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The Journal of Clinical Endocrinology & Metabolism 89(7):3455–3461
Copyright © 2004 by The Endocrine Society
doi: 10.1210/jc.2003-032143
Thyroid Function and Blood Pressure Homeostasis in
Euthyroid Subjects
OLGA GUMIENIAK, TODD S. PERLSTEIN, PAUL N. HOPKINS, NANCY J. BROWN,
LAINE J. MURPHEY, XAVIER JEUNEMAITRE, NORMAN K. HOLLENBERG, AND
GORDON H. WILLIAMS
Endocrinology, Diabetes and Hypertension Division, Department of Medicine (O.G., T.S.P., G.H.W.), and Department of
Radiology (N.K.H.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of
Cardiovascular Genetics, Cardiology Division (P.N.H.), University of Utah, Salt Lake City, Utah 84112; Department of
Medicine (N.J.B., L.J.M.), Vanderbilt University, Nashville, Tennessee 37232; and Department of Genetics and Clinical
Investigation Centre (X.J.), Hôpital Europeen Georges Pompidou, Paris 75908, France
Overt and subclinical hypothyroidism are associated with increased systemic vascular resistance and hypertension. We
examined the relationship between thyroid function and
blood pressure homeostasis in euthyroid individuals. A total
of 284 subjects (68% hypertensive) consumed high- (200 mmol)
and low- (10 mmol) sodium diets, and their blood pressure
responses were assessed as percentage change in the mean
arterial pressure (MAP). p-Aminohippuric acid clearance was
used to estimate effective renal plasma flow. Renal vascular
resistance (RVR) was calculated as MAP divided by effective
renal plasma flow. Serum free T4 index (FTI) was lower (P <
0.0001) and TSH was higher (P ⴝ 0.046) in hypertensive compared with normotensive subjects independent of other baseline characteristics. FTI (␤ ⴝ ⴚ1.51, P < 0.0001), baseline MAP,
and race independently predicted MAP salt sensitivity. The
H
YPOTHYROID HUMANS AND animals have increased systemic vascular resistance, which is
thought to be the main pathophysiological mechanism by
which hypertension is associated with the hypothyroid state
(1, 2). Hypothyroidism also leads to alterations in sodium
homeostasis, and blood pressure salt sensitivity is reported
in hypothyroid patients (3). The upper limit of the normal
range for serum TSH has decreased over the years as insights
were gained into the health consequences of even mild degrees of thyroid deficiency. Indeed, many cardiovascular
manifestations of primary hypothyroidism are found in the
subclinical phase, including hypertension and disturbances
of sodium metabolism (4 – 8).
In euthyroid subjects it has been observed that serum
thyroid hormone concentrations have an impact on cardiovascular health. Low free T4 concentration was found to be
an independent risk factor for atherosclerosis in euthyroid
subjects (9). Subjects with TSH values in the upper normal
range had endothelial dysfunction (10) and hypercholesterAbbreviations: BMI, Body mass index; CI, confidence interval; DBP,
diastolic blood pressure; ERPF, effective renal plasma flow; FTI, free T4
index; HOMA, homeostasis model assessment; MAP, mean arterial
pressure; OR, odds ratio; PRA, plasma renin activity; RVR, renal vascular resistance; THBR, thyroid hormone binding ratio.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
FTI relationship with salt sensitivity adjusted for baseline
MAP and race was similar among normotensive (␤ ⴝ ⴚ1.42, P ⴝ
0.008) and hypertensive subjects (␤ ⴝ ⴚ1.66, P ⴝ 0.0001). FTI
correlated negatively with high- (P ⴝ 0.0001) and low- (P ⴝ
0.008) salt RVR, whereas TSH correlated positively with high(P ⴝ 0.016) and low- (P ⴝ 0.012) salt RVR independent of age,
gender, race, and body mass index. We have found that FTI is
lower and TSH is higher in hypertensive compared with normotensive euthyroid subjects and that FTI independently predicts blood pressure salt sensitivity. These data show that the
influence of thyroid function on blood pressure homeostasis
extends into euthyroid range and likely reflects the action of
thyroid hormone on peripheral vasculature. (J Clin Endocrinol Metab 89: 3455–3461, 2004)
olemia (11). Treatment with levothyroxine improved lipid
profiles of hyperlipidemic patients with serum TSH concentrations in the upper normal range, whereas no significant
effects were observed in patients with low-normal TSH values (12).
