REVIEW
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The role of sodium in hypertension is more
complex than simply elevating arterial pressure
Edward D Frohlich* and Jasmina Varagic
S U M M A RY
Excessive salt intake exacerbates hypertension and further increases
left-ventricular mass in clinical essential and experimental hypertension.
Additionally, a growing body of evidence strongly suggests that high
dietary salt loading exerts detrimental cardiac effects independently of
its hemodynamic load. The clinical evidence of cardiac structural and
functional alterations associated with salt is, however, scarce. In order to
explore the purported beliefs in humans, in this review we draw on our
experimental studies in naturally occurring hypertension and discuss the
clinical implications of the nonhemodynamic mechanisms underlying
these salt-related changes.
KEYWORDS dietary salt loading, hypertension, left-ventricular hypertrophy,
ventricular dysfunction, ventricular fibrosis
REVIEW CRITERIA
We searched the National Library of Medicine MEDLINE database using following
keywords: hypertension, salt, left ventricle, hypertrophy, fibrosis, and left
ventricular function. Only English-language articles were obtained, all of them
in extensor, which were searched to identify other relevant articles.
ED Frohlich is the Alton Ochsner Distinguished Scientist and Jasmina Varagic
is a staff scientist at the Oschner Clinic Foundation, New Orleans, LA, USA.
Correspondence
*Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA
efrohlich@ochsner.org
Received 2 July 2004 Accepted 11 September 2004
www.nature.com/clinicalpractice
doi:10.1038/ncpcardio0025
24 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE
INTRODUCTION
A large body of evidence has emerged from
clinical epidemiological and interventional
investigations as well as experimental studies
that have repeatedly identified a positive rela-
tionship between salt and hypertension. The
multinational Intersalt study1,2 clearly related
dietary sodium and blood pressure across
many populations and, even more difficult to
demonstrate, within populations. In support of
these epidemiological findings, well-controlled
clinical trials have provided strong evidence
that reduction of sodium intake lowers arte-
rial pressure in both hypertensive and normo-
tensive people.3,4
In addition to elevated arterial pressure, left-
ventricular hypertrophy (LVH) is an independ-
ent cardiovascular risk factor in hypertension
in association with impaired coronary hemo-
dynamics, ventricular fibrosis and dysfunction,
and apoptosis.57 Over many years, clinical and
experimental studies have demonstrated the
additional potential of salt to adversely affect
cardiac structure and function independ-
ently of its influence on arterial pressure.811
This finding is exceedingly important since
only a small fraction of hypertensive patients
are said to demonstrate SODIUM-SENSITIVE
HYPERTENSION. In some large epidemiological
studies,12,13 but not in others,14 high sodium
intake has notably been indicated as a strong
and independent contributor to increased
cardiovascular risks and mortality.
This review summarizes the increasing
strong clinical and experimental evidence that
supports the concept that sodium, rather than
simply elevating arterial pressure, has a far
more complex role in hypertension. Although
not comprehensive, we present compelling
evidence for a pattern of cardiac structural
and functional changes that accounts for the
observed cardiovascular risk of increased
sodium consumption. Where clinical evidence
is less strong, we add our experience from
studies with experimental naturally occurring
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300 - 8- GLOSSARY
Systolic arterial pressure (mmHg)

ab SODIUM-SENSITIVE
7-
a a HYPERTENSION

LV-mass index (mg/g)

250 - 6- Increased arterial pressure
response to sodium loading
a
5-
a OVERT CARDIAC
200 - 4- FAILURE
ab Symptomatic impaired
3- systolic ventricular function
150 - 2-

1-

100 - 0-

0.22 - 0.90 -
a ab

LV end-diastolic diameter (cm)

Posterior wall diameter (cm)

0.21 - a 0.85 -
a
0.20 - 0.80 -

0.19 - 0.75 -

0.18 - 0.70 -

0.17 - 0.65 -

0.16 - 0.60 -
Control Salt Salt Control Salt Control Salt Salt Control Salt
without with without with
CHF CHF CHF CHF
Young SHR Old SHR Young SHR Old SHR

Figure 1 Systolic arterial pressure and left-ventricular geometry in salt-loaded younger (16 weeks) and
older (52 weeks) adult spontaneously hypertensive rats. Data are presented as mean value 1 SEM.
aP <0.05 vs respective control group. bP <0.05 vs salt without congestive heart failure. CHF, congestive
heart failure; SHR, spontaneously hypertensive rats.

