Skip to main content
SpringerLink
Log in

Personalized Therapy of Hypertension: the Past and the Future

  • Novel Treatments for Hypertension (T Unger, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

During the past 20 years, the studies on genetics or pharmacogenomics of primary hypertension provided interesting results supporting the role of genetics, but no actionable finding ready to be translated into personalized medicine. Two types of approaches have been applied: a “hypothesis-driven” approach on the candidate genes, coding for proteins involved in the biochemical machinery underlying the regulation of BP, and an “unbiased hypothesis-free” approach with GWAS, based on the randomness principles of frequentist statistics. During the past 10–15 years, the application of the latter has overtaken the application of the former leading to an enlargement of the number of previously unknown candidate loci or genes but without any actionable result for the therapy of hypertension. In the present review, we summarize the results of our hypothesis-driven approach based on studies carried out in rats with genetic hypertension and in humans with essential hypertension at the pre-hypertensive and early hypertensive stages. These studies led to the identification of mutant adducin and endogenous ouabain as candidate genetic-molecular mechanisms in both species. Rostafuroxin has been developed for its ability to selectively correct Na+ pump abnormalities sustained by the two abovementioned mechanisms and to selectively reduce BP in rats and in humans carrying the gene variants underlying the mutant adducin and endogenous ouabain (EO) effects. A clinical trial is ongoing to substantiate these findings. Future studies should apply both the candidate gene and GWAS approaches to fully exploit the potential of genetics in optimizing the personalized therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Polanyi M. Science, faith, and society. London: Oxford University Press; 1946.

    Google Scholar 

  2. Arwood MJ, Cavallari LH, Duarte JD. Pharmacogenomics of hypertension and heart disease. Curr Hypertens Rep. 2015;17:586.

    Article  PubMed  CAS  Google Scholar 

  3. Fontana V, Luizon MR, Sandrim VC. An update on the pharmacogenetics of treating hypertension. J Hum Hypertens. 2015;29:283–91.

    Article  CAS  PubMed  Google Scholar 

  4. El Rouby N, Cooper-DeHoff RM. Genetics of resistant hypertension: a novel pharmacogenomics henotype. Curr Hypertens Rep. 2015;17:583.

    Article  PubMed  CAS  Google Scholar 

  5. Franceschini N, Chasman DI, Cooper-DeHoff RM, Arnett DK. Genetics, ancestry, and hypertension: implications for targeted antihypertensive therapies. Curr Hypertens Rep. 2014;16:461.

    Article  PubMed  CAS  Google Scholar 

  6. Manunta P, Lavery G, Lanzani C, et al. Physiological interaction between alpha-adducin and WNK1-NEDD4L pathways on sodium-related blood pressure regulation. Hypertension. 2008;52:366–72.

    Article  CAS  PubMed  Google Scholar 

  7. Kurtz TW. Genome-wide association studies will unlock the genetic basis of hypertension: con side of the argument. Hypertension. 2010;56:1021–5.

    Article  CAS  PubMed  Google Scholar 

  8. Ganesh SK, Chasman DI, Larson MG, et al. Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. Am J Hum Genet. 2014;95:49–65. An association with blood pressure is found for these loci in 49,626 individuals of European ancestry.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tragante V, Barnes MR, Ganesh SK, et al. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet. 2014;94:349–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Natekar A, Olds RL, Lau MW, et al. Elevated blood pressure: our family’s fault? The genetics of essential hypertension. World J Cardiol. 2014;6:327–37. A comprehensive review on genetic factors associated to arterial hypertension.

    PubMed  PubMed Central  Google Scholar 

  11. Padmanabhan S, Caulfield M, Dominiczak AF. Genetic and molecular aspects of hypertension. Circ Res. 2015;116:937–59. The current status of genetic hypertension is reviewed and two targets (NOS and Uromodulin) to be successfully used for drug development are illustrated.

    Article  CAS  PubMed  Google Scholar 

  12. Doaei S, Gholamalizadeh M. The association of genetic variations with sensitivity of blood pressure to dietary salt: a narrative literature review. ARYA Atheroscler. 2014;10:169–74.

