The occurrence of a causal link between chronic high sodium intake, high blood pressure (BP), and cardiovascular diseases is supported by consistent evidence. In addition to and independently from favouring a rise in BP, high-dietary sodium is associated with a number of other damaging effects on the cardiovascular system . A high-dietary intake of sodium increases left ventricular mass, favours thickening of conduit arteries walls with the consequent increase in their rigidity, leads to narrowing of resistance arteries and increases platelets aggregability, thereby leading to an overall increase in cardiovascular risk.
Available data in animals and in humans have shown a large between individual variability in the sensitivity to the effects of high sodium intake, a variability which may have clinical relevance. Indeed, several prospective cohort studies have confirmed that sodium sensitivity of BP increases not only the risk of cardiovascular disease  but also the rate of all-cause mortality . Thus, identification of sodium sensitivity in a given participant may have a relevant diagnostic, prognostic and therapeutic importance.
In spite of this, however, tests for sodium-sensitivity assessment are rarely prescribed in a clinical setting. This is because, unlike the diagnosis of hypertension, the evaluation of a sodium-sensitivity status requires a time-consuming protocol that is often challenging for both patients and physicians. The classic tests for identification of sodium sensitivity are based on the finding of BP values substantially greater at the end of a high-sodium diet (over 1 week) than at the end of a low-sodium diet (over 1 additional week). Based on such an evaluation, participants can then be dichotomously classified as ‘salt sensitive’ if the mean arterial pressure rise from the low-sodium to the high-sodium diet is larger than a given threshold (set to 3, 5, 8 or 10 mmHg according to various authors), otherwise they are classified as ‘salt resistant’. A continuous index of the severity of sodium sensitivity, the salt-sensitivity index, can also be calculated as the ratio between the BP differences and the corresponding differences in urinary sodium excretion at the end of the two different diet periods . A faster sodium-sensitivity test, but based on a more complex protocol, has also been proposed, in which the week of high-sodium diet is substituted by intravenous administration of 2 liters of 0.9% w/v of NaCl solution over 4 h, and the week of low-sodium diet is shortened to one day of diet with volume and sodium deprivation induced by oral intake of an appropriate dose of furosemide .
It was because of the complexity of such protocols, which has been responsible for their limited practical applicability in a clinical setting, that simpler surrogate indices of sodium sensitivity, based on parameters derived from analysis of 24-h ambulatory BP monitoring (ABPM) data obtained under every day diet, have been proposed . This more recent approach is based on the finding that, at least in essential hypertensive patients, a condition of salt sensitivity is associated with changes in BP and heart rate dynamics, which, in principle, could be detected by 24-h ABPM performed under habitual diet conditions.
In particular, the ABPM parameters, which appear most useful for identifying a condition of salt sensitivity are those associated to BP nondipping patterns at night, such as the nocturnal fall of mean arterial pressure, or the night/day ratios of SBP or DBP. In fact, evidence is available that in salt-sensitive hypertensive patients sodium load dampens the BP nocturnal fall, while sodium deprivation tends to restore the dipping pattern, reducing the difference in the circadian BP profile between salt-sensitive and salt-resistant hypertensives . Given the changes in sodium excretion with posture and in relation to the day–night changes in BP , a possible finalistic explanation for the disappearance of a BP dipping pattern in salt-sensitive hypertensive patients during sodium load is that the night-time increase in BP could facilitate a greater sodium excretion by stimulating natriuresis in response to a higher renal perfusion pressure, maintaining in this way a correct sodium balance. On the contrary, there would be no need to remove an excess of sodium and therefore to raise the arterial pressure at night, during a low sodium diet.
Hypertensive salt-sensitive patients have also been found to be characterized by an impaired cardiac vagal modulation  and by a higher sympathetic activity . These autonomic alterations could be highlighted by beat-to-beat analysis of heart rate variability  through the additional recording of an ECG and/or through a continuous beat-by-beat BP tracing over 24 h, the latter only possible through invasive methods  or through sophisticated continuous ABPM instrumentations based on photoplethysmographic finger cuff technology . However, autonomic alterations may induce changes also in mean heart rate, which is easily measurable by any ABPM device. Actually, it has been observed that during sodium load resting heart rate increases with the severity of sodium sensitivity in hypertensive patients .