To further explore the influence of thyroid function on
cardiovascular system we examined the relationship between thyroid function and blood pressure homeostasis in
euthyroid subjects.
Subjects and Methods
Subjects in this report were studied by the international HyperPath
(Hypertensive Pathotype) group. All subjects were generally healthy
community-dwelling normotensive and hypertensive individuals. Included in this report are a total of 284 euthyroid Caucasian and AfricanAmerican subjects who had both serum TSH and free T4 index (FTI)
concentrations available, whose TSH values were within the laboratory
reference range and who were not taking thyroid hormone therapy.
Blood samples for thyroid function testing were obtained in the morning
of the high-salt study day, and assays were performed in the central
laboratory. FTI was used to estimate the free thyroid hormone concentration because free T4 measurements were not available. FTI was calculated as total T4 multiplied by the thyroid hormone binding ratio
(THBR).
Patients were studied at the General Clinical Research Centers
(GCRC) of the Brigham and Women’s Hospital in Boston, Massachusetts
(n ⫽ 93), Hospital Broussais in Paris, France (n ⫽ 64), University of Utah
Medical Center in Salt Lake City, Utah (n ⫽ 79), and Vanderbilt University in Nashville, Tennessee (n ⫽ 48). The institutional review boards
of the respective institutions approved the study, and all subjects gave
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written informed consent before enrollment. Subjects at each site underwent an identical protocol, which has been described in detail previously (13, 14). There were 154 patients studied with no other sibling
included, 112 patients from sibling pairs, and 18 from sibling trios.
All subjects had high- (200 mmol/d) and low- (10 mmol/d) sodium
diets consumed as outpatients for 4 –7 d each. The order of the diets was
high-salt week first, followed by a low-salt week in most cases. For some
subjects the sequence was reversed for scheduling reasons. Two hundred seventeen subjects who achieved sodium balance on both diets are
included in the analyses involving blood pressure salt sensitivity. Sodium balance was defined as urinary excretion of at least 150 mmol
Na/24 h and 30 mmol Na or less/24 h on the high- and low-salt diets,
respectively.
Hypertension in a proband was defined as a diastolic blood pressure
(DBP) of at least 100 mm Hg while off medications or at least 90 mm Hg
while taking one medication or more, or treatment with two or more
medications. Hypertensive siblings had to have a DBP of at least 90 mm
Hg while off medication, DBP of at least 80 mm Hg while taking one
antihypertensive medication, or were being treated with two or more
agents. Normotensive subjects, in addition to having blood pressure less
than 140/90 mm Hg, reported no first-degree relatives diagnosed with
hypertension before the age of 60 yr. All subjects had a screening history,
physical examination, and laboratory tests. Those with secondary forms
of hypertension, diabetes mellitus, obesity [body mass index (BMI) ⬎34
kg/m2, renal insufficiency, alcohol intake greater than 12 oz per week,
or any significant medical or psychiatric illnesses were excluded. Subjects were between 18 and 65 yr of age. All antihypertensive medications
were stopped 2– 4 wk before the study.
Subjects were admitted to the GCRC the night before high- and
low-sodium studies. Baseline blood pressure was defined as the mean
of three consecutive readings (by Dinamap; Critikon, Inc., Tampa, FL)
separated by 5 min each, measured at bed rest in the morning after a
week of high-salt intake. Mean arterial pressure (MAP) was calculated
from the baseline blood pressure using the following formula: 1/3 [systolic blood pressure ⫺ DBP] ⫹ DBP. Blood pressure salt sensitivity was
assessed as percentage change in the MAP in low-sodium balance from
the high-salt MAP. Effective renal plasma flow (ERPF) (as p-aminohippuric acid clearance) was calculated from steady-state plasma p-aminohippuric acid concentrations as previously described (15, 16). ERPF was
normalized to a body surface area of 1.73 m2 by the equation body
surface area ⫽ W0.452 ⫻ H0.0725 ⫻ 0.007184, where H is height in centimeters and W is weight in kilograms. Renal vascular resistance (RVR)
was calculated as the ratio of MAP to ERPF. High- and low-salt RVR data
were available for 141 and 86 subjects, respectively.