    PubMed  PubMed Central  Google Scholar 

  13. Manolio TA. Bringing genome-wide association findings into clinical use. Nat Rev Genet. 2013;14:549–58.

    Article  CAS  PubMed  Google Scholar 

  14. Aronson SJ, Rehm HL. Building the foundation for genomics in precision medicine. Nature. 2015;526:336–42. A thorough discussion on the various issues to be addressed to develop a precision medicine.

    Article  CAS  PubMed  Google Scholar 

  15. Joyner MJ, Paneth N. Seven questions for personalized medicine. JAMA. 2015;314:999–1000.

    Article  CAS  PubMed  Google Scholar 

  16. Caro JJ, Salas M, Speckman JL, et al. Persistence with treatment for hypertension in actual practice. Can Med Assoc J. 1999;160:31–7. Withdrawal rate from hypertensive drugs is four times higher in newly discovered and never treated patients compared to the patients under therapy.

    CAS  Google Scholar 

  17. Barrett JC, Dunham I, Birney E. Using human genetics to make new medicines. Nat Rev Genet. 2015;16:561–2.

    Article  CAS  PubMed  Google Scholar 

  18. Rodriguez R, Miller KM. Unraveling the genomic targets of small molecules using high-throughput sequencing. Nat Rev Genet. 2014;15:783–96. A comprehensive review on genomic target application in the search for drug development.

    Article  CAS  PubMed  Google Scholar 

  19. Frye SV, Arkin MR, Arrowsmith CH, et al. Tackling reproducibility in academic preclinical drug discovery. Nat Rev Drug Discov. 2015;14:733–4. The problem related to the use of genetic targets discovered in Academic research applicable to drug development is discussed.

    Article  CAS  PubMed  Google Scholar 

  20. Noble D, Jablonka E, Joyner MJ, et al. Evolution evolves: physiology returns to centre stage. J Physiol. 2014;592:2237–44. The importance of considering physiological functions in discussing evolution is highlighted.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Milot E, Mayer FM, Nussey DH, et al. Evidence for evolution in response to natural selection in a contemporary human population. Proc Natl Acad Sci. 2011;108:17040–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bianchi G, Fox U, Di Francesco GF, et al. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med. 1974;47:435–48.

    CAS  PubMed  Google Scholar 

  23. Bianchi G, Fox U, Di Francesco GF, et al. The hypertensive role of the kidney in spontaneously hypertensive rats. Clin Sci Mol Med. 1973;45:135–9.

    Google Scholar 

  24. Guidi E, Bianchi G, Dallosta V, et al. Influence of familial hypertension of the donor on the blood pressure and antihypertensive therapy of kidney graft recipients. Nephron. 1982;30:318–23.

    Article  CAS  PubMed  Google Scholar 

  25. Guidi E, Bianchi G, Rivolta E, et al. Hypertension in man with a kidney transplant: role of familial versus other factors. Nephron. 1985;41:14–21.

    Article  CAS  PubMed  Google Scholar 

  26. Guidi E, Menghetti D, Milani S, et al. Hypertension may be transplanted with the kidney in humans: a long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in the family. J Am Soc Nephrol. 1996;7:1131–8.

    CAS  PubMed  Google Scholar 

  27. Dahl LK, Heine M. Primary role of renal homografts in setting chronic blood pressure levels in rats. Circ Res. 1975;36:692–6.

    Article  CAS  PubMed  Google Scholar 

  28. Rettig R, Stauss H, Folberth C, et al. Hypertension transmitted by kidneys from stroke-prone spontaneously hypertensive rats. Am J Physiol. 1989;257:F197–203.

    CAS  PubMed  Google Scholar 

  29. Bianchi G, Tenconi LT, Lucca R. Effect in the conscious dog of constriction of the renal artery to a sole remaining kidney on hemodynamics, sodium balance, body fluid volumes, plasma renin concentration and pressor responsiveness to angiotensin. Clin Sci. 1970;38:741–66.

    Article  CAS  PubMed  Google Scholar 

  30. Bing RF, Russell GI, Swales JD, Thurston H. Effect of 12-hour infusions of saralasin or captopril on blood pressure in hypertensive conscious rats. Relationship to plasma renin, duration of hypertension, and effect of unclipping. J Lab Clin Med. 1981;98:302–10.

    CAS  PubMed  Google Scholar 

  31. Watkins BE, Davis JO, Freeman RH, et al. Continuous angiotensin II blockade throughout the acute phase of one-kidney hypertension in the dog. Circ Res. 1978;42:813–21.