hypertension to provide important clinical rel- In the adult spontaneously hypertensive rat,
evance and to establish the validity for further which is the best experimental model of natu-
clinical investigation. rally occurring hypertension, we have deter-
mined the cardiac response to different levels
SALT AND ALTERED LEFT-VENTRICULAR of dietary salt excess.21,8 Rats were given 8%
STRUCTURE salt in food, roughly corresponding to twice
Salt and left-ventricular mass the salt intake in human societies with the
Excess dietary salt exacerbates hypertensive higher salt consumption. Younger rats started
disease14 and further increases LV mass in their high-salt diet at 8 weeks of age and older
clinical essential and experimental hyper- rats began salt loading at 20 weeks. The groups
tension. 811,1517 Although an expanded were studied echocardographically at age
intravascular volume in response to high salt 16 weeks in the younger and 52 weeks in the
intake may also occur, sodium intake in hyper- older group. In most rats, salt excess induced
tensive patients correlates more strongly with concentric LVH associated with impaired
LV wall thickness than with LV end-diastolic ventricular relaxation and increased arte-
diameters.17,18 Furthermore, a growing body rial pressure. Of the younger group, however,
of clinical and experimental evidence also sug- 25% developed OVERT CARDIAC FAILURE; and
gests an important interaction between salt and these were the only rats in which LV diastolic
myocardial mass that may be independent of diameter increased significantly with sodium
hemodynamic overload. Thus, increased salt loading, reflecting impaired ventricular func-
intake is a critical independent predictor of tion (Figure 1). Notably, sustained salt excess
LV enlargement in patients with essential elevated arterial pressure only slightly (17%)
hypertension.11,1720 in younger and older adult spontaneously

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GLOSSARY 7.5 - ab
EXTRACELLULAR MATRIX
A stable complex of 7.0 -
concentration (mg/g)
macromolecules that
LV hydroxyproline
surrounds cells in the
6.5 -
ventricular interstitium
6.0 - a tensive rats, 6 weeks of 1% salt in drinking water
5.5 -
4.5 -
4.0 -
Control Salt Salt
without with
CHF CHF
Young SHR
Figure 2 Left-ventricular hydroxyproline
concentration in spontaneously hypertensive
rats receiving high-salt diet. Data are presented
as mean value 1 SEM. aP <0.05 vs respective
control group. bP <0.05 vs salt without congestive
heart failure. CHF, congestive heart failure; SHR,
spontaneously hypertensive rats.
hypertensive rats, but it substantially increased
LV-mass index in young adult rats (88%) as
compared with the older rats (25%).21 We also
demonstrated that the correlation between the
level of sodium-intake and cardiac mass was
stronger than between mean arterial pres-
sure and cardiac mass.8 Even in normoten-
sive Wistar Kyoto control rats receiving excess
dietary salt, LV mass increased without hemo-
dynamic changes.8,10 On the other hand, there
is increasing evidence from clinical as well
as experimental studies demonstrating that
reduction in salt intake diminishes LV mass
independently of arterial pressure changes.22,23
These findings provide further support to the
concept that increased LV mass associated
with sodium excess may not totally reflect the
pressure overload. It seems, therefore, that
in hypertension, dietary sodium overload
exacerbates cardiac hypertrophic response to
pressure increase.
Salt and myocardial fibrosis
Although ventricular fibrosis frequently com-
plicates hypertensive LVH clinically and experi-
mentally,6 few clinical studies have addressed
the role of salt as a mediator of cardiac fibro-
sis. Serum carboxy-terminal propeptide of
procollagen type I and carboxy-terminal telo-
peptide of collagen type I have been shown clin-
ically to be useful markers of collagen turnover
in the myocardium,24 and these surrogates may
26 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE
open new avenues in clinical evaluation of salt-
related cardiac structural alterations.
In experimental hypertension, the potential of
a
salt to exaggerate collagen deposition has been
recognized. In stroke-prone spontaneously hyper-
increased collagen mRNA in the left ventricu-
lum.25 Increased LV hydroxyproline concentra-
tion (an index of ventricular collagen content)
can be seen in response to dietary salt excess in
Control Salt
younger and older adult spontaneously hyperten-
sive rats (Figure 2). Fibrosis was also more prom-
inent in younger rats that developed heart
Old SHR
failure.21 Furthermore, in a morphological study,
increased interstitial as well as perivascular col-
lagen deposition was demonstrated in Wistar
Kyoto and spontaneously hypertensive rats receiv-
ing a high-salt diet.9 Although the profibrotic
effect of salt has usually been coupled with
elevated blood pressure, an increasing body of
experimental evidence supports the concept of a
pressure-independent link between salt and the
EXTRACELLULAR MATRIX. Indeed, the Wistar
Kyoto rats receiving salt excess developed cardiac
fibrosis to a similar extent as the untreated spon-
taneously hypertensive rats, and their systolic
pressure was much lower.9 Additionally, a calcium
antagonist reduced the degree of salt-induced col-
lagen deposition in stroke-prone spontaneously
hypertensive rats in the absence of blood-pressure
changes, providing further evidence for a
pressure-independent effect of salt.25
EFFECTS OF SALT EXCESS ON
LEFT-VENTRICULAR FUNCTION
As suggested above, LVH has been recognized
for many years as a major risk factor for cardiac
failure, ventricular dysrhythmias and coronary
arterial disease. Moreover, increasing evidence
indicates that, in hypertension, salt excess
further increases LV mass and fibrosis out of
proportion to any rise in arterial pressure; this
finding has major implications concerning
cardiovascular risk.
The possible relationship between salt and
LV functional changes has rarely been tested
clinically. Two reports have demonstrated that
impaired LV diastolic filling was positively cor-
related with sodium excretion or blood-pressure
sodium sensitivity.26,27 For example, a reduced
maximum of early diastolic filling velocity (VE) as
well as an early to atrial (VA) filling velocity ratio
(VE/VA) were demonstrated in sodium-sensitive
essential hypertensive patients but not in sodium-
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55 - 0.06 - GLOSSARY
DIASTOLIC
a DYSFUNCTION
50 -
a Inability of heart to fill with
ab
0.04 - blood during diastole

