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Salt sensitivity and CVD
New research seasons the diet-vs-genes
debate and supports practical clinical interventions
BY Pavel Hamet, MD
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What
is salt sensitivity?
Salt consumption has accompanied human civilization since its beginning,
because of salt's important role in food preservation and taste
enhancement. Today, however, the key issue is whether current sodium
intakes exceed our needs and, if so, should they be limited for
the entire population?
In 1939, Walter Kempner was the first to use
a very low-salt diet (of boiled rice) in patients with malignant
hypertension, with relative success. Extremely low sodium intake
clearly reduces the blood pressure (BP) of many hypertensive subjects,
but its impact on the entire population still hasn't been tested
in prospective trials with cardiovascular disease (CVD) outcomes.
It's now understood that salt sensitivity increases with
age, is more prevalent in certain ethnic groups, such as blacks,
and manifests in the presence of certain diseases, particularly
hypertension. Salt sensitivity is defined as BP that declines during
salt restriction and increases in response to salt loading.1
Among whites, about 55% of hypertensive patients
exhibit salt sensitivity, compared to only 30% of normotensive subjects.
Salt sensitivity is even more prevalent in blacks, expressed in
72% of those with hypertension and 43% of those with normal BP.2
How
can we tell who's salt-sensitive?
Salt sensitivity testing is a complex process, as summarized in
Table
1. The first step is to withdraw all BP medication for at least
two weeks, followed by sodium chloride loading to achieve a high
serum sodium level. Next, the patient is switched to a very low-sodium
diet and given three doses of the loop diuretic, furosemide, to
produce sodium and volume depletion. Subjects who respond with a
decrease in mean arterial pressure (MAP) of 10 mm Hg or more are
labelled as "salt-sensitive," while those showing a decline of 5
mm Hg or less, or even an increase, are called "salt-resistant."
MAP rises in most subjects during the first, salt-loading phase
of the test, but only a fraction react to rapid sodium depletion
with a large decrease in MAP. This pioneering test has many versions
in the literature,1,2 in some
cases involving up to five weeks of hospitalization.3
Even the shortest protocol requires supervised sodium intake and
hospitalization, so it's not feasible for usual clinical practice.
At present, there's no useful validated test for determining salt
sensitivity on an outpatient basis. Eventually, genomic-based predictive
medicine will fulfill this need, hopefully in the foreseeable future.
Which
genes are involved in salt sensitivity?
The effect of salt sensitivity on BP was initially captured in Guyton's
hypothesis of "renal-body fluid feedback" for long-term regulation
of BP and body fluid volumes, and the genetic component is increasingly
recognized.4 While sodium intake
is considered largely "environmental," sodium sensitivity is at
least partly inherited,5 in both
whites and blacks.6
Over the last 15 years, several candidate
genes have been explored for their potential involvement in the
sodium-BP relationship. One of the first to be implicated was kallikrein,7
followed by angiotensin-converting enzyme (ACE), beta2-adrenergic
receptor, adducin, sodium-lithium countertransport, and the G-protein
beta-3 subunit.8-11 Very convincing
recent evidence in experimental models suggests that salt-sensitive
hypertension may be triggered by calcium entry into cells via the
exchange of sodium and calcium in vascular smooth muscle (Fig.
2).12,13
 Pavel
Hamet, MD, PhD, FRCPC, FCAHS is an endocrinologist and Chief of
Gene Medicine Services at the Centre Hospitalier de l'Université
de Montréal, and Canada Research Chair in Predictive Genomics
at the Université de Montréal.
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