The homeostasis model assessment (HOMA) of insulin resistance was
calculated as [fasting plasma glucose (millimoles per liter) 䡠 fasting
plasma insulin (microunits per milliliter)]/22.5. Creatinine clearance
(milliliters per minute) was calculated as [(urine creatinine (milligrams
per deciliter)/serum creatinine (milligrams per deciliter)] 䡠 [urine volume (milliliters)/time (hour) 䡠 60].
Details of most laboratory assays have been described previously (15,
16). TSH, total T4, and THBR assays were performed centrally at the
Brigham and Women’s Hospital core laboratory. Serum TSH measurements were performed using Beckman Access chemiluminescence analyzer (Beckman Coulter, Inc., Fullerton, CA). The reference range for
serum TSH was 0.5–5.0 mIU/liter. Serum T4 measurements were performed with Beckman Coulter Access Immunoassay system using
chemiluminescent technology (Beckman Coulter, Inc.). Diagnostic Products Corp. (Los Angeles, CA) RIA was used for THBR measurements.
Some characteristics of this population have been reported previously
(13, 14); however the present analyses are original.
Statistical analysis
Statistical analysis was performed with the SAS 8.0 software (SAS
Institute Inc., Cary, NC). For descriptive analyses, mean and sd values
were used for continuous variables, and counts and percentages were
used for discrete variables. The log-transform was applied to nonnormally distributed variables to achieve normality, where appropriate.
Serum TSH values were log-transformed for logistic regression analyses.
Generalized estimating equations methods in PROC GENMOD (SAS
Institute Inc.) with family number as the repeated variable were used to
account for potential nonindependence of observations, when subjects
Gumieniak et al. • Thyroid Function and Blood Pressure in Euthyroid Subjects
were related. These methods may be preferred over other techniques for
various reasons to account for correlated data. Baseline characteristics
between normotensive and hypertensive subjects were compared using
univariate linear or logistic regression clustered by family in PROC
GENMOD. The logit option was used to determine whether FTI and TSH
associations with hypertension were independent of other covariates.
Baseline characteristics (age, BMI, gender, race, and hypertension status)
of subjects who did not provide salt sensitivity or RVR measurements
were compared with those of participants who had analyzable data. All
regression analyses were controlled for correlated structure of the data.
Nonsignificant covariates were reintroduced into the model to detect a
substantial (20%) change in regression coefficients of the significant
variables as a test for confounding. For each model, the independent
predictive value of FTI or TSH was confirmed by the enter method,
including all covariates in the model simultaneously. All reported P
values are based on two-sided tests.
Results
The baseline characteristics of 284 subjects are shown in
Table 1. The mean age of the subjects was 45 yr, 44% were
female, 17% were black, and 68% were hypertensive. As
anticipated, hypertensive subjects had a higher blood pressure (P ⬍ 0.0001), were older (P ⬍ 0.0001), and had a higher
BMI (P ⬍ 0.0001) than normotensive subjects. There were a
greater proportion of males among hypertensive than among
normotensive subjects (P ⫽ 0.044). As we have reported
previously, there was no significant difference in insulin
sensitivity between our normotensive and hypertensive subjects using HOMA index (16), which is likely related to the
heterogeneity of our hypertensive population and to the
exclusion of subjects with diabetes mellitus, significant obesity, renal insufficiency, or any significant medical illness.
