Salt-sensitivity, hypertension and cardiovascular ageing: broadening our view without missing the point

In this issue of the journal, Aviv [1] offers an insight into the relationship between salt intake, blood pressure and the process of cardiovascular ageing. Central in the author's perception of this important issue is the role played by an altered oxidation-reduction state at the vascular level. The concept that hypertension, similar to other major cardiovascular risk factors, is associated with loss of the correct balance between pro-oxidant and anti-oxidant factors, and that this unbalance predisposes to target organ damage, is not new [2]. The possible role of locally produced angiotensin II in the pathogenesis of hypertensive and atherosclerotic complications has been highlighted in several recent studies with an emphasis on angiotensin as a potent mediator of oxidative stress [3,4]. What is intriguing in Aviv's position is his attempt to define the role of salt in this conceptual framework and his view that the long-lasting debate on salt-sensitivity of blood pressure generally has disregarded the probability that salt may exert direct effects on human health which are distinct and, to some extent, independent of its effects on blood pressure. A substantial number of studies have demonstrated that high salt intake is associated with left ventricular hypertrophy (LVH) [5], atherothrombotic stroke [6] and end-stage renal disease [7,8]. More recently, population-based observational studies and clinical trials have focused on the association between high salt intake and cardiovascular morbidity and mortality. The Trial of Nonpharmacological Intervention in the Elderly (TONE) showed a reduction in cardiovascular complications and in the need for drug treatment with dietary counselling for reducing sodium intake [9]. The analysis of stroke mortality rates and dietary habits in 17 countries by Sasaki and coworkers indicated a highly significant positive association between 24-h urinary sodium intake and death rate for stroke [10]. An analysis of the database of the first National Health and Nutrition Examination Survey (NHANES I) showed that high sodium intake was strongly and independently associated with an increased risk of cardiovascular disease and all-cause mortality in overweight individuals [11]. Thus, there appears to be sufficient evidence in support of Aviv's position that, besides affecting blood pressure, salt exerts other important health-related biological effects. The question remains, to what extent are these effects truly independent of salt-induced blood pressure changes? Perhaps the answer to this question is not yet at hand and it would be wise to leave the final judgement on hold until more knowledge becomes available regarding the mechanisms of the effects of sodium chloride on the vascular tree. In fact, the same studies that demonstrated an effect of salt intake on morbidity and mortality for cardiovascular disease, and other similar recent studies [12,13], also have confirmed that a high salt intake increases the risk of developing hypertension, and that reduction of salt intake is an effective means of treating and preventing hypertension. Hypertension, even in its mildest form, is the primary modifiable risk factor for cardiovascular morbidity and mortality, and blood pressure salt-sensitivity is associated with other major predictors of cardiovascular risk, such as obesity [14], hyperinsulinemia [15], dyslipidemia [16] and last, but not least, age (perhaps through the mechanisms that Aviv focuses upon in his article). Finally, in a recent study that awaits confirmation, the risk of fatal and non-fatal cardiovascular events was itself associated with blood pressure salt-sensitivity [17]. Aviv's suggestion that we should adapt our definition of salt-sensitivity to new scientific evidence ought to be shared in as much as we realize that there are several components of salt-sensitivity and that it is time to spend more effort in moving on from the simple blood pressure response to salt. The theory that an increased production of reactive oxygen species (ROS) is an important component of salt-sensitivity is intellectually attractive but still requires more solid experimental support. The concept that many forms of salt-sensitivity are marked by insufficient nitric oxide production in response to salt intake is supported by a reasonably large body of evidence [18,19]. On the other hand, the hypothesis of a salt-induced increase in ROS production is based on a rather complex chain of events. Elevated salt intake, through extracellular fluid volume expansion, would stimulate the production of a substance that promotes natriuresis by inhibiting sodium-pump activity [20–22]. This in turn would be associated with a rise in the cellular production of ROS and with growth-promoting effects similar to the effects of ROS, as suggested by several