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

In this plethora of candidate genes, it's conceivable that each of them plays a very small role in the polygenic aspect of salt sensitivity, or that they're related by a still-unrecognized unifying pathway. A more global approach, such as total genome scans, is required to settle this question. This type of approach has had limited success until now, but points to chromosome 10 as one of the possible candidates.14

What are the cardiovascular consequences of salt sensitivity?
The relationship between BP and salt intake was carefully explored by the INTERSALT Cooperative Research Group, which evaluated salt levels by 24-hour urinary sodium excretion in 11,000 subjects from 52 centres in 39 countries.15 With the exception of four ethnic groups that still practice a Paleolithic culture, the investigators saw only a very weak relationship, amounting to about 1 mm Hg per 100 mM/day difference in sodium intake. Nevertheless, more recent evidence has linked salt sensitivity to CVD mortality.

The pioneering studies of Myron Weinberger and colleagues established that mortality is indeed higher in salt-sensitive people. In fact, a prospective observational trial found greater mortality in both hypertensive and normotensive salt-sensitive participants -- only salt-resistant people with normal BP had clear CVD protection (Figure 1).16 In a Japanese population, salt sensitivity was not only a predictor of cardiovascular events, but also more frequently associated with left ventricular hypertrophy than was salt resistance (28% vs 16%).17

There's been heated debate lately about whether or not salt intake should be cut in the general population. Not having interventional trials, observational studies were used as an argument. The largest observational study in this area is the National Health and Nutrition Examination Survey (NHANES) from the U.S. The first NHANES study concluded that sodium intake has an inverse relationship with all-cause and cardiovascular mortality, but is directly proportional to the ratio of sodium:calorie intake.18 Based on these results, the consensus was that there's no justification for any particular dietary recommendation. But another analysis of the same data reached a different conclusion, by excluding participants on a low-salt diet and with a history of CVD.19 These investigators found positive correlations for sodium intake with stroke and mortality from coronary heart disease (CHD) -- but only in overweight subjects, who actually constituted a minority in the NHANES population. In non-overweight participants, sodium intake had no impact on stroke, CHD mortality or all-cause mortality.19 This group also demonstrated that dietary sodium intake was a strong, independent risk factor for heart failure (HF) in overweight individuals.20

What's the connection between salt, obesity and hypertension?
Abnormal cortisol metabolism to inactive cortisone in fat tissue may play a role in linking salt sensitivity to the metabolic components of hypertension.21 Overnutrition also decreases levels of adiponectin, a hormone that modulates glucose metabolism and fatty acid breakdown, which may be involved in salt-sensitive hypertension, as well as in hypertensive HF and insulin resistance in the presence of increased abdominal fat.22

The diurnal cortisol cycle is considered to be one of the major drivers of daily BP variation, which normally declines 10-20% at night and is termed the "dipper" pattern. In people whose BP doesn't drop during sleep, known as "nondippers," this lack of nocturnal dipping is a risk predictor for CVD outcomes, whether they're normal or hypertensive. It's been shown, however, that dietary sodium restriction can shift hypertensive nondipper patients to dipper status.23 In addition, it's been suggested that hypertension, metabolic syndrome, enhanced sodium sensitivity and nondipping nocturnal BP may all be interrelated.24

Which diet is best for hypertension?
While low-sodium diets have usually been successful in managing BP in short-term, non-outcome studies, initial experimental investigations suggested that the impact of sodium is actually modulated by other ingredients, macronutrients and electrolytes. Interventions that aimed to lower BP by boosting calcium intake have had the greatest impact in the presence of a high-sodium diet. We evaluated the complexity of this interrelationship in a Montreal study, which concluded that 28% of systolic BP is predicted by the combination of gender and sodium and calcium intakes. For diastolic BP, 37% is determined by the same characteristics, plus alcohol intake. This initial investigation clearly demonstrated that sodium's impact on BP is largely modulated by calcium intake.25

These findings help to explain the success of the Dietary Approaches to Stop Hypertension (DASH) diet, which is based on increasing consumption of fruits and vegetables.26 It's also been shown that adding low-fat dairy products to this diet substantially decreases BP. Further refinement of the DASH diet by lowering sodium intake heightened the efficacy of its high-potassium, high-calcium components even more. The benefits of the DASH diet clearly demonstrate the complex interactions of macro- and micronutrients in controlling BP. New observations with this diet, though, have cast doubt on the utility of identifying salt sensitivity, as the trait apparently varies significantly with time in the same individual.26

At the moment, the DASH diet (rich in low-fat dairy products, fruits and vegetables, with limited sodium) is the most highly recommended nonpharmacologic approach to controlling BP, with potential impact on CVD development and complications.

What are the clinical implications?
Looking at all the epidemiologic, environmental and genomic studies, the metabolic component of salt sensitivity is probably the most obvious target of intervention. The consequences of high-salt intake seem to be uniquely exaggerated in obese people. Clearly, it's troubling that salt sensitivity is yet another health-related problem in these individuals. From a dietary point of view, the DASH diet is the best preventive measure to date in the fight against hypertension. It's especially encouraging to see that cutting sodium intake can restore the normal circadian rhythm of BP in nondippers.23

Right now, our recommendations are still limited by the lack of CVD outcome data from controlled, prospective intervention trials. We also know from pharmacologic interventions that BP reduction doesn't always translate into clinical benefits, as seen in trials of several potent vasodilators and alpha2-receptor blockers. Studies of safety, effectiveness and proof of outcomes reduction are needed in target populations, such as obese subjects, as well as in the general population, before evidence-based recommendations on sodium diets will have any clinical relevance.

In the future, it's expected that individualized predictive medicine, based on genomic knowledge, will allow us to detect those with salt sensitivity and higher CVD risk from a simple blood test, to design individualized prevention patterns in future cardiovascular medicine.27