Effects of Salt Sensitivity on Neural Cardiovascular
Regulation in Essential Hypertension
Paolo Coruzzi, Gianfranco Parati, Lorenzo Brambilla, Valerio Brambilla, Massimo Gualerzi,
Almerico Novarini, Paolo Castiglioni, Marco Di Rienzo
Abstract—Salt-sensitive hypertensive subjects, as defined by conventional categorical classification, exhibit alterations of
autonomic cardiovascular control. The aim of our study was to explore whether, in hypertensive subjects, the degree of
autonomic dysfunction and the level of salt sensitivity are correlated even when the latter is only mildly elevated and
displays under-threshold values. Salt sensitivity of 34 essential hypertensive subjects was assessed on a continuous basis
by the salt sensitivity index after low- and high-sodium diet. Beat-by-beat finger blood pressure was recorded after each
diet period. Autonomic cardiovascular control was evaluated by spectral analysis of blood pressure and pulse interval
and by assessment of spontaneous baroreflex sensitivity (sequence technique). Salt sensitivity and baroreflex sensitivity
showed a negative relationship during low and high sodium intake, starting from low values of the salt sensitivity index.
All spectral indexes of pulse interval, except the ratio between low- and high-frequency powers, were inversely related
to salt sensitivity index after high sodium intake. In subjects with lower salt sensitivity, baroreflex sensitivity and pulse
interval power in the high-frequency band were higher after high sodium intake than after low sodium intake. In contrast,
subjects with a higher salt sensitivity index showed lower values of baroreflex sensitivity and pulse interval power in
the high-frequency band, uninfluenced by salt intake. Our results provide the first demonstration of an impairment of
parasympathetic cardiac control in parallel with the increase in the degree of salt sensitivity, also in subjects who were
not ranked as salt-sensitive by the conventional categorical classification. (Hypertension. 2005;46:1-6.)
Key Words: autonomic nervous system 䡲 heart rate 䡲 baroreflex 䡲 blood pressure 䡲 sodium, dietary
T
he higher rate of cardiovascular events occurring in
salt-sensitive subjects, either normotensive or hypertensive, has led to the suggestion that a salt sensitivity condition
might represent an independent cardiovascular risk factor.1,2
An enhanced sympathetic cardiovascular drive has been
suggested to play a role in determining the increased cardiovascular risk associated with salt sensitivity. In fact, an
impaired sympathetic inhibition has been described during
high sodium intake in salt-sensitive hypertensive humans,3
and a deranged reflex cardiovascular control has been proposed as one of the responsible mechanisms.4,5
Usually, salt sensitivity is considered a categorical parameter, with salt-sensitive individuals being defined as those
with a difference in mean arterial pressure (MAP) between
low- and high-sodium diet ⬎10%, and salt-resistant subjects
those in whom MAP does not increase or shows an increase
⬍5% under sodium loading.6 – 8 However, adoption of this
categorical approach does not allow exploring whether an
impairment of cardiovascular autonomic regulation may occur also in subjects with salt-related blood pressure (BP)
changes smaller than those defining salt sensitivity.
In the present study, we specifically addressed the above
open issue by investigating whether signs of an autonomic
dysfunction are detectable in mild hypertensive subjects with
under-threshold salt sensitivity values. To this aim, we explored
the transition between salt resistance and frank salt sensitivity in
a continuous fashion, making use of a relatively new index,
proposed by Kimura and Brenner9 and previously used by
Coruzzi et al10 for quantification of salt sensitivity. This index,
called salt sensitivity index (SSI), relates the changes in BP
induced by sodium loading with the concomitant changes in
urinary sodium output without any arbitrary definition of threshold levels.
Methods
Subjects
The study included 34 outpatients (21 men and 13 women) with a
never- treated mild or moderate uncomplicated essential hypertension, and with repeated office auscultatory diastolic BP (DBP)
measurements, in the seated position, between 95 and 109 mm Hg.
The patients had neither a history nor physical or laboratory evidence
of cardiovascular disease. They were free from target organ damage
Received May 16, 2005; first decision June 2, 2005; revision accepted August 23, 2005.