IVRT (s)
45 -
FS (%)

ISOVOLUMIC
RELAXATION TIME
Echocardiographically
40 -
0.02 - determined time interval
ab between aortic-valve
35 - closure and the start of
mitral flow

30 - 0- DECELERATION TIME
OF E
Echocardiographically
3.0 - 30 - determined time interval
between the peak of early
2.5 - b diastolic filling velocity
a
25 - a and the intersection of the
deceleration of flow with the
2.0 -
baseline
VP (cm/s)
VE /VA

1.5 - a 20 -

1.0 -
15 -
0.5 -

0- 10 -
Control Salt Salt Control Salt Control Salt Salt Control Salt
without with without with
CHF CHF CHF CHF
Young SHR Old SHR Young SHR Old SHR

Figure 3 Echocardiografically measured systolic and diastolic function in spontaneously hypertensive rats
fed with an 8% salt diet. Data are presented as mean value 1 SEM. aP < 0.05 vs respective control group.
bP <0.05 vs salt without congestive heart failure. CHF, congestive heart failure; FS, fractional shortening;
IVRT, isovolumic relaxation time; SHR, spontaneously hypertensive rats; VE/VA, early and atrial filling
velocity ratio; Vp, propagation velocity of early filling.

resistant patients whose arterial pressure was
comparable.26
In our studies of spontaneously hypertensive
rats, dietary salt excess increased arterial pressure
more than in rats receiving normal salt diets and
promoted DIASTOLIC DYSFUNCTION manifested
by extended ISOVOLUMIC RELAXATION TIME,
decreased VE/VA ratio and slower propagation
velocity of early filling (VP , Figure 3).21 These
echocardiographically measured ventricular relax-
ation abnormalities were associated with a further
increase in LV mass and hydroxyproline concen-
tration. Moreover, the subgroup of younger salt-
loaded spontaneously hypertensive rats developed
heart failure with impaired systolic (decreased
fractional shortening) and diastolic function asso-
ciated with a still greater LV mass and myocardial
fibrosis. The significantly increased VE /Vp ratio
(an index of LV filling pressure) and restrictive fill-
ing pattern (shorter DECELERATION TIME OF E)
clearly indicated a stiffer chamber (Figure 4).
Thus, salt-induced myocytic hypertrophy and
accumulated fibrillar collagen within the extra-
cellular matrix seems to promote LV functional
alterations clinically and experimentally. It has
been suggested that diffuse interstitial fibrosis
interferes with ventricular relaxation and con-
tributes importantly to abnormal ventricular
stiffness.28 Additionally, perivascular fibrosis
might restrict coronary vasodilation, thereby
diminishing blood supply to the hypertrophic
LV, having increased oxygen demand.2931 We
demonstrated profound impairment in LV
coronary vasodilatory reserve response (to
dipyridamole) in salt-loaded young adult spon-
taneously hypertensive rats as compared with
untreated rats of the same age (ED Frohlich,
unpublished data). Therefore, sodium-loading
in such rats seems to be manifested not only by
further elevated pressure but also by significant
LV functional impairment related to enhanced
ventricular fibrosis.

