; 2, regular activity but <30 minutes 3 times also higher in SS than in SR patients, but the values
weekly; 3, between 30 minutes and 1 hour 3 or 4 times did not reach statistical significance. The ethnic dis-
weekly; 4, any level >3. tribution of the study participants was as follows:
An oral glucose tolerance test was performed in all 75.8% of SS and 80% of SR were mixed Hispanic,
patients at the beginning and at the end of the study. and the rest were white.
An oral load of 75 g of D-glucose was administered The combined caloric restriction, aerobic exercise,
after a 12-hour overnight fast. Blood samples were and metformin intervention produced comparable
obtained at just before and after 30, 60, 90, 120, and percent reductions in weight, BMI, waist circumfer-
180 minutes for determination of plasma glucose and ence, low-density lipoprotein cholesterol, triglyc-
insulin. Plasma glucose was measured with an auto- erides, and basal and postload insulin and glucose
mated glucose analyzer (Beckman Instruments, Palo concentrations in SR and SS individuals (Table and
Alto, CA), employing a glucose oxidase technique. Figure 1). Systolic BP was decreased by 8.8 mm Hg
Plasma insulin was quantified by solid-phase radio- and diastolic BP by 6.1 mm Hg in the SS individuals,
immunoassay (Diagnostic Products Corporation, while no BP lowering was observed in SR persons,
Los Angeles, CA). Urinary albumin excretion was despite comparable reductions in weight and insulin
quantified in 24-hour urine samples (mg/24 h) by and lipid levels (Figure 1 and Figure 2). Similarly, uri-
nephelometric techniques (Coulter-Beckman, Los nary albumin excretion was reduced by nearly 60%
Angeles, CA). Urinary sodium was also measured in in SS patients, while it was not significantly changed
the 24-hour urine samples. Plasma lipids were mea- in SR persons (Table, Figure 1). In addition, in SS
sured by espectrophotometric techniques (Chiron individuals correction of adiposity markedly reduced
Diagnostic Corp, East Walpole, MA). the sensitivity of BP to dietary salt; whereas in SR
persons, the BP reactivity to salt was unchanged after
Statistical Analyses the intervention (Figure 2).
Results were reported as means ± SEM and as per- Figure 2 depicts the BP levels obtained under
centage of change from baseline ± SEM. Two-way conditions of high, usual, and low salt intake in
analysis of variance with repeated measures (paired SS and SR patients, before (when obese) and after

VOL. 10 NO. 5 may 2008 THE Journal of Clinical Hypertension 357

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 BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
 ®

Table. Baseline Characteristics and Effects of Lifestyle/Metformin Intervention in SR and SS Obese Patients
SR SS
Baseline Intervention Baseline Intervention
No. 15 (8 F/7 M) 15 (8 F/7 M) 29 (19 F/10 M) 29 (19 F/10 M)
Age, y 39.2±2.8 40.2±2.7a 47.8±2b 48.9±2.1a,b
Weight, kg 80.9±3.5 73.8±3.5a 78±3.2 70.6±3.3a
BMI, kg/m2 29.2±1.2 26.7±1.3a 31.1±0.9 28±0.9a
Waist, cm 95.5±1 90.9±2a 95.7±2 87.5±3a
Physical activityc 1.01±0.3 2.13±0.2a 0.80±0.2 1.93±0.2a
SBP, mm Hg 115±3 114±3 129±3b 120±2.3a,b
DBP, mm Hg 76±2 74±2 82±2b 76±1.8a
HR, beats/min 65±2 65±1.2 67±1.6 64±1.9
FSG, mg/dL 99±5 90±1.6 97±4 90±2
FSI, mIU/mL 22±3 10±2a 18±3 11±2a
2-h Glucose,d mg/dL 112±7 104±8 126±10 120±8
2-h Insulin,d mIU/mL 109±18 72±14a 98±12 74±7a
LDL-C, mg/dL 144±12 132±8a 142±6 131±6a
HDL-C, mg/dL 38±3 47±3a 42±2 46±1.5a
Triglyceride, mg/dL 151±16 117±12a 140±13 102±11a
Albuminuria, mg/d 7.8±0.7 7.1±1.0 14.7±2b 5.6±1.0a
Urinary Na+, mmoles/d 137±12 145±14 148±12 145±14
Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; F, female; FSG, fasting serum glucose; FSI, fasting serum insulin;
HDL-C, high-density lipoprotein cholesterol; HR, heart rate; LDL-C, low-density lipoprotein cholesterol; M, male; SBP, systolic blood pres-
sure; SR, salt-resistant; SS, salt-sensitive. Values are mean ± SEM for values obtained at baseline and at end of intervention in obese SR and
SS patients. aSignificant difference at P<.01 between baseline and intervention. bSignificant difference between SR and SS at P<.01. cPhysical
activity was quantified employing a 0–4 activity score. dSerum level 2 hours after a 75-g glucose load. Statistical significance was assessed by
2-way analysis of variance with paired measures (repeated measures) and Bonferroni posttests to compare replicate means by SS status.

