Why is salt-sensitivity of blood pressure, a known cardiovascular risk factor, not treated?

No medical practitioner in his right mind would refuse nowadays to treat hypertension, because it has been thoroughly documented that it is a major risk factor for cardiovascular (CV) morbidity and mortality. Is there an equally powerful CV risk factor that we neglect to treat? Weinberger et al. [1] reported 20 years ago that salt sensitivity (SS) of blood pressure (BP) is such a risk factor. They followed 596 normotensive and hypertensive subjects for a mean of 27 years after their classification into SS and salt resistant (SR) groups using an acute protocol of salt loading and depletion. They concluded that there was no difference in the survival curve of normotensive SS subjects compared to those of the hypertensive SR group, categorically establishing SSBP as a CV risk factor independent of and as powerful as hypertension [1]. Moreover, an extensive body of research on the topic has documented that prevalence of SSBP is about 25% in the normotensive population, 50% in hypertensive subjects, and even higher in certain subgroups, such as African Americans, the obese, and women, making it not only an untreated risk factor but one affecting millions of people with great potential for universal reduction of CV morbidity and mortality.

In all honesty, the question in the title of this essay is rhetorical for several reasons. First and foremost, SSBP cannot be diagnosed in the clinic because the methodologies employed to do so (prolonged dietary interventions or admission to the hospital for acute protocols) are expensive, laborious, and cumbersome, which is why they are used in research only. Second, there has been little progress in the investigation of biomarkers of SSBP, such as dopamine receptors in renal tubular cells and renal microRNAs in exosomes shed in the urine (reviewed in Ref. [2]), whereas research on others, such as stimulation of isolevuglandins in antigen presenting cells by salt, is in its preliminary stages (personal communication, Dr. Annet Kirabo). Third, BP responses to salt are not dichotomous, but rather, continuous and normally distributed, so classification of subjects into SS and SR requires an artificial cutoff that is entirely arbitrary. Fourth, a lot of the research on salt and cardiovascular disease has been carried out with estimates of salt intake derived from formulas applied to random urine samples or from 24-hr urine collections. Not even the latter, considered the “gold standard”, reflects salt intake accurately, as shown in subjects in a biosphere who were on constant salt intakes, much different from the situation in the general population, who nonetheless exhibited circaseptan (6–7 day) rhythms in Na ​+ ​excretion [3]. Fifth, investigation of the mechanisms and genetics of SSBP in experimental animals and humans has shown innumerable putative abnormalities in vasoactive substances, renal transporters, signal transduction pathways, etc. (also reviewed in Ref. [2]), such that there is no unifying underlying pathophysiologic mechanism for SSBP to date, precluding the search for therapies against specific identified targets.

If the obstacles to diagnose and treat the SS phenotype are so many, why not just abandon their pursuit and resort to enforcing salt restriction as a public health measure instead? First of all, because such measures should be applied to the entire population, whether normotensive or hypertensive, a tough proposition in view of the well-known difficulty of achieving meaningful dietary salt restriction even in subjects who will benefit subjectively from it (e.g., those with congestive heart failure). Second and most importantly, because in hypertensive subjects, normalization of BP by any means, including salt restriction, does not restore CV risk to the level observed in never-treated normotensive subjects with the same BP. In hypertensive SS subjects, it is not only conceivable but also likely that this residual CV risk is linked somehow to the mechanisms underlying SSBP, independent of BP itself, which will require specific therapy to remove the CV risk component conferred by them.

Therefore, what action is required, from the scientific and public health communities, to reverse the tide and ultimately make SSBP a diagnosable and treatable trait? We believe, and therefore agree with the recommendation of the World Hypertension League [4] that there should be a shift in the funding provided by major research sponsors (e.g., NIH and AHA), from studies on the epidemiology and clinical interventions pertaining to salt and cardiovascular disease, to mechanistic research seeking to discover a biomarker for SSBP. More than fifty years of research on the role of salt in CV disease have produced significant knowledge, but also fallacies, such as the decades-long discussion on the J-curve relationship between cardiovascular morbidity and salt intake, a major distraction in the scientific discourse, which is now known to be due to inaccurate estimates of salt intake [5].

In contrast, discovery of a biomarker for SSBP would have major beneficial consequences. First, it would very likely produce an exponential growth in the search for mechanisms of SSBP in humans, since classification of research participants will no longer depend on laborious and expensive methods. Second, once this research potentially identifies actionable targets, the same biomarkers could be used in the clinic to diagnose individual-level SSBP and to enact newly discovered therapies for those targets.

Ultimately, SSBP could be diagnosed and treated, not only in hypertensive patients, but also in the normotensive individuals who might benefit from this approach, not different from what we do nowadays for primary prevention of cardiovascular disease when we address hyperlipidemia or smoking.