Serum TSH (P ⫽ 0.66) and FTI (P ⫽ 0.09) were similar in
males and females. Black subjects had similar FTI (P ⫽ 0.97)
and lower TSH concentrations (P ⫽ 0.035) compared with
whites, which is in agreement with the National Health and
Nutrition Examination Survey III results (17). Interestingly,
a lower serum FTI concentration (P ⬍ 0.0001) and a higher
TSH level (P ⫽ 0.046) were associated with hypertension
(Table 1). To determine whether these results differed after
controlling for other baseline characteristics, we performed
multivariable logistic regression analyses separately with
serum TSH and FTI. We found that higher levels of serum
TSH (log-transformed values) [odds ratio (OR) ⫽ 1.7; 95%
confidence interval (CI), 1.1, 2.9; P ⫽ 0.032] and lower FTI
(OR ⫽ 0.64; 95% CI, 0.53, 0.77; P ⬍ 0.0001) were associated
with hypertension independently of age, BMI, gender, race,
smoking, and insulin sensitivity. Gender or race did not
modify the relationships between FTI and TSH with hypertension status. In a multivariable model including both serum FTI and TSH as covariates, FTI had a stronger association with hypertension (OR ⫽ 0.65; 95% CI, 0.54, 0.79; P ⬍
0.0001) than did TSH (OR ⫽ 1.4; 95% CI, 0.81, 2.5; P ⫽ 0.22).
Serum FTI negatively correlated with high-salt DBP (r ⫽
⫺0.228, P ⫽ 0.003), which was independent of age, gender,
race, BMI, and insulin sensitivity (␤ ⫽ ⫺1.96; 95% CI, ⫺3.2,
⫺0.7; P ⫽ 0.003). Presence of hypertension did not modify
this relationship (P ⫽ 0.52 for an interaction term). Each
microgram-per-deciliter decrease in FTI was associated with
an approximately 1.96-mm Hg rise in DBP. Thus, a decrease
in FTI from 10 to 5 ␮g/dl is anticipated to lead to an approximately 10-mm Hg elevation of DBP.
Gumieniak et al. • Thyroid Function and Blood Pressure in Euthyroid Subjects
J Clin Endocrinol Metab, July 2004, 89(7):3455–3461 3457
TABLE 1. Characteristics of subjects
Characteristic
Age (yr)
Gender (female %)
Race (black %)
Systolic blood pressure (mm Hg)
DBP (mm Hg)
TSH (mIU/liter) (nl range 0.5–5.0)
FTI (␮g/dl) (nl range 5.0 –11.0)a
BMI (kg/m2)
HOMA
Current smoking (%)
Serum protein (g/dl)b
Creatinine clearance (ml/min)c
All subjects
(n ⫽ 284)
Hypertensive subjects
(n ⫽ 194)
Normotensive subjects
(n ⫽ 90)
P value
45.0 ⫾ 9.9
44.4
17.1
137.8 ⫾ 25.4
82.2 ⫾ 14.9
1.6 ⫾ 0.9
Range 0.5–5.0
7.1 ⫾ 1.4
Range 3.1–11.4
27.3 ⫾ 3.9
2.2 ⫾ 1.4
10.7
7.35 ⫾ 0.54
108.7 ⫾ 34.1
48.2 ⫾ 7.7
40.2
18.8
150.7 ⫾ 19.0
89.4 ⫾ 11.4
1.7 ⫾ 0.9
38.2 ⫾ 10.5
53.3
13.5
109.9 ⫾ 11.1
66.5 ⫾ 7.7
1.5 ⫾ 0.8
⬍0.0001
0.044
0.15
⬍0.0001
⬍0.0001
0.046
6.8 ⫾ 1.3
7.8 ⫾ 1.4
⬍0.0001
28.1 ⫾ 3.4
2.2 ⫾ 1.5
10.8
7.34 ⫾ 0.54
107.4 ⫾ 37.1
25.3 ⫾ 2.3
2.2 ⫾ 1.2
10.0
7.35 ⫾ 0.56
110.4 ⫾ 29.9
⬍0.0001
0.66
0.83
0.98
0.63
Values reported as mean ⫾ SD. Univariate linear or logistic regression clustered by family was used to compare baseline characteristics
between normal (nl) and hypertensive subjects.
a
Conversion factor for Systeme International units, multiply by 12.87.
b
Conversion factor for Systeme International units, multiply by 10.0.
c
Conversion factor for Systeme International units, multiply by 0.0167.