    Article  CAS  PubMed  Google Scholar 

  32. Freeman RH, Davis JO, Watkins BE, et al. Effects of continuous converting enzyme blockade on renovascular hypertension in the rat. Am J Physiol. 1979;236:F21–4.

    CAS  PubMed  Google Scholar 

  33. Edmunds ME, Russell GI, Bing RF. Reversal of experimental renovascular hypertension. J Hypertens. 1991;9:289–301.

    Article  CAS  PubMed  Google Scholar 

  34. Davis JO. The pathogenesis of chronic renovascular hypertension. Circ Res. 1977;40:439–44.

    Article  CAS  PubMed  Google Scholar 

  35. Bianchi G, Baer PG, Fox U, et al. Changes in renin, water balance, and sodium balance during development of high blood pressure in genetically hypertensive rats. Circ Res. 1975;36&37:153–61.

    Article  Google Scholar 

  36. Baer PG, Bianchi G. Micropuncture study of altered renal function in rats of the Milan hypertensive strain (MHS). Proceedings of: the Symposium on Spontaneous Genetic Hypertension in rats. Clin Exp Pharmacol Physiol. 1976;3:41s-5s.

  37. Baer PG, Bianchi G, Duzzi L. Renal micropuncture study of normotensive and Milan hypertensive rats before and after development of hypertension. Kidney Int. 1978;13:452–66.

    Article  CAS  PubMed  Google Scholar 

  38. Ferrari P, Cusi D, Barber B, et al. Erythrocyte membrane and renal function in relation to hypertension in rats of the Milan hypertensive strain. Clin Sci. 1982;63:61–4.

    Article  CAS  Google Scholar 

  39. Persson AE, Boberg U, Hahne B, et al. Interstitial pressure as a modulator of tubuloglomerular feedback control. Kidney Int. 1982;12:S122–8.

    CAS  Google Scholar 

  40. Persson AE, Bianchi G, Boberg U. Evidence of defective tubuloglomerular feedback control in rats of the Milan hypertensive strain (MHS). Acta Physiol Scand. 1984;122:217–19.

    Article  CAS  PubMed  Google Scholar 

  41. Persson AE, Bianchi G, Boberg U. Tubuloglomerular feedback in hypertensive rats of the Milan strain. Acta Physiol Scand. 1985;123:139–46.

    Article  CAS  PubMed  Google Scholar 

  42. Salvati P, Pinciroli GP, Bianchi G. Renal function of isolated perfused kidneys from hypertensive (MHS) and normotensive (MNS) rats of the Milan strain at different ages. J Hypertens. 1984;2:351–3.

    Google Scholar 

  43. Salvati P, Ferrario RG, Parenti P, Bianchi G. Renal function of isolated perfused kidneys from hypertensive (MHS) and normotensive (MNS) rats of the Milan strain: role of calcium. J Hypertens. 1987;5:31–8.

    Article  CAS  PubMed  Google Scholar 

  44. Capasso G, Rizzo M, Evangelista C, et al. Altered expression of renal apical plasma membrane Na + transporters in the early phase of genetic hypertension. Am J Physiol Renal Physiol. 2005;288:F1173–82.

    Article  CAS  PubMed  Google Scholar 

  45. Capasso G, Rizzo M, Garavaglia ML, et al. Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol. 2008;295:F556–67.

    Article  CAS  PubMed  Google Scholar 

  46. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008;371:1921–6.

    Article  CAS  PubMed  Google Scholar 

  47. Young WF. Primary aldosteronism-one picture is not worth a thousand words. Ann Intern Med. 2009;151:357–8.

    Article  PubMed  Google Scholar 

  48. Monticone S, Else T, Mulatero P, et al. Understanding primary aldosteronism: impact of next generation sequencing and expression profiling. Mol Cell Endocrinol. 2015;399:311–20.

    Article  CAS  PubMed  Google Scholar 

  49. Beretta-Piccoli C, Fischbacher A, Rothenbühler A, et al. Body sodium/blood volume state in normotensive members of normotensive and hypertensive families. J Hypertens. 1986;4:229–34.

    Article  CAS  PubMed  Google Scholar 

  50. Bianchi G, Cusi D, Gatti M, et al. A renal abnormality as a possible cause of “essential” hypertension. Lancet. 1979;1:173–7.