From the Department of Clinical Sciences (P.C., A.N.), University of Parma, Italy, and Fondazione Don C. Gnocchi ONLUS, Parma, Italy; Prevention
and Rehabilitation Unit (L.B., V.B., M.G.,), Fondazione Don C. Gnocchi ONLUS, Parma, Italy; Department of Clinical Medicine, Prevention, and
Applied Biotechnologies (G.P.), University of Milano-Bicocca and S. Luca Hospital, IRCCS, Istituto Auxologico Italiano, Milan, Italy; and Centro di
Bioingegneria (P.C., M.D.), Fondazione Don C. Gnocchi ONLUS, Milan, Italy.
Correspondence to Marco Di Rienzo, Centro di Bioingegneria, Fondazione Don C. Gnocchi, via Capecelatro 66, I-20148 Milano, Italy. E-mail
mdirienzo@cbi.dongnocchi.it
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.116110.1161/01.HYP.0000189183.50301.5c
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Hypertension
December 2005
at the heart level as assessed by echocardiography. Renal disease was
excluded by normal urinalysis and creatinine clearance. Subjects
under concomitant treatment with estrogens or nonsteroidal antiinflammatory agents, or with drugs known to influence salt, potassium, calcium, water, hemodynamic, or neural regulation, were
excluded. Subjects were nonsmokers with body mass index of
24.8⫾3 kg/m2, 45⫾7 years of age, sedentary lifestyle, and no history
of excessive alcohol consumption.
Measurements
Before starting the controlled sodium diets, we determined serum
and urinary sodium and creatinine concentrations (Technicon analyzer). The 24-hour ambulatory BP was monitored by an oscillometric automated device (Spacelabs model 90207) to quantify baseline
24-hour systolic BP (SBP), DBP, MAP, and heart rate (HR) average
values and SDs. The inflatable cuff was wrapped around the
nondominant arm after excluding between-arm differences in BP
⬎5 mm Hg. The accuracy of the oscillometric device was assessed
in each patient by comparison with 3 auscultatory readings simultaneously taken from the same arm with a Y-tube connection between
the Spacelabs device pump and a mercury column.
Salt Sensitivity Assessment
According to a method described previously,11 after the baseline
assessment, the 34 hypertensive patients followed either a highsodium (200 mmol NaCl per day) and a low-sodium (30 mmol NaCl
per day) diet for 1 week in a randomized sequential order. The
24-hour urinary sodium excretion was quantified on the last day of
each diet week. This measure was also used to verify the patients’
compliance with the dietary regimen. Compliance with caloric intake
was controlled through repeated phone calls aimed at ensuring that
patients were following a diet with the prescribed caloric content.
The degree of salt sensitivity was estimated as follows: after
overnight fasting, at 7:30 AM on days 7 and 14 (ie, at the end of each
diet period), patients came to our laboratory, where they remained
quietly seated for 150 minutes. After a 30-minute period of familiarization with the environment, SBP, DBP, MAP, and HR were
measured at 15-minute intervals over the following 2 hours, from
8:00 to 10:00 AM, by the Spacelabs automated device. Simultaneously, continuous finger BP and HR were monitored by a
Portapres model-2 device (Finapres Medical Systems), the finger
cuffs of which were wrapped around the mid- and the ring fingers of
the hand contralateral to the arm carrying the Spacelabs cuff and
were always kept at heart level throughout the recording time.
During the recording, subjects were asked to avoid sudden changes
in respiratory rate, which remained ⬇12 to 15 breaths per minute.
The SSI was calculated as the ratio of the change in brachial
oscillometric MAP (⌬MAP), expressed in mm Hg, between the
high- and the low-sodium diet periods, with the corresponding
change in urinary sodium excretion rate (⌬UNaV) expressed
in mmol/L per day, multiplied by a factor of 1000 to facilitate
readability of results, namely: SSI⫽(⌬MAP/⌬UNaV)⫻1000
[mm Hg/(mol/L per day)].