TABLE 2. Univariate predictors of MAP response to changes in
sodium balance
Covariate
␤ estimate
95% CI
P value
Age (yr)
Female gender
Black race
Hypertension status
High-salt MAP (mm Hg)
BMI (kg/m2)
Serum protein (g/dl)
Creatinine clearance (ml/min)
HOMA
TSH (mIU/liter)
FTI (␮g/dl)
0.22
1.5
4.0
6.7
0.22
0.24
0.21
⫺0.03
⫺0.11
0.73
⫺1.68
0.11, 0.32
⫺1.2, 4.3
0.58, 7.5
4.4, 9.0
0.16, 0.28
⫺0.08, 0.58
⫺2.4, 2.8
⫺0.07, ⫺0.007
⫺0.92, 0.69
⫺0.43, 1.89
⫺2.3, ⫺1.0
⬍0.0001
0.27
0.021
⬍0.0001
⬍0.0001
0.14
0.87
0.015
0.77
0.21
⬍0.0001
TABLE 3. Final model for predicting MAP salt sensitivity
FIG. 1. MAP sensitivity to dietary sodium decreases with increasing
quartile of FTI in all subjects (P ⬍ 0.0001 for trend) (A) and does not
significantly change with increasing quartile of TSH (P ⫽ 0.45 for
trend) (B). Bars represent mean response, error bars are ⫾ SE. Values
on the x-axis represent mean FTI or TSH for each quartile. Normal
values: FTI, 5.0 –11.0 ␮g/dl (to convert to SI, multiply by 12.87); TSH,
0.5–5.0 mIU/liter.
What biological mechanisms could explain our finding of
the independent association between thyroid function and
hypertension status in euthyroid subjects? We hypothesized
that, perhaps, thyroid function influences blood pressure salt
sensitivity. Subjects who achieved sodium balance and are
included in salt sensitivity analyses did not differ in their
baseline characteristics from those who were not in salt balance. Both hypertensive and normotensive subjects had significant blood pressure reductions with the low-sodium diet.
Covariate
␤ estimate
95% CI
P value
FTI (␮g/dl)
High-salt MAP (mm Hg)
Black race
⫺1.51
0.18
2.6
⫺2.22, ⫺0.79
0.14, 0.24
0.05, 5.2
⬍0.0001
⬍0.0001
0.046
Hypertensive subjects’ high-salt MAP was 109.6 ⫾ 13.2 mm
Hg, whereas their low-salt MAP was 99.1 ⫾ 13.3 mm Hg (P ⬍
0.0001). Normotensive subjects’ high-salt MAP was 80.8 ⫾
8.2 mm Hg, and their low-salt MAP was 77.8 ⫾ 6.9 mm Hg
(P ⬍ 0.0001).
Figure 1 illustrates univariate relationships between FTI
and TSH with MAP salt sensitivity by quartile of FTI and
TSH. Salt sensitivity progressively decreases with increasing
serum FTI in all subjects (P ⬍ 0.0001), whereas no significant
relationship is observed between serum TSH and salt sensitivity. Table 2 shows univariate predictors of MAP response to changes in dietary sodium. Age (P ⬍ 0.0001),
hypertension status (P ⬍ 0.0001), black race (P ⫽ 0.021),
baseline MAP (P ⬍ 0.0001), FTI (P ⬍ 0.0001), and creatinine
clearance (P ⫽ 0.015) had significant univariate relationships
with blood pressure salt sensitivity.
A multivariable linear regression analysis determined that
lower FTI (␤ ⫽ ⫺1.51, P ⬍ 0.0001), baseline MAP (␤ ⫽ 0.18,
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Gumieniak et al. • Thyroid Function and Blood Pressure in Euthyroid Subjects
P ⬍ 0.0001), and black race (␤ ⫽ 2.6, P ⫽ 0.046) were independent predictors of MAP response to low sodium balance
(Table 3). Although significantly associated with blood pressure response to changes in sodium balance in the univariate
analysis, age, hypertension status, and creatinine clearance
were not independent predictors of MAP salt sensitivity in
a multivariable model because of strong confounding by
baseline MAP. None of the nonsignificant covariates confounded the effect of FTI. Serum FTI contributed approximately 6% of the variability in MAP salt sensitivity above
that accounted for by baseline MAP and race. The regression
estimates for the effect of FTI on MAP response to low sodium balance adjusted for baseline MAP and race were very
similar in normotensive (␤ ⫽ ⫺1.42; 95% CI, ⫺2.47, ⫺0.36;
P ⫽ 0.008) and hypertensive (␤ ⫽ ⫺1.66; 95% CI, ⫺2.51,
⫺0.82; P ⫽ 0.0001) subjects. Serum TSH was not significantly
associated with blood pressure salt sensitivity in a multivariable analysis. Hypertension status, gender, or race did not
modify the relationships between FTI and TSH with blood
pressure salt sensitivity.