the intervention (after weight loss). The BP of SR diastolic BP from 112.7±1.5/72±1 to 107.1±2/69±1
patients was insensitive to changes in salt intake mm Hg. In SR patients with systolic BP >120 mm
and to the lifestyle/metformin intervention (Figure Hg, the intervention failed to induce any BP lower-
2); whereas the BP of obese SS patients was sensitive ing (128±3/81±3 mm Hg at baseline and 127±7/80±3
both to salt intake and to the lifestyle/metformin mm Hg after the intervention).
intervention. The BP reactivity to salt of SS persons
was markedly reduced after the intervention (Figure Discussion
2). At the end of the 1-year intervention, the BP of The results of this study indicate that in a group of
SS persons was not different from that of SR per- obese middle-aged individuals of whom 80% are of
sons. In addition, the BP reduction induced by low Hispanic descent, the SR and SS phenotypes play an
salt in SS persons at baseline (when obese) was com- important role in determining the basal level of BP
parable to that induced by the intervention under and the BP response to changes in body weight. It
usual levels of salt intake (nearly 8.5 g). Of interest, was observed that the SR phenotype was character-
in SS individuals, only the BP obtained under high ized by lower BP at baseline and lack of BP lowering
or usual salt intake was reduced by the interven- after correction of obesity and related metabolic
tion. Baseline BP under low salt was not decreased abnormalities. On the other hand, the SS phenotype
by the intervention, suggesting that the BP lowering was associated with higher baseline BP and substan-
induced by weight reduction was due to correction tial BP lowering after weight reduction. Of impor-
of salt sensitivity (Figure 2). tance, these differences in BP and BP response to the
Because SS patients had higher BP than SR intervention were present despite comparable base-
patients, a subgroup analysis in SS participants line measurements of adiposity in SR and SS persons.
with systolic BP <120 mm Hg and in SR patients Our results suggest that in some individuals (perhaps
with systolic BP >120 mm Hg was performed. In genetically predisposed?), obesity and obesity-related
SS individuals, the intervention lowered systolic BP/ derangements may induce the expression of the SS

358 THE Journal of Clinical Hypertension VOL. 10 NO. 5 May 2008

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 BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
 ®

phenotype. Once the SS phenotype is expressed, BP 25 HDL

increases due to dietary salt intake. When the SS
phenotype is corrected by reducing adiposity, the BP