Overall, these observations suggest that a condition of cardiovascular risk associated to salt sensitivity could be indirectly detected in hypertensive patients by the combined finding of lack of a nocturnal dipping pattern in BP and presence of a relatively high heart rate over the 24 h. Both these patterns can be easily identified from a simple analysis of 24-h ABPM recordings during everyday diet (see Fig. 1) and represent possible surrogate markers of sodium sensitivity . This suggestion is based on the hypothesis that, because most subjects habitually follow a diet rich of salt, activation of physiological mechanisms triggered by the excess in sodium intake may alter heart rate and dipping pattern in salt-sensitive individuals, thus making sodium sensitivity detectable from the ABPM recording. As salt deprivation restores the dipping behaviour and lowers heart rate, this approach cannot distinguish between salt-sensitive and salt-resistant patients if both follow a diet strictly poor of sodium. Nevertheless, identification of these night-time BP and 24-h heart rate patterns during habitual diet (with high sodium content) may be able to describe the level of cardiovascular risk associated to salt sensitivity in everyday life, and this information may become particularly important to decide when changes of diet and food habits have to be recommended.
This approach could also be applied to re-analyze historical databases of ABPM recordings, searching for signs of salt sensitivity and for novel prognostic markers. In this issue of the Journal of Hypertension, Bursztyn and Ben-Dov report on the results obtained by applying such an ABPM-based approach to identify the sodium-sensitivity risk in a large cohort of patients in whom 24-h ABPM was previously performed, and to assess the impact of the derived surrogate marker of sodium-sensitivity risk on mortality. This is indeed the first study in which the definition of cardiovascular risk associated with salt sensitivity and its possible prognostic impact are assessed from analysis of 24-h ABPM data without making use of dietary restrictions. Interestingly, the group classified by the authors as being at high salt-sensitivity risk, based on ABPM analysis in condition of habitual diet at the time of the recording, matches most of the characteristics that other studies reported for salt-sensitive patients defined on the basis of the traditional dietary tests. For instance, the group considered at highest sodium-sensitivity risk is older, with a higher percentage of female patients, and higher BMI than the groups considered at low and intermediate salt-sensitivity risk. This is in agreement with previous studies similarly showing that salt sensitivity increases with age , is more common in females  and is associated with obesity and adiposity [16,17]. Moreover, the prevalence of treated diabetic patients in the study by Bursztyn and Ben-Dov  is almost twice in the group at higher salt-sensitivity risk than in the groups at lower risk, which is in line with the demonstration that insulin resistance is also associated with salt sensitivity . However, the more striking feature of the group classified at higher salt-sensitivity risk based on ABPM patterns is its mortality rate: even when focusing on all causes of death and not on cardiovascular deaths only, mortality rate is almost twice than in the groups at low and intermediate sodium-sensitivity risk.
The authors applied this ABPM-based approach on a very large and heterogeneous population of patients. It is therefore possible that the presence of specific diseases, like sleep-related breathing disorders, may have caused misclassifications of some patients, reducing the nocturnal BP fall and/or increasing the overall heart rate. Moreover, ABPM recordings were obtained both in normotensive and in hypertensive patients. So far, salt-sensitivity indices have been mainly investigated in patients with high BP levels. In particular, the damped nocturnal dipping pattern and the higher resting heart rate associated with salt sensitivity were described in groups of hypertensive patients [6,8], and the ABPM-based salt-sensitivity risk assessment method was originally tested in essential hypertensive patients . Can we safely assume that similar ABPM alterations occur in salt-sensitive normotensive patients, too? Among the few studies on salt sensitivity performed in normotensive individuals, one considered a population of black adolescents during ad libitum diet and found a clear association between salt sensitivity and nondipping status . This conclusion would therefore support the use of ABPM recordings during habitual diet for detecting a condition of salt-sensitivity risk also in normotensive individuals. However, a more recent article did not provide any evidence of a blunted circadian rhythm of BP in a normotensive population of salt-sensitive white children and young adults . The reason for the discrepancies between these studies might depend on the different severity of salt sensitivity between the two groups of black-American and white normotensive patients, respectively, a difference which was not quantified because both studies adopted a dichotomous classification of sodium sensitivity only. Therefore it cannot be excluded that among normotensive patients, mildly salt-sensitive individuals (i.e. those with a relatively low salt-sensitivity index) may excrete the excess of sodium by increasing the day-time BP only, while more severe salt-sensitive individuals (those with a high salt-sensitivity index) may need also to increase night-time BP to maintain the sodium balance, thus dampening their circadian BP profile. In any case, the limited information available emphasizes the need of having the long-term control of BP in relation to sodium intake more exhaustively studied in normotensive patients, taking into account also the degree of sodium sensitivity.