We explored at a greater depth the possible mechanisms
of the relationship between serum FTI and blood pressure
salt sensitivity, particularly focusing on the relationship between thyroid function and RVR. Table 4 shows plasma renin
activity (PRA), aldosterone concentrations, and renal hemodynamic parameters determined while in balance on highand low-sodium intake. As expected, plasma aldosterone
(P ⬍ 0.0001) and PRA (P ⬍ 0.0001) levels were higher during
the low- compared with the high-sodium diet. ERPF increased with a high-sodium diet (P ⬍ 0.0001), whereas RVR
did not significantly change (P ⫽ 0.10).
Subjects who provided high- and/or low-salt RVR data
did not significantly differ from the remaining participants
except for a greater proportion of whites among those with
analyzable high-salt RVR (90.4 vs. 72.4%, P ⫽ 0.045) and
fewer hypertensive subjects among those with available lowsalt RVR measurements (49.0 vs. 82.4%, P ⬍ 0.0001). Figure
2 illustrates univariate relationships between serum FTI and
TSH with RVR by quartiles of FTI and TSH. Serum TSH was
positively and FTI was negatively correlated with both highand low-salt RVR (Table 5). These relationships were independent of age, BMI, gender, and race (Table 6). Not
surprisingly, these relationships were not independent of
absolute levels of MAP since RVR was calculated as the ratio
of MAP to ERPF. In the linear regression model with blood
pressure salt sensitivity as an outcome variable, addition of
high-salt RVR resulted in a 41% decrease in the FTI effect
estimate. Thus, our findings are consistent with the hypoth-
TABLE 4. Plasma aldosterone, PRA, and renal hemodynamics in a steady-state high- and low-sodium balance
Plasma aldosterone (ng/dl)a
Supine PRA (␮g/liter䡠h)
ERPF (ml/min䡠1.73 m2)
RVR (mm Hg/ml䡠min䡠1.73 m2)
a
High-sodium balance
Low-sodium balance
P value
5.4 ⫾ 4.2
0.51 ⫾ 0.56
530.6 ⫾ 112.4
0.20 ⫾ 0.06
18.2 ⫾ 11.9
2.6 ⫾ 2.5
521.6 ⫾ 112.3
0.17 ⫾ 0.05
⬍0.0001
⬍0.0001
⬍0.0001
0.103
Conversion factor for Systeme International units, multiply by 27.74.
FIG. 2. RVR decreases with increasing quartile of FTI (P ⫽ 0.001 for trend with high-salt RVR; P ⫽ 0.001 for trend with low-salt RVR) (A)
and increases with increasing quartile of TSH (P ⫽ 0.005 for trend with high-salt RVR; P ⫽ 0.011 for trend with low-salt RVR) (B). Bars represent
mean response, error bars are ⫾ SE. Values on the x-axis represent mean FTI or TSH for each quartile. Normal values: FTI, 5.0 –11.0 ␮g/dl
(to convert to SI, multiply by 12.87); TSH, 0.5–5.0 mIU/liter.