% Change From Baseline

becomes insensitive to salt, decreasing to levels com- 0
Wt BMI Waist LDL TG FSI UAE
parable to those observed under salt-restricted diets
and to those of SR obese patients (present study).
Our results support previous findings indicating
–25
that the mechanism by which BP is elevated in obese
persons is to a large extent due to development of salt
sensitivity.23, 26 Thus, it is assumed that correction of
–50
adiposity lowers BP because it corrects salt sensitivity.
This is supported by the observation that in obese SS SR
SS
participants, salt restriction achieves similar BP low- a
ering as correction of adiposity with a 1-year lifestyle/ –75
metformin intervention. We thus propose that due to Figure 1. Effects of the lifestyle/metformin intervention on
the development of the SS phenotype, dietary salt is a salt-resistant (SR) and salt-sensitive (SS) overweight/obese
major reason for the increases in BP associated with patients. Shown are the mean change ± SEM from base-
line induced by the lifestyle/metformin intervention for the
obesity and for the BP response to weight loss. In SR following variables: weight (Wt) in kg; body mass index
individuals, in whom dietary salt does not impact (BMI) in kg/m2; waist in cm; low-density lipoprotein
BP, no BP lowering was observed with the lifestyle/ (LDL) and high-density lipoprotein (HDL) cholesterol in
mg/dL; triglycerides (TG) in mg/dL; fasting serum insulin
metformin intervention. (FSI) in mIU/mL; and urinary albumin excretion (UAE)
Limitations of this study are that obese SR partici- ing/d. aSignificantly different from SR at P<.01.
pants had lower baseline BP than obese SS patients
and that the results may not be generalizable to other High
populations. The lower BP levels of SR persons at Basal salt
Usual
baseline may have limited additional BP lowering Intervention
a
salt
with the intervention. Studies investigating the effects 130 a
of weight reduction on BP of SR and SS individu-
SBP (mm Hg)

b
als with comparable baseline BP are needed to best Low
High Low salt
answer this question. Nevertheless, we compared 120 salt Usual salt b
salt
the effects of the intervention on BP in SR persons
with baseline BP >120/80 mm Hg with those of SS
persons. Even with BP within the range of that of SS 110
individuals, correction of adiposity failed to lower
BP in these SR patients. SS patients with baseline BP
of <120/80 mm Hg retained significant BP lowering 100
with the intervention. Consequently, and despite the
well-known limitations of post hoc analyses, our SR SS
results suggest that the higher BP of obese SS persons
than of obese SR persons results from dietary salt; Figure 2. Blood pressure levels at baseline and after the
lifestyle/metformin intervention in obese salt-resistant (SR)
under conditions of salt restriction, BP of obese SS and salt-sensitive (SS) individuals, obtained under high-,
patients was not different from that of SR patients. usual-, and low-salt diets. Shown are the mean values
Persons with the SS phenotype were on the aver- ± SEM for the systolic blood pressure (SBP) of SR and
SS patients obtained during high, usual, and low dietary
age 8 years older than those expressing the SR phe- salt intake before (baseline) and at the end of a 1-year
notype. This observation raises several questions. lifestyle/metformin intervention. Statistical significance
How long does it take for obesity to induce salt was assessed by 2-way analysis of variance with paired
measures (repeated measures) and Bonferroni posttests to
sensitivity and thus increase BP? Would obese SR compare replicate means by SS status. aSignificantly differ-
patients convert to SS if more time were allowed? ent from SR and bsignificantly from baseline at P<.01.
Is there an SR or SS genotype that predisposes indi-
viduals to become SS when obese? Although we have persons were SR when lean. Similar results have been
no final answers to these questions, the fact that the reported in obese adolescents.23 The investigators
intervention converted salt sensitivity into salt resis- reported in markedly obese adolescents that weight
tance suggests that at least in some individuals these reduction decreased salt sensitivity. In addition, in
phenotypes are interchangeable and that possibly SS animal models, increases in salt intake raised the BP

VOL. 10 NO. 5 may 2008 THE Journal of Clinical Hypertension 359

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 BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
 ®