studies performed in vitro [23–26]. In a recent report, resting arteriolar and venular wall oxidant activity was shown to be consistently higher in rats fed a very-high-salt diet (7% NaCl) for 5 weeks compared with rats fed a 0.45% NaCl diet, with increased NADPH oxidase and xanthine oxidase enzymatic activity [27]. It was also reported that myocardial ROS production was significantly increased in Dahl-S rats kept for 10 weeks on 8% NaCl compared with a 0.3% NaCl diet. Furthermore, the increase in ROS myocardial levels was associated with the development of hypertension, LVH and heart failure. The concomitant administration of the angiotensin-converting enzyme-inhibitor, cilazapril, prevented the increase in ROS production and the progression of LVH to heart failure despite only a modest effect on blood pressure [28]. Can this chain of events provide a rational explanation for the independent contribution of salt to target organ damage and cardiovascular ageing? Fascinating as it may be, the evidence for this hypothesis is still circumstantial and is restricted to animal models under extreme experimental conditions and to studies performed in vitro. It is a challenging question, however, and warrants careful investigation. What is puzzling in Aviv's hypothesis is the speculation about a ‘random distribution in the relation between salt consumption and ROS production’ which would reflect the variable propensity of individuals to develop age-related diseases due ‘not only to high but also to low salt consumption'. More specifically, the possibility is envisaged that, in a subset of the population, excessive stimulation of the renin–angiotensin system by salt restriction or by high-dose diuretics may account for increased morbidity and mortality, due to angiotensin-mediated increase of ROS production in vascular tissue. Here, in the attempt to pursue a ‘unifying’ solution to the controversy between supporters and detractors of the ‘salt hypothesis', we may miss the point. The point is that: (i) excess salt consumption does cause hypertension in humans, as Aviv correctly points out, referring to a number of monogenic forms of hypertension that share a renal inability to handle the huge sodium load imposed by Western diets; (ii) clinical trials have consistently shown that reducing salt consumption lowers blood pressure; (iii) probably, as Aviv and others suggest [29], salt is a perpetrator of target organ damage over and above its effects on blood pressure. On the other hand, what is the evidence that an habitually ‘low’ salt intake poses a danger to health under normal living conditions? Apart from two studies by a single group of investigators [30,31] that have been challenged on several grounds, and have not been confirmed by others [11], there is nothing to justify concern about a moderate reduction in habitual salt intake as recommended to the general population by current guidelines for the prevention and treatment of hypertension and coronary heart disease [32,33]. An exaggerated plasma renin (and sympathetic) response may be elicited by short-term, drastic sodium chloride restriction and, as such, has no clinical relevance. With respect to diuretics, in spite of their tendency to increase plasma renin activity, the evidence in favour of their protective role in the prevention of cardiovascular accidents in hypertensive individuals is overwhelming [34]. Indeed, plasma renin activity should be considered in relation to habitual sodium intake, rather than in an isolated context, was well illustrated by Schmieder et al. [35], who showed that LVH developed more commonly in those hypertensive individuals who were unable to suppress the renin–angiotensin system appropriately for the level of sodium intake. Similarly, while a high salt intake is generally associated with a lower aldosterone level in the systemic circulation, the local aldosterone system is upregulated and may exert an adverse effect by stimulating fibrotic and hypertrophic processes. In conclusion, Aviv's article is provocative and stimulates us to broaden our view of the salt-sensitivity issue by raising the challenging question of an independent contribution of salt to organ disease through its influence on oxidative stress in the vascular tree. It highlights the need to intensify our research at the molecular level. It may miss the point, however, when proposing a ‘unifying’ theory for salt-sensitivity in an attempt to reconcile contrasting views. The public health problem is salt, not salt-sensitivity, and the bulk of the evidence indicates a unidirectional, not bidirectional, problem. Acknowledgements The collaboration of Dr Gianvincenzo Barba in the preparation of this commentary is gratefully acknowledged. Professor Strazzullo's research on salt-sensitivity in human beings is supported by the Italian Ministry of University and of Scientific and Technological Research (COFIN 1998 and 2000).