The experimental protocol was approved by the ethical committee
of our institution, and the patients gave their written informed
consent after having received a detailed explanation of the study
procedures and purposes.
Analysis of Continuous BP Recordings
Beat-by-beat SBP, DBP, and MAP values were identified from the
2-hour finger arterial BP recordings performed at the end of each
dietary regimen. The heart interval was computed as pulse interval
(PI; ie, the time interval between consecutive systolic peaks, after
their parabolic interpolation to increase the accuracy of the estimate).
After removal of artifacts and ectopic beats, mean values and SDs of
SBP, DBP, MAP, and PI were calculated from each recording.
Spontaneous arterial baroreflex sensitivity (BRS) was estimated
by the sequence technique.12,13 SBP and PI beat-by-beat series were
scanned searching for sequences of ⱖ3 consecutive heart beats in
which a progressive increase in SBP values was followed, with lags
ranging from 0 to 2 beats, by a progressive PI lengthening or, vice
versa, in which a progressive SBP decrease was followed by a
progressive PI shortening. The slope of the regression line between SBP
and PI values included in each sequence was taken as an estimate of
BRS. The baroreflex effectiveness index (BEI) was computed as the
ratio between the number of SBP–PI sequences and the total number of
SBP progressive changes14 to quantify how often the baroreflex takes
the control of the sinus node in response to BP transients.
SBP and PI beat-by-beat series were interpolated and resampled at 10
Hz for the spectral analysis. Fast Fourier transform power spectra were
computed over consecutive, 50% overlapped, 300-s Hann data windows. For each subject, a final spectrum was estimated by averaging the
spectra computed over the whole recording. Each spectrum was integrated over low-frequency (LF; 0.04 to 0.15 Hz) and high-frequency
(HF; 0.15 to 0.40 Hz) bands. The PI HF power is an indirect measure of
vagal cardiac modulation,4 whereas the LF/HF ratio of PI powers is
taken as a measure of the sympatho-vagal balance.15 The LF power of
SBP variability can be considered an indirect index of sympathetic
control of peripheral resistance.16
Statistical Analysis
The strength of the association between SSI and each cardiovascular
variable was assessed by the nonparametric Kendall’s ␶ correlation
coefficient. Positive ␶ coefficients mean that greater values of SSI
are associated with higher values of the analyzed variable whereas
they are associated to lower values in case of negative ␶.
We also evaluated how the sodium depletion/repletion maneuver
influenced BRS and parameters of PI and BP variability associated
with autonomic cardiovascular control as a function of SSI by the
following procedure. First, the patient population was subdivided
into quartiles of SSI distribution. Then, the statistical significance of
the effect of the sodium depletion/repletion maneuver was assessed
by repeated-measures ANOVA. When the effect of the maneuver
was significant, mean values during sodium depletion and during
sodium repletion were compared in each SSI quartile by the Fisher’s
least significant difference test (Statistica 6.0; Statsoft Inc.). All
variables were preliminarily tested for gaussianity; LF powers, HF
powers, and the LF/HF power ratio had to be log-transformed to
obtain normal distributions.17,18 The level of statistical significance
was set at P⬍0.05.
Results
Baseline Data
Over the group of 34 subjects, 24-hour ambulatory SBP,
DBP, and HR (mean⫾SD) were 138⫾11 mm Hg,
89⫾9 mm Hg, and 70⫾8 bpm, respectively; SSI was
33.8⫾7.2 mm Hg/(mol/L per day) ranging between ⫺44 and
⫹146. The degree of salt sensitivity was not associated with
age (␶⫽0.02; P⫽0.84), body mass index (␶⫽0.03; P⫽0.80),
or with the baseline levels of 24-hour SBP (␶⫽0.19; P⫽0.11),
DBP (␶⫽0.12; P⫽0.33), and HR (␶⫽0.19; P⫽0.11).