    Article  CAS  PubMed  Google Scholar 

  51. Bianchi G, Staessen JA, Ferrari P. Pharmacogenomics of primary hypertension-the lessons from the past to look toward the future. Pharmacogenomics. 2003;4:279–96.

    Article  CAS  PubMed  Google Scholar 

  52. Huan T, Esko T, Peters MJ, et al. A meta-analysis of gene expression signatures of blood pressure and hypertension. PLoS Genet. 2015;11:e1005035.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Munroe PB, Tinker A. Genome-wide association studies and contribution to cardiovascular physiology. Physiol Genomics. 2015;47:365–75.

    Article  PubMed  Google Scholar 

  54. Chakravarti A. Genomics is not enough. Science. 2011;334:15.

    Article  CAS  PubMed  Google Scholar 

  55. Ryan CJ, Cimermančič P, Szpiech ZA, et al. High-resolution network biology: connecting sequence with function. Nat Rev Genet. 2013;14:865–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Le Novère N. Quantitative and logic modeling of molecular and gene networks. Nat Rev Genet. 2015;16:146–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Mooney MA, Nigg JT, McWeeney SK, Wilmot B. Functional and genomic context in pathway analysis of GWAS data. Trends Genet. 2014;30:390–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ritchie MD, Holzinger ER, Li R, et al. Methods of integrating data to uncover genotype-phenotype interactions. Nat Rev Genet. 2015;16:85–97.

    Article  CAS  PubMed  Google Scholar 

  59. Sorrells TR, Johnson AD. Making sense of transcription networks. Cell. 2015;161:714–23.

    Article  CAS  PubMed  Google Scholar 

  60. Mazzocchi F. Could big data be the end of theory in science? A few remarks on the epistemology of data-driven science. EMBO Rep. 2015;16:1250–5.

    Article  CAS  PubMed  Google Scholar 

  61. Ségalat L. System crash. EMBO Rep. 2010;11:86–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Baddeley M. Herding, social influences and behavioral bias in scientific research: simple awareness of the hidden pressures and beliefs that influence our thinking can help to preserve objectivity. EMBO Rep. 2015;16:902–5. Many non scientific factors influence the choice of research approaches.

    Article  CAS  PubMed  Google Scholar 

  63. MacArthur DG, Manolio TA, Dimmock DP, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508:469–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Marian AJ. Causality in genetics: the gradient of genetic effects and back to Koch’s postulates of causality. Circ Res. 2014;114:e18–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Williams SM, Haines JL, Moore JH. The use of animal models in the study of complex disease: all else is never equal or why do so many human studies fail to replicate animal findings? Bioessays. 2004;26:170–9.

    Article  CAS  PubMed  Google Scholar 

  66. Romiguier J, Gayral P, Ballenghien M, et al. Comparative population genomics in animals uncovers the determinants of genetic diversity. Nature. 2014;515:261–3.

    Article  CAS  PubMed  Google Scholar 

  67. Editorial. Of men, not mice. Nat Med. 2013;19:379.

  68. Bianchi G. Genetic variations of tubular sodium reabsorption leading to “primary” hypertension. Am J Physiol. 2005;289:R1536–49. In this review, the most peculiar aspects of our strategy have been indicated and discussed.

    CAS  Google Scholar 

  69. Bianchi G, Picotti GB, Bracchi G, et al. Familial hypertension and hormonal profile, renal haemodynamics and body fluids of young normotensive subjects. Clin Sci Mol Med. 1978;55:367–71.

    Google Scholar 

  70. Cusi D, Barlassina C, Ferrandi M, et al. Relationship between altered Na+-K+ cotransport and Na+-Li+ countertransport in the erythrocytes of “essential” hypertensive patients. Clin Sci. 1981;61:33s–6.

    Article  CAS  PubMed  Google Scholar 

  71. Cusi D, Barlassina C, Ferrandi M, et al. Erythrocyte membrane transport systems as possible markers for essential hypertension. Clin Sci. 1982;63:57–9.

    Article  Google Scholar 

  72. Bianchi G, Cusi D, Guidi E. Renal hemodynamics in human subjects and in animals with genetic hypertension during the prehypertensive stage. Am J Nephrol. 1983;3:73–9.