An interesting finding in the study by Bursztyn and Ben-Dov  is that ABPM-derived estimation of increased salt-sensitivity risk was associated with an increased mortality risk in men but not in women, in spite of the fact that salt sensitivity was more common in female patients. Indeed, women with a high sodium-sensitivity risk had a mortality rate indistinguishable from those with low and intermediate sodium-sensitivity risk. This was the case despite the fact that women were significantly older than men.
The reason by which men with high sodium-sensitivity risk were more likely to die than older women with a similarly high sodium-sensitivity risk remains to be investigated. Given that the ABPM-derived index of sodium sensitivity is based on the combination of BP nondipping with a 24-h heart rate higher than 70 bpm  while on usual salt intake, a possible explanation is that of a different impact on mortality by BP nondipping and by a high 24-h heart rate in men and women. However, the prediction of mortality significantly associated with BP nondipping has been shown not to be restricted to men, being a sex-independent predictor [21,22]. Conversely 24-h heart rate may not have an independent impact on mortality . Thus the combined assessment of BP nondipping with 24-h average heart rate higher than 70 bpm could not in itself explain the finding of an increased mortality in men but not in women with high sodium-sensitivity index. Conversely, this observation may to a certain extent reflect the generally higher mortality of men as compared to women . Such a sex-related difference in the mortality rate of men and women at high sodium-sensitivity risk is an issue which deserves to be further investigated in future studies.
In spite of its interest, the study by Bursztyn and Ben-Dov also has some limitations. Acknowledged limitations are the retrospective nature of the data analysis, and the absence of groups under high and low salt diet, that might have been useful to validate the conclusions reached on salt-sensitivity risk simply based on 24-h ABPM analysis. Moreover, given that patients were on their usual diet at the time of 24-h ABPM performance, some truly salt-sensitive patients who were under therapeutic low-salt intake might have been erroneously classified as patients at low or intermediate sodium-sensitivity risk. On the contrary the authors, while discussing their data, refer to a study showing that in Israel an average intake of about 8.5 g salt per day can be expected in middle-aged patients , which makes the possibility of patients’ sodium-sensitivity risk misclassification unlikely. Another limitation of this study, acknowledged by the authors themselves, is the absence of information on cause-specific mortality, in particular the lack of information on a possible increase in cardiovascular mortality. However, use of all-cause mortality as an unbiased endpoint has been justified and supported in previous studies .
In conclusion, although not free from methodological limitations, the article by Bursztyn and Ben-Dov  offers information on sodium-sensitivity risk assessment through analysis of preexisting 24-h ABPM databases. It also shows that such an assessment bears a prognostic value, as this ABPM-derived sodium-sensitivity risk index predicts mortality at least in men. These data support the possibility that, if further validated through comparison with classic salt-loading studies in a larger group of patients, ABPM-derived sodium-sensitivity assessment might be proposed for daily practice, and might in this way greatly simplify estimation of sodium sensitivity in a clinical setting.
Finally, the results of this study offer further support to the importance of more frequently implementing 24-h ABPM in daily practice, as recommended by recent hypertension guidelines [25,26], as a tool for a better clinical characterization of cardiovascular risk in hypertensive patients.
Conflicts of interest
There are no conflicts of interest.
1. Zoccali C, Mallamaci F. The salt epidemic: old and new concerns. Nutr Metab Cardiovasc Dis
2. Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S, et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet
3. Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension
2001; 37 (2 Part 2):429–432.
4. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension
1996; 27 (3 Pt 2):481–490.
5. Castiglioni P, Parati G, Brambilla L, Brambilla V, Gualerzi M, Di Rienzo M, et al. Detecting sodium-sensitivity in hypertensive patients: information from 24-h ambulatory blood pressure monitoring. Hypertension
6. Sachdeva A, Weder AB. Nocturnal sodium excretion, blood pressure dipping, and sodium sensitivity. Hypertension
7. Uzu T, Takeji M, Yamauchi A, Kimura G. Circadian rhythm and postural change in natriuresis in nondipper type of essential hypertension. J Hum Hypertens
8. Coruzzi P, Parati G, Brambilla L, Brambilla V, Gualerzi M, Novarini A, et al. Effects of salt sensitivity on neural cardiovascular regulation in essential hypertension. Hypertension
9. Strazzullo P, Barbato A, Vuotto P, Galletti F. Relationships between salt sensitivity of blood pressure and sympathetic nervous system activity: a short review of evidence. Clin Exp Hypertens
10. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J
11. Parati G, Castiglioni P, Di Rienzo M, Omboni S, Pedotti A, Mancia G. Sequential spectral analysis of 24-h blood pressure and pulse interval in humans. Hypertension
12. Castiglioni P, Parati G, Omboni S, Mancia G, Imholz BP, Wesseling KH, et al. Broad-band spectral analysis of 24 h continuous finger blood pressure: comparison with intra-arterial recordings. Clin Sci (Lond)
13. Bursztyn M, Ben-Dov IZ. Sex differences in salt sensitivity risk approximated from ambulatory blood pressure monitoring and mortality. J Hypertens
14. Ishibashi K, Oshima T, Matsuura H, Watanabe M, Ishida M, Ishida T, et al. Effects of age and sex on sodium chloride sensitivity: association with plasma renin activity. Clin Nephrol
15. He J, Gu D, Chen J, Jaquish CE, Rao DC, Hixson JE, et al. Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study. J Hypertens
16. Strazzullo P, Barba G, Cappuccio FP, Siani A, Trevisan M, Farinaro E, et al. Altered renal sodium handling in men with abdominal adiposity: a link to hypertension. J Hypertens
17. Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med
18. Zavaroni I, Coruzzi P, Bonini L, Mossini GL, Musiari L, Gasparini P, et al. Association between salt sensitivity and insulin concentrations in patients with hypertension. Am J Hypertens
19. Wilson DK, Sica DA, Miller SB. Ambulatory blood pressure nondipping status in salt-sensitive and salt-resistant black adolescents. Am J Hypertens
1999; 12 (2 Pt 1):159–165.
20. Simonetti GD, Farese S, Aregger F, Uehlinger D, Frey FJ, Mohaupt MG. Nocturnal dipping behaviour in normotensive white children and young adults in response to changes in salt intake. J Hypertens
21. Ben-Dov IZ, Kark JD, Ben-Ishay D, Mekler J, Ben-Arie L, Bursztyn M. Blunted heart rate dip during sleep and all-cause mortality. Arch Intern Med
22. Ben-Dov IZ, Kark JD, Ben-Ishay D, Mekler J, Ben-Arie L, Bursztyn M. Predictors of all-cause mortality in clinical ambulatory monitoring: unique aspects of blood pressure during sleep. Hypertension
23. Shamiss A, Carroll J, Orda S, Fostick M, Peleg E, Rosenthal T. Preliminary report of the cardiovascular diseases and alimentary comparison study: the Israeli experience. J Cardiovasc Pharmacol
1990; 16 (Suppl 8):S22–S23.
24. Lauer MS, Topol EJ. Clinical trials: multiple treatments, multiple end points, and multiple lessons. JAMA
25. Head GA, McGrath BP, Mihailidou AS, Nelson MR, Schlaich MP, Stowasser M, et al. Ambulatory blood pressure monitoring in Australia: 2011 consensus position statement. J Hypertens
26. McManus RJ, Caulfield M, Williams B. NICE hypertension guideline 2011: evidence based evolution. BMJ