Gumieniak et al. • Thyroid Function and Blood Pressure in Euthyroid Subjects
J Clin Endocrinol Metab, July 2004, 89(7):3455–3461 3459
TABLE 5. Correlations of renal hemodynamic parameters, plasma aldosterone, and PRA with serum FTI and TSH
FTI (␮g/dl)
High-salt RVR (mm Hg/ml䡠min䡠1.73 m2)
Low-salt RVR (mm Hg/ml䡠min䡠1.73 m2)
High salt MAP (mm Hg)
Low-salt MAP (mm Hg)
High-salt SBP (mmHg)
Low-salt SBP (mm Hg)
High-salt DBP (mmHg)
Low-salt DBP (mm Hg)
High-salt ERPF (ml/min䡠1.73 m2)
Low-salt ERPF (ml/min䡠1.73 m2)
High-salt plasma aldosterone (ng/dl)
Low-salt plasma aldosterone (ng/dl)
High-salt PRA (␮g/liter䡠h)
Low-salt PRA (␮g/liter䡠h)
TSH (mIU/liter)
Correlation coefficient
P value
Correlation coefficient
P value
⫺0.386
⫺0.298
⫺0.226
⫺0.065
⫺0.207
⫺0.055
⫺0.228
⫺0.105
0.278
0.251
⫺0.041
0.056
0.122
0.127
0.0001
0.008
0.054
0.8
0.7
0.8
0.003
0.49
0.001
0.016
0.7
0.28
0.16
0.19
0.270
0.343
0.090
0.089
0.074
0.052
0.088
0.105
⫺0.183
⫺0.372
0.037
⫺0.098
⫺0.085
⫺0.053
0.016
0.012
0.37
0.8
0.26
0.9
0.7
0.7
0.13
0.012
0.8
0.05
0.12
0.26
Pearson or Spearman correlation coefficients reported. Univariate linear regression clustered by family was used to determine statistical
significance. SBP, Systolic blood pressure.
TABLE 6. Multivariable linear regression determined that the
associations between FTI and TSH with RVR are independent of
age, gender, race, and BMI
Covariate
␤ estimate
95% CI
P value
High-salt RVR with age, gender, race, and BMI in the model
FTI (␮g/dl)
TSH (mIU/liter)
⫺0.0099
0.0098
⫺0.02, ⫺0.004
0.0016, 0.018
0.001
0.019
Low-salt RVR with age, gender, race, and BMI in the model
FTI (␮g/dl)
TSH (mIU/liter)
⫺0.0073
0.019
⫺0.01, ⫺0.001
0.012, 0.026
0.021
⬍0.0001
esis that the relationship between FTI and salt sensitivity is
in part mediated by the vascular action of thyroid hormone.
Why were the results of the analyses with serum TSH
involving absolute level of blood pressure and salt sensitivity
not significant? We hypothesized that the effect of serum FTI
on blood pressure salt sensitivity and absolute blood pressure levels may have been easier to detect than the effect of
TSH. Serum TSH and FTI were correlated, but the strength
of their correlation was not very high (r ⫽ ⫺0.266). This is not
unexpected given the pulsatile nature of TSH secretion and
individual variations in the feedback mechanism between
serum T4 and TSH secretion (18). In fact, Framingham Heart
Study investigators reported no correlation between serum
TSH with any of the thyroid hormone levels in euthyroid
subjects (19). Therefore, identical serum TSH levels do not
correspond to the same thyroid hormone concentrations in
different people, which may explain the greater sensitivity of
serum FTI compared with TSH in our analyses.
Discussion
We have shown that lower serum FTI and higher TSH are
associated with hypertension in euthyroid subjects and that
serum FTI has a stronger relationship with hypertension than
TSH. A lower FTI level was independently associated with
higher absolute values of baseline DBP consistent with hypothyroidism predominantly affecting DBP (1, 20, 21).
We also found that a lower serum FTI level was an independent predictor of blood pressure salt sensitivity as determined when subjects were in balance on a high- and
low-sodium intake. The relationship between serum FTI and
blood pressure salt sensitivity was significant after controlling for baseline blood pressure, hypertension status, age,
BMI, gender, renal function, serum protein concentration,
and insulin resistance and was not different among hypertensive and normotensive subjects. Although qualitatively
higher serum TSH was associated with greater salt sensitivity, statistical significance was not reached.
Epidemiological factors associated with blood pressure
salt sensitivity are advanced age, black race, family history
of hypertension, male gender, and hypertension type (22, 23).