Effects of Sodium Intake
Figure 1 shows the frequency histogram of percent changes in
MAP in response to sodium loading (⌬MAP) and the relationship between ⌬MAP percent changes and SSI. The modal
value of ⌬MAP distribution fell below the 10% value commonly
used to define salt sensitivity according to the traditional
classification. The relationship between ⌬MAP and SSI was
not linear, and a good fit was obtained by the parabola
SSI⫽0.178⫻⌬MAP2⫹5.294⫻⌬MAP⫺0.631. This means
that ongoing toward high levels of salt sensitivity the SSI
score is progressively more amplified with respect to the
⌬MAP score.
Coruzzi et al
Salt Intake and Autonomic Cardiovascular Control
3
Figure 2. Individual values of 2-hour average SBP (top panels)
and of spontaneous BRS (bottom panels) at the end of the lowsodium (left) and high-sodium (right) diets, plotted vs SSI in our
34 patients.
BRS values being associated with lower SSI values. This
trend characterized both dietary conditions but appeared more
pronounced after the high sodium intake diet (right panel).
Figure 1. a, Histogram refers to the distribution of percent
changes of MAP (⌬MAP%) in response to sodium loading in our
34 hypertensive subjects; the arrow shows the threshold for
identification of salt sensitivity by the conventional dichotomous
approach.7 b, Relationship between SSI and ⌬MAP%. Subjects
with above-threshold salt sensitivity are shown by squares.
Dashed curve is the parabolic least-square regression line.
TABLE 2. Correlations (Kendall’s ␶ and significance P )
Between SSI and Cardiovascular Parameters Derived From
Beat-by-Beat Recordings at the End of Sodium Depletion and
Repletion Periods
Low Sodium
Table 1 reports BP values measured during the last day of
each week of sodium diet and sodium excretion values at the
end of each diet week (mean of the last 2 days). All these
parameters significantly increased at the end of the high
sodium intake period.
Individual values of SBP and BRS at the end of highsodium and low-sodium diets are plotted versus SSI in Figure
2. This figure shows a positive relationship between SBP and
SSI at the end of the high-sodium intake diet (right panel),
which disappears after the low-sodium diet (left panel). A
negative association was found between BRS and SSI, higher
TABLE 1. BP and Urinary Sodium Excretion After Low-Sodium
and High-Sodium Diets (meanⴞSD)
Quantity
Low Sodium
High Sodium
P
SBP
129⫾11 (mm Hg)
138⫾13 (mm Hg)
⬍10⫺4
DBP
88⫾8 (mm Hg)
91⫾9 (mm Hg)
⬍10⫺2
MAP
102⫾9 (mm Hg)
107⫾10 (mm Hg)
⬍10⫺3
221⫾69 (mmol/L per day)
⬍10⫺15
UNaV
44⫾15 (mmol/L per day)
BP data refer to average values of 2-hour arm cuff oscillometric recordings;
P indicates statistical significance; UNaV, urinary excretion rate of sodium.
Cardiovascular
Parameters
␶
High Sodium
P
␶
P
BP
SBP mean
0.09
NS (0.43)
0.28
⬍0.02
DBP mean
0.09
NS (0.47)
0.19
NS (0.12)
MAP mean
0.08
NS (0.48)
0.22
NS (0.07)
SBP SD
⫺0.07
NS (0.56)
0.05
NS (0.67)
DBP SD
⫺0.07
NS (0.56)
0.03
NS (0.80)
MAP SD
⫺0.06
NS (0.60)
0.04
NS (0.73)
SBP LF
0.08
NS (0.50)
0.19
NS (0.12)
SBP HF
0.02
NS (0.87)
0.08
NS (0.48)
Baroreflex function
BRS
⫺0.30
⬍0.02
⫺0.43
⬍0.0004
BEI
⫺0.13
NS (0.29)
⫺0.14
NS (0.24)
PI mean
⫺0.18
NS (0.13)
⫺0.29
⬍0.02
PI SD
⫺0.24
⬍0.05
⫺0.44
⬍0.0003
PI LF
⫺0.22
NS (0.07)
⫺0.36
⬍0.003
PI HF
⫺0.23
NS (0.06)
⫺0.44
⬍0.0003
LF/HF
0.16
NS (0.23)
0.19
NS (0.11)
HR
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Hypertension
December 2005
Figure 3. BRS (meansⴞSEM) in the 4 quartiles of SSI at the end
of low-sodium intake (䡬) and high-sodium intake (●) diets; significant differences between diets are shown by the asterisk
(P⬍0.05).
