Pub Date: Thursday, Jul 21, 2016
Author: Robert M. Carey, MD, MACP, FAHA
Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia
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.
Elijovich F, Weinberger MH, Anderson CAM, Appel LJ, Bursztyn M, Cook NR, Dart RA, Newton-Cheh CH, Sacks FM, Laffer CL; on behalf of the American Heart Association Professional and Public Education Committee of the Council on Hypertension; Council on Genomic and Precision Medicine; and Stroke Council. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association [published online ahead of print July 21, 2016]. Hypertension. doi: 10.1161/HYP.0000000000000047
- Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Després J-P, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360.
- Kanbay M, Chen Y, Solak Y, Sanders PW. Mechanisms and consequences of salt sensitivity and dietary salt intake. Curr Opin Nephrol Hypertens. 2011;20:37-43.
- Sanada H, Jones JE, Jose PA. Genetics of salt-sensitive hypertension. Curr Hypertens Rep. 2011;13:55-66.
- Morimoto A, Uzo T, Fujii T, Nishimura M, Kuroda S, Nakamura S, Inenaga T, Kimura G. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet. 1997;350:1734-1737.
- Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension. 2001;37(2 pt 2):429-432.
- Weinberger MH. Salt sensitivity is associated with an increased mortality in normal and hypertensive humans. J Clin Hypertens (Greenwich). 2002;4:274-276.
- Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(6 pt 2):II127-II134.
- Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension. 1996;27:481-90.
- Cogswell ME, Zhang Z, Carriquiry AL, et al. Sodium and potassium intakes among US adults: NHANES 2003-2008. Am J Clin Nutr. 2012;96:647-657.
- Weinberger MH. Pathogenesis of salt sensitivity of blood pressure. Curr Hypertens Rep. 2006;8:166-170.
- Sanders PW. Dietary salt intake, salt sensitivity and cardiovascular health. Hypertension. 2009;53:442-445.
- Miller JZ, Weinberger MH, Christian JC, Daugherty SA. Familial resemblance in blood pressure response to sodium restriction. Am J Epidemiol. 1987;126:822-830.
- Svetky LP, McKeown SP, Wilson AF. Heritability of salt sensitivity in black Americans. Hypertension. 1996;28:854-858.
- Beeks E, Kessels AG, Kroon AA, van der Klauw MM, de Leuw PW. Genetic predisposition to salt sensitivity: a systematic review. J Hypertens. 2004;22:1243-1249.
- Wain LV, Verwoert GC, O'Reilly PF, Shi G, Johnson T, Johnson AD, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet. 2011;43:1005-1011.
- Kelly TN, He J. Genomic epidemiology of blood pressure salt sensitivity. J Hypertens. 2012;30:861-873.
- Guo L, Liu F, Chen S, Yang X, Huang J, He J, Jaquish CE, Zhao Q, Gu CC, Hixson JE, Gu D. Common variants in the Na-coupled bicarbonate transporter genes and salt sensitivity of blood pressure: the GenSalt study. J Hum Hypertens. 2015;1-6.
- Carey RM, Schoeffel CD, Gildea JJ, Jones JE, McGrath HE, Gordon LN, Park MJ, Sobota RS, Underwood PC, Williams J, Sun B, Raby B, Lasky-Su J, Hopkins PN, Adler GK, Williams SM, Jose PA, Felder RA. Salt sensitivity of blood pressure is associated with polymorphisms in the sodium-bicarbonate cotransporter. Hypertension. 2012;60:1359-1366.
- Elijovich F, Weinberger MH, Anderson CAM, Appel LJ, Bursztyn M, Cook NR, Dart RA, Newton-Cheh CH, Sacks FM, Laffer CL. Salt sensitivity of blood pressure: a Scientific Statement from the Council on Hypertension, American Heart Association. Hypertension. 2016; doi: 10.1161/HYP.0000000000000047
- Garza AE, Rariy CM, Sun B, Williams JS, Lasky-Su J, Baudrand R, Yao T, Moize B, Hafiz WM, Romero JR, Adler GK, Ferri C, Hopkins PN, Pajoga LH, Williams GH. Variants in striatin gene are associated with salt-sensitive blood pressure in mice and humans. Hypertension. 2015;65:211-217.
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