We were able to control for these potential confounders in
our analyses and show that the relationship between FTI and
blood pressure salt sensitivity is independent of these known
risk factors. Blood pressure salt sensitivity is considered one
of the key elements in the pathogenesis of hypertension (24).
Our findings are compelling in light of recent evidence indicating that blood pressure response to change in sodium
balance among normotensive individuals predicts future
risk of developing hypertension (25). Therefore, thyroid
function may play a role in the pathogenesis of blood
pressure salt sensitivity and hypertension in euthyroid
individuals.
The mechanisms by which lower thyroid function as reflected by lower FTI values would cause blood pressure salt
sensitivity are unclear. However, clues are available from
studies in hypothyroid subjects who have an increased systemic vascular resistance, vasoconstriction in systemic and
renal vessels, decreased glomerular filtration rate, increased
total body sodium content, and abnormal renal sodium handling (2, 26). Additional clues come from basic science experiments dissecting the mechanisms of the effect of thyroid
hormone on the peripheral vasculature. T3 is a vasodilator
acting directly on vascular smooth muscle cells (27). Serum
T4 caused relaxation of skeletal muscle resistance arterioles
(28), indicating the importance of both thyroid hormones for
vascular function. In addition, local T3 conversion from T4 in
the vascular cells likely has an important role in the maintenance of vascular tone because type II iodothyronine deiodinase has been found in cultured human coronary artery
and aortic smooth muscle cells (29). Our findings of the
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J Clin Endocrinol Metab, July 2004, 89(7):3455–3461
association between thyroid function and RVR support the
hypothesis that vascular actions of thyroid hormone underlie
the relationship between thyroid function with blood pressure salt sensitivity and hypertension.
Although hypertension of hypothyroidism is usually a
low-renin state (2), overall effects of hypothyroidism on the
renin-angiotensin-aldosterone system are thought to be minimal and not responsible for alterations in sodium homeostasis (30). In this study, we have not detected any significant
relationships between thyroid function and the renin-angiotensin-aldosterone system.
Other investigators observed that thyroid function appears to influence the state of health in euthyroid subjects
(9 –12, 31, 32). We extend these previous observations to
suggest that the effect of thyroid hormone on blood pressure
homeostasis may be seen in euthyroid individuals.
Our findings must be interpreted in the context of study
design. These analyses were exploratory and require confirmation. Our data are from individuals younger than age 66
yr and may not apply to an older age group. The strengths
of this study are its large sample size, ability to control for
relevant confounders, and carefully controlled experimental
conditions.
In summary, we have found that serum FTI is lower and
TSH is higher in hypertensive compared with normotensive
euthyroid subjects and that serum FTI independently predicts blood pressure salt sensitivity. Moreover, both TSH and
FTI are associated with RVR. These data show that the influence of thyroid function on blood pressure homeostasis
extends into euthyroid range and likely reflects the vascular
action of thyroid hormone. It has been suggested that thyroid
hormone analogs that selectively target vascular smooth
muscle cells to promote vasodilation may serve as a new class
of antihypertensive agents (33). Our findings suggest that
these novel agents will have a positive effect on blood pressure salt sensitivity, which may have a role in the prevention
of hypertension.
Acknowledgments
We gratefully acknowledge the assistance of the dietary, nursing,
administrative, and laboratory staffs of the four clinical research centers.
Received December 15, 2003. Accepted April 8, 2004.
Address all correspondence and requests for reprints to: Gordon H.
Williams, M.D., Endocrine-Hypertension Division, 221 Longwood
Avenue, RFB-2, Boston, Massachusetts 02115. E-mail: gwilliams@
partners.org.
This research was supported by the following grants: National Institutes of Health (NIH) Grants HL47651, HL59424, and DK63214; Specialized Center of Research in Hypertension from the National Heart,
Lung and Blood Institute Grant HL55000; National Center for Research
Resources (General Clinical Research Centers), Boston, Massachusetts
(M01 RR 02635), Salt Lake City, Utah (M01 RR 00064), and Vanderbilt,
Nashville, Tennessee (M01 RR 00095). O.G. and T.S.P. were supported
in part by the NIH Training Grant T32 HL007609.
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