The quantification of the coupling between SSI and each
cardiovascular variable through the Kendall’s ␶ correlation
coefficient is reported in Table 2. Concerning the BP parameters, at the end of the high-sodium diet, a significant positive
correlation with SSI was found for average SBP; also, MAP
and DBP displayed a positive relationship with SSI that fell
short of statistical significance. In contrast, no relationship
was found between SSI and mean values of SBP, MAP, and
DBP at the end of the low-sodium diet or between SSI and
overall BP variability (quantified by the SD). As to SBP
spectral powers, SSI showed a tendency to be directly related
with LF powers only at the end of the high-sodium diet,
although this trend did not reach the level of statistical
significance.
Concerning the baroreflex control of HR, a significant
negative relationship was found between SSI and BRS in the
low-sodium and high-sodium conditions, whereas BEI was
not related to the degree of salt sensitivity.
All indexes of PI variability showed a significant negative
correlation with SSI at the end of the high-sodium diet, with
the exception of the LF/HF powers ratio, which showed a
tendency to increase with SSI (␶⫽0.19; P⫽0.11). After the
low-sodium diet, only PI overall variability, quantified by PI
SD, was significantly and inversely related to SSI.
We also investigated in a deeper detail how the sodium
depletion/repletion maneuver affected BRS, and BP and PI
variability parameters known to be related to autonomic
cardiovascular regulation (SBP LF power, PI LF and HF
powers, and LF/HF powers ratio), as a function of the levels
of salt sensitivity. To this aim, and to evaluate the statistical
significance of differences between SSI levels, we considered
levels of SSI defined by subdivision into quartiles, which, in
our patients, were: SSIⱕ0 (first quartile); 0⬍SSIⱕ27.5 (second quartile); 27.5⬍SSIⱕ56 (third quartile); and SSI⬎56
(fourth quartile). It is worth noting that all patients conventionally classified as salt sensitive fell in the fourth quartile of
SSI distribution. A post hoc analysis was performed on the
variables in which ANOVA displayed significant differences
between the 2 diets, namely BRS (⫹20% at the end of the
high-sodium diet; P⬍0.002), PI HF power (⫹55%; P⬍0.005)
and the LF/HF powers ratio of PI (⫺22%; P⬍0.002). The
effects of sodium diets on SBP LF (⫺14%; P⫽0.12) and on PI
LF (⫹12%; P⫽0.18) did not reach the statistical significance.
Figure 3 shows that BRS was significantly lower at the end
of the low-sodium diet in the first 3 SSI quartiles. In contrast,
subjects within the highest SSI class showed the same low
values of BRS independently of the administered diet. In line
with Table 2, BRS clearly decreased from the first to the last
SSI quartile, in the low- and high-sodium diet groups.
Figure 4 shows the relationship of PI powers and of LF/HF
PI powers ratio with SSI. Also, HF power was lower at the
end of the low-sodium diet in the first 3 SSI quartiles,
whereas subjects in the fourth quartile showed similarly low
HF powers, independently of the amount of sodium intake.
The LF/HF powers ratio was always higher at the end of the
low-sodium diet, the difference being significant in the first 2
SSI quartiles.
Figure 4. LF and HF PI powers and LF/HF powers ratio (meansⴞSEM) in the 4 quartiles of SSI at the end of low-sodium (䡬) and highsodium (●) diets. significant differences between diets are shown by *(P⬍0.05) and **(P⬍0.01).
Coruzzi et al
Discussion
Our study offers novel information on the relationship between salt sensitivity and reflex cardiovascular regulation by
exploring such a relationship on a continuous basis through
use of the SSI9,10 and by focusing mainly on subjects with
MAP changes in response to sodium loading below the
conventional threshold used to define sodium sensitivity,
according to the classical dichotomous approach.