    Article  CAS  PubMed  Google Scholar 

  73. Bianchi G, Cusi D, Barlassina C, et al. Renal dysfunction as a possible cause of essential hypertension in predisposed subjects. Kidney Int. 1983;23:870–5.

    Article  CAS  PubMed  Google Scholar 

  74. Beck F, Bianchi G, Dörge A, et al. Sodium and potassium concentrations of renal cortical cells in two animal models of primary arterial hypertension. J Hypertens. 1983;1:38–9.

    CAS  Google Scholar 

  75. Thurau K, Beck F, Borst M, et al. Intracellular electrolyte composition in various experimental models of hypertension: an electron microprobe study. J Cardiovasc Pharmacol. 1984;6:28–31.

    Article  Google Scholar 

  76. Bianchi G, Ferrari P, Salvati P, et al. Relationship between red blood cell function, kidney function and blood pressure in genetic hypertension. Klin Wochenschr. 1985;63:59–60.

    PubMed  Google Scholar 

  77. Cusi D, Alberghini E, Pati P, et al. Pathogenetic mechanisms in essential hypertension. Analogies between a rat model and the human disease. Int J Cardiol. 1989;25:29–36.

    Article  Google Scholar 

  78. Bianchi G, Baldoli E, Lucca E, Barbin P. Pathogenesis of arterial hypertension after the constriction of the renal artery leaving the opposite kidney intact both in the anaesthetized and the conscious dog. Clin Sci. 1972;42:651–64.

    Article  CAS  PubMed  Google Scholar 

  79. Trizio D, Ferrari P, Ferrandi M, et al. Expression at the hemopoietic stem cell level of the genetically determined erythrocyte membrane defects in the Milan hypertensive rat strain (MHS). J Hypertens. 1983;1:S6–8.

    Google Scholar 

  80. Bianchi G, Ferrari P, Trizio D, et al. Red blood cell abnormalities and spontaneous hypertension in the rat: a genetically determined link. Hypertension. 1985;7:319–25.

    CAS  PubMed  Google Scholar 

  81. Parenti P, Hanozet G, Bianchi G. Sodium and glucose transport across renal brush-border membranes of Milan hypertensive rats. Hypertension. 1986;8:932–9.

    Article  CAS  PubMed  Google Scholar 

  82. Ferrari P, Torielli L, Ferrandi M, et al. Volumes and Na+ transports in intact red blood cells, resealed ghosts and inside-out vesicles of Milan hypertensive rats. J Hypertens. 1986;4:379–81.

    Google Scholar 

  83. Ferrari P, Ferrandi M, Torielli L, et al. Relationship between erythrocyte volume and sodium transport in the Milan hypertensive rat and age-dependent changes. J Hypertens. 1987;5:199–206.

    Article  CAS  PubMed  Google Scholar 

  84. Ferrandi M, Salardi S, Parenti P, et al. Na+/K+/Cl−-cotransporter mediated Rb+ fluxes in membrane vesicles from kidneys of normotensive and hypertensive rats. Biochim Biophys Acta. 1990;1021:13–20.

    Article  CAS  PubMed  Google Scholar 

  85. Ferrari P, Torielli L, Cirillo M, et al. Sodium transport kinetics in erythrocytes and inside-out vesicles from Milan rats. J Hypertens. 1991;9:703–11.

    Article  CAS  PubMed  Google Scholar 

  86. Parenti P, Ferrari P, Ferrandi M, et al. Effect of amiloride analogues on sodium transport in renal brush border membrane vesicles from Milan hypertensive rats. Biochem Biophys Res Commun. 1992;183:55–61.

    Article  CAS  PubMed  Google Scholar 

  87. Ferrari P, Torielli L, Salardi S, et al. Na+/K+/Cl− cotransport in resealed ghosts from erythrocytes of the Milan hypertensive rats. Biochim Biophys Acta. 1992;1111:111–9.

    Article  CAS  PubMed  Google Scholar 

  88. Salardi S, Modica R, Ferrandi M, et al. Characterization of erythrocyte adducin from the Milan hypertensive strain of rats. J Hypertens. 1988;6:196s–8.

    Article  Google Scholar 

  89. Salardi S, Saccardo B, Borsani G, et al. Erythrocyte adducin differential properties in normotensive and hypertensive rats of the Milan strain (characterization of spleen adducin m-RNA). Am J Hypertens. 1989;2:229–37.