of Wistar fatty but not of Wistar lean rats.30 It thus higher BP, which is most likely determined by an
appears that acquired factors (eg, obesity) may in increased BP sensitivity to salt. Correction of the lat-
some individuals increase the BP due to development ter by the intervention lowered BP, which in turn may
of salt sensitivity. The interplay of factors, such as have reduced intraglomerular pressure, decreasing the
duration of obesity and presence of inflammation amount of albumin in the urine.36 However, interven-
and/or endothelial dysfunction and of genetic pre- tion-induced improvements in glomerular hyperfiltra-
disposition (SR vs SS genotype) in determining the tion, endothelial dysfunction, vascular inflammation,
SS phenotype needs further research. Unfortunately, and renal nitric oxide production were not assessed;
available procedures for measuring salt sensitivity their contributory role in lowering albuminuria cannot
are cumbersome and time-consuming. There is no be ruled out.
simple method to establish the SR/SS phenotype or A combination of lifestyle measures and metform-
the genetic predisposition to develop salt sensitivity in therapy was employed in this study to achieve
other than by measuring BP changes induced by salt correction of the SS phenotype. Dietary restriction,
loading and unloading.31,32 aerobic exercise, and/or metformin therapy indi-
The possible contribution of genetic factors to vidually are known to induce weight loss, correct
the sensitivity of BP to weight reduction has been metabolic abnormalities associated with central
investigated.24 In overweight white hypertensive obesity, and reduce development of type 2 diabetes
patients, a greater decrease in BP after weight mellitus.25–29 Because our goal was to establish
loss was seen in those carrying the DD genotype whether the SS phenotype was correctable by inter-
than those carrying the ID or II genotypes for the ventions known to reduce adiposity and related
angiotensin-converting enzyme insertion/deletion metabolic derangements, the relative contributions
polymorphism.24 In elderly hypertensive persons, of caloric restriction, exercise, and metformin to the
presence of the DD genotype was reported to be correction of salt sensitivity are unknown.
associated with increased salt sensitivity.33 These A limitation of this study is the lack of ambula-
observations support our view that the SS pheno- tory BP data. Therefore, we do not know whether
type plays a pivotal role in determining the sensitiv- the intervention-induced BP lowering and salt sensi-
ity of BP to weight loss. Further research is needed tivity correction were associated with changes in the
on the role of genetic factors, since other investiga- dipping/nondipping status of the participants. This
tors have failed to observe an association between is particularly relevant because the incidence of non-
salt sensitivity and angiotensin-converting enzyme dipping is known to be increased in SS individuals.32
DD polymorphism34 and in addition reported Further studies are needed to answer this question.
opposite results. In fact, Japanese hypertensive
patients carrying the ID + II genotype were more Conclusions
SS than those carrying the DD genotype.35 Not BP lowering induced by weight reduction was deter-
surprisingly, obese Japanese carrying the ID + II mined by the SR/SS phenotype. A combined lifestyle/
genotype were more SS than nonobese subjects.35 metformin intervention leading to weight reduction
and correction of metabolic abnormalities did not
Albuminuria and Salt Sensitivity lower BP in a significant number of obese middle-
Increased urinary albumin excretion has been shown aged individuals of whom 80% were of Hispanic
to be an independent risk factor for cardiovascular descent. Those in whom increased dietary sodium did
events.36–39 In addition, it has been shown that SS not increase BP, known as SR, showed no decreases
patients have higher urinary albumin excretion levels in BP, whereas SS individuals experienced BP lower-
than SR patients (present study).16,17 The increased ing. Such differences in BP response were observed
levels of albuminuria may be related to the higher BP despite comparable reductions in obesity and serum
of SS persons than of SR individuals (present study). lipid and glucose/insulin levels in both groups. We also
Therefore, BP lowering and correction of salt sensitiv- demonstrated that in some individuals, obesity and
ity induced by the lifestyle/metformin intervention may obesity-related derangements induce the expression of
account for the reduction in albuminuria observed in the SS phenotype. Once the SS phenotype is expressed,
SS individuals. In salt resistance, the lack of BP decrease BP increases due to dietary salt intake. When the SS
is most likely responsible for the lack of reduction in phenotype is repressed, the BP becomes insensitive to
albuminuria despite correction of adiposity and related salt, decreasing to levels comparable to those observed
metabolic derangements. These results suggest that under salt-restricted diets and to those of SR obese
the increased urinary albumin excretion observed in patients. The SR phenotype may offer protection from
SS compared with SR persons may result from their the increases in BP commonly associated with obesity.

360 THE Journal of Clinical Hypertension VOL. 10 NO. 5 May 2008

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 BHarkinson@bos.blackwellpublishing.com or 781-388-8511.
 ®
Disclosure: This study was supported by grants from the Consejo
de Desarrollo Cientifico y Humanistico de la Universidad Central
de Venezuela: CDCH 06116247 and Locti IIF-03(1BA) and
CDCH 06006248 2006, 06006513 2008 and Locti IFF-02 (IHS)
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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
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