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GLOSSARY 0.05 - water. Additionally, experimental data increas-

TRANSFORMING
GROWTH FACTOR-
A factor synthesized in
various tissues that is
involved in transformation
ingly suggest that even a short period of salt
a excess is harmful in early life.21,33 This finding
0.04 - is supported by our experimental work; spon-
a
taneously hypertensive rats are more suscepti-

DTE (s)
with respect to inflammation
and fibrosis ble to cardiac damage when high dietary salt is
introduced earlier in life.21 Therefore, a care-
0.03 -
ful evaluation of cardiovascular consequences
of salt excess at a young age is also strongly
recommended.
0.02 -

POTENTIAL FACTORS IN SALT-EXCESS

0.05 -
EFFECTS
ab In addition to the hemodynamic factors
0.04 - cited, nonhemodynamic salt-induced adverse
cardiovascular mechanisms must be con-
0.03 -
sidered. In particular, evidence suggests that
VE /VP

salt-related cardiomyocyte hypertrophy and

0.02 -
0.01 -
Control Salt Salt Control Salt
without with
CHF CHF
Young SHR Old SHR
Figure 4 Deceleration time of mitral E wave
and left-ventricular filling pressure. aP < 0.05 vs
respective control group. Data are presented as
mean value 1 SEM. bP <0.05 vs salt without
congestive heart failure. CHF, congestive heart
failure; DTE, deceleration time of E; SHR,
spontaneously hypertensive rats; VE/VP , ratio of
early to propagation velocity of early filling time.
(Figure used with permission from the American
Journal of Physiology.)
DOES AGE MATTER?
Considerable evidence has been derived from
population studies indicating that blood pres-
sure progressively increases with increasing
age, and that the prevalence of hypertension is
also related to salt consumption.1,2 Therefore, a
moderately restricted sodium diet has been rec-
ommended for healthy adults worldwide, par-
ticularly for older individuals and patients with
hypertension and renal disease. Equally impor-
tant are the conclusions drawn from the funda-
mental and clinical studies that have addressed
the detrimental effects of high salt intake early
in life. For example, in the trial conducted by
Pomeranz et al.,32 formula milk diluted with
high-sodium tap water increased blood pres-
sure in neonates compared with that in children
fed formula prepared with low-sodium spring
exaggerated accumulation of fibrillar col-
lagen within the extracellular matrix are, at
least in part, independent of hemodynamic
load.9,18,22,33,34 In some clinical studies,
reduction in salt intake modulated the hemo-
dynamic response to noradrenalin, imply-
ing overactive adrenergic function.35 General
sympathetic activity is enhanced with excessive
sodium intake in some studies10,15,36,37 but
not in others.38 Intriguingly, salt loading did
not increase plasma noradrenalin concentra-
tions in patients;39 cardiac sympathetic activity
tended to be diminished in some experimental
studies.10,22 Additionally, Grassi et al.40 dem-
onstrated that reduced sodium intake, after
1 or 8 weeks increased sympathetic activity
in essential hypertensive patients and thereby
could aggravate damage to target organs. This
and other reports relating reduced salt intake
to risk of myocardial infarction associated with
elevated plasma renin activity41,42 raise some
concern about severe salt restriction, although
they are heavily criticized.43,44
The possible role of certain growth-promoting
hormones and factors in salt-induced cardio-
vascular alterations has also been raised. To
this end, participation of locally as well as sys-
temically generated components of the renin-
angiotensin-aldosterone sytem,4548 endothelin49
and TRANSFORMING GROWTH FACTOR-9 has
been suggested.
Finally, in-vitro studies have added sup-
port to the concept that salt may have a direct
influence on cardiovascular growth.50 Elevated
sodium concentration in culture medium
induced hypertrophy of both cardiac myoblasts

28 NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE FROHLICH AND VARAGIC NOVEMBER 2004 VOL 1 NO 1

and vascular myocytes by promoting protein
synthesis and impeding protein degradation.
It appears, therefore, that excessive salt intake,
in addition to increasing arterial pressure, may
adversely affect cardiovascular structure and
function directly or through the local interplay
with various growth hormones and factors.
CONCLUSIONS
Cardiovascular effects due to salt loading in
hypertensive patients, independent of salt-
increased blood pressure, are becoming increas-
ingly defined. Excessive salt intake, directly or
through locally activated growth hormones and
factors, increases LV mass and extracellular col-
lagen deposition and, in that way, aggravates
hypertension-related LV functional distur-
bances. A more comprehensive recognition of
the underlying pathophysiologic cardiovascular
mechanisms will clarify more effective long-
term management of hypertensive patients and
reduce cardiovascular morbidity and mortality
related to that disease.
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Acknowledgments
This work was supported
by an award from the
American Heart Association,
Southeast Affiliate.
Competing interests
The authors declared
they have no competing
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