Salt Sensitivity of Blood Pressure: An Enigmatic Hypertension Phenotype

Hypertension affects 32.6% of the U.S. adult population and is a major risk factor for cardiovascular events and death.¹ However, the mechanisms by which hypertension develops and is sustained are not well understood. A major proposed mechanism for the initiation of hypertension in both humans and experimental animal models involves a fundamental defect in the capacity of the kidneys to excrete sodium.² Over time, a compensatory increase in blood pressure (BP) and, consequently, an increase in renal perfusion pressure increase sodium excretion but also induce hypertension.

The kidneys maintain the composition of body fluids and regulate extracellular fluid volume homeostasis, and abnormalities in sodium balance play a critical role in the pathophysiology of hypertension. Salt sensitivity of BP is a quantitative trait in which an increase in dietary sodium intake engenders an increase in BP.^3,4 Salt sensitivity occurs in normotensive as well as hypertensive humans and predicts increased cardiovascular events and mortality, irrespective of unchallenged BP levels.^3-7 Overall, salt sensitivity has been estimated to be present in approximately 51% of hypertensive and 26% of the normotensive population, posing a major public health problem.⁸ Salt sensitivity is especially common in African Americans, older adults, and in people with a higher level of BP or comorbidities such as chronic kidney disease, diabetes mellitus, or the metabolic syndrome.⁹ Altogether, these groups constitute more than half of the adult population in the United States.¹⁰

The molecular mechanisms underlying the salt sensitivity trait are not well understood,¹¹ but strong evidence exists that genetic mechanisms determine BP responses to salt intake.^4,12-14 However, genome-wide association studies (GWAS) have collectively identified genes that influence only 2% of BP variability and have not identified many genes that affect salt sensitivity.^15,16 Only a few genes are associated with salt-sensitive hypertension using candidate gene association studies.^2,16 Recent examples of the discovery of genes involved in salt sensitivity in humans include the sodium-bicarbonate cotransporters, SLC4A4 and SLC4A5, and striatin deficiency.^17-19

Against this enigmatic background of salt sensitivity of BP, the American Heart Association has published an up-to-date, balanced, authoritative, and comprehensive Scientific Statement that promises to increase interest in this important topic.²⁰ Salt sensitivity of BP is a compelling topic of interest given the small number of subphenotypes of the common, complex disease, hypertension. This review is expected to provide guidance to investigators, both basic and clinical, regarding design and prioritization of future studies on salt sensitivity. The review covers in detail the definition of salt sensitivity of BP, the development of salt sensitive animal models, and the known pathophysiologic mechanisms of salt sensitivity. One of the most helpful features of the Scientific Statement is the exhaustive but easily digestible review of the role of genetics in the salt sensitive phenotype in rodent models. This is markedly facilitated by a tabular summary of genes and gene families thought to play a role in this polygenic disorder. However, based on existing knowledge there is no logical method to prioritize these genes according to likelihood of a major role in the pathogenesis of salt sensitivity. The article further discusses the measurement of salt sensitivity, potential demographic and environmental factors, prognostic significance, and potential surrogate markers that would eliminate the need to perform time consuming, expensive and logistically difficult analyses of human blood pressure responses to sodium loading and depletion. For clinicians, this Scientific Statement assesses implications of salt sensitivity in the management of individual patients as well as for public health at large. The Statement concludes with a useful evaluation of knowledge gaps and methodological recommendations for measurement of salt sensitivity of BP in human studies in the future.

At present there is no information on the treatment of salt sensitivity per se or the treatment of hypertension in patients with as opposed to without the salt sensitivity trait. If hypertension in salt sensitive individuals can be treated specifically in the future, then documenting the existence of salt sensitivity undoubtedly will become an important component of managing antihypertensive drug therapy. The recent demonstration that treatment with the specific angiotensin receptor blocker azilsartan improves salt sensitivity in mice (by selectively decreasing renal proximal tubule sodium-hydrogen exchange by ubiquitin-proteosomal degradation)²¹ encourages the future potential of identifying and treating the salt sensitive phenotype in humans.