The important new finding is that spontaneous BRS, in
spite of being already reduced because of the high BP
condition,19,20 was progressively further impaired as a direct
function of the degree of salt sensitivity. In particular, this
impairment also occurred in hypertensive patients ranked as
not salt sensitive according to the conventional classification.
Furthermore, the reduction in BRS was paralleled by a
reduction in HR variability, as quantified by its overall variance
and, more specifically, by its HF power. Given the evidence that
BRS and HR variability are largely markers of vagal cardiac
modulation,21,22 our results provide evidence of a progressive
impairment in parasympathetic cardiac control in parallel with
the increase in salt sensitivity on top of the alterations already
induced by the hypertensive state.13,23 Because of the reciprocal
changes that usually characterize modifications in sympathetic
and parasympathetic control of the heart, these data appear to be
in line with previous reports on the occurrence of sympathetic
activation in salt-sensitive subjects.24 Because autonomic
dysfunction is a well-identified predictor of cardiovascular
morbidity and mortality,25,26,27 our results may thus suggest
that salt sensitivity could also have a role in this setting, being
itself a reliable predictor of an impaired reflex autonomic
control of the heart.
A second important result of our study is that in subjects with
a lower salt sensitivity, a high-sodium diet was characterized by
higher BRS and HR variability values than a low-sodium diet.
This may depend on the fact that when the reflex cardiovascular
regulation is preserved, high sodium intake may activate cardiopulmonary receptors through an increase in plasma volume,
leading to a reflex reduction in sympathetic efferent activity,28
whereas the opposite may occur under low sodium intake.29 This
modulation was not observed in subjects displaying the highest
degree of salt sensitivity, in whom no changes in their impaired
autonomic cardiovascular control resulted from manipulation of
sodium intake. Based on our data, the salt-dependent BP
increase in hypertensive subjects with the higher degree of SSI
might thus be attributable, at least in part, either to an impaired
baseline arterial baroreflex function or to the inability to increase
BRS in response to the increase in plasma volume determined by
the sodium loading. The observed lack of correlation between
the degree of salt sensitivity (evaluated by SSI) and either
baseline 24-hour BP and HR, age, or body mass index supports
the interpretation that the impaired autonomic control of circulation observed in our study as a function of SSI was actually
related to the increasing SSI levels and not to the influence of
other confounding factors.
Finally, some implications of the methodology for sodium
sensitivity assessment in our study deserve to be discussed. It
should be emphasized that use of SSI, in addition to providing a
continuous assessment of the degree of salt sensitivity, allowed
us to explore the effects of diet sodium manipulation in a more
Salt Intake and Autonomic Cardiovascular Control
5
accurate fashion with respect to the traditional approach. Indeed,
SSI supplies a measure of salt sensitivity on the basis of the
sodium output without requiring information on the actual
sodium intake.9 Thus, at variance from the traditional approach,
accuracy of SSI does not rely on patients’ full compliance with
the dietary regimen.
In conclusion, the results of our study indicate that an
impairment of autonomic control can also be observed in
hypertensive subjects with under-threshold scores of salt
sensitivity, as measured by SSI. This approach might thus
represent a more sensitive way to explore the relationship
between neural autonomic regulation and sodium sensitivity
in hypertensive patients, in whom an increased salt sensitivity
carries a higher risk of cardiovascular complications.
Perspectives
Our study demonstrates an impaired autonomic control of
circulation in hypertensive subjects with under-threshold salt
sensitivity levels, providing additional information on mechanisms involved in the continuous link between sodium
sensitivity and cardiovascular risk in hypertension. Additional studies of larger size, and possibly with a longitudinal
design, would now be required to explore the possibility of a
causal link between salt sensitivity and alterations in neural
cardiovascular control. It would also deserve to be investigated whether a relationship between changes in SSI and
differences in autonomic cardiovascular regulation might
characterize not only hypertensive patients (as demonstrated
in our article) but also normotensive subjects with and
without family history of hypertension.
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