    CAS  PubMed  Google Scholar 

  90. Salardi S, Hofstede J, Op Den Camp JA. F, Bianchi G. Protein and lipid composition of erythrocytes from the Milan hypertensive strain rat. J Vasc Med Biol. 1989;1:262–8.

  91. Tripodi MG, Piscone A, Borsani G, et al. Molecular cloning of an adducin-like protein: evidence of a polymorphism in the normotensive and hypertensive rats of the Milan strain. Biochem Biophys Res Commun. 1991;177:939–47.

    Article  CAS  PubMed  Google Scholar 

  92. Bianchi G, Tripodi MG, Casari G, et al. Two point mutations within the adducin genes are involved in blood pressure variation. Proc Natl Acad Sci. 1994;91:3999–4003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Casari G, Barlassina C, Cusi D, et al. Association of the α-adducin locus with essential hypertension. Hypertension. 1995;25:320–6.

    Article  CAS  PubMed  Google Scholar 

  94. Tripodi MG, Casari G, Tisminetzky S, et al. Characterization and chromosomal localization of the rat α- and β-adducin-encoding genes. Gene. 1995;166:307–11.

    Article  CAS  PubMed  Google Scholar 

  95. Tisminetzky S, Devescovi G, Tripodi MG, et al. Genomic organisation and chromosomal localisation of the gene encoding human beta adducin. Gene. 1995;167:313–6.

    Article  CAS  PubMed  Google Scholar 

  96. Melzi ML, Bertorello A, Fukuda Y, et al. Na, K-ATPase activity in renal tubule cells from Milan hypertensive rats. Am J Hypertens. 1989;2:563–6.

    CAS  PubMed  Google Scholar 

  97. Ferrandi M, Tripodi MG, Salardi S, et al. Renal Na, K-ATPase in genetic hypertension. Hypertension. 1996;28:1018–25.

    Article  CAS  PubMed  Google Scholar 

  98. Ferrandi M, Salardi S, Tripodi MG, et al. Evidence for an interaction between adducin and Na, K ATPase: relation to genetic hypertension. Am J Physiol. 1999;277:1338–49.

    Google Scholar 

  99. Ferrari P, Bianchi G. Pathophysiology of hypertension. Membrane ion transports in hypertension. Hypertension. 1997;17:935–74.

    CAS  Google Scholar 

  100. Ferrandi M, Molinari I, Torielli L, et al. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 1: experimental studies. Sci Transl Med. 2010;2:59ra86.

    Article  CAS  PubMed  Google Scholar 

  101. Tripodi MG, Valtorta F, Torielli L, et al. Hypertension-associated point mutations in the adducin α and β subunits affect actin cytoskeleton and ion transport. J Clin Invest. 1996;97:2815–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cusi D, Barlassina C, Azzani T, et al. Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet. 1997;349:1353–7.

    Article  CAS  PubMed  Google Scholar 

  103. Citterio L, Lanzani C, Manunta P, Bianchi G. Genetics of primary hypertension: the clinical impact of adducin polymorphisms. Biochim Biophys Acta. 1802;2010:1285–98.

    Google Scholar 

  104. Liu K, Liu Y, Liu J, et al. Alpha-adducin Gly460Trp polymorphism and essential hypertension risk in Chinese: a meta-analysis. Hypertens Res. 2011;34:389–9.

    Article  CAS  PubMed  Google Scholar 

  105. Li YY. α-Adducin Gly460Trp gene mutation and essential hypertension in a Chinese population: a meta-analysis including 10,960 subjects. PLoS ONE. 2012;7:e30214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schoner W, Scheiner-Bobis G. Endogenous and exogenous cardiac glycosides and their mechanisms of action. Am J Cardiovasc Drugs. 2007;7:173–89.

    Article  CAS  PubMed  Google Scholar 

  107. Manunta P, Maillard M, Tantardini C, et al. Relationships among endogenous ouabain, alpha-adducin polymorphisms and renal sodium handling in primary hypertension. J Hypertens. 2008;26:914–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Manunta P, Ferrandi M, Bianchi G, Hamlyn JM. Endogenous ouabain in cardiovascular function and disease. J Hypertens. 2009;27:9–18.

    Article  CAS  PubMed  Google Scholar 

  109. Ferrandi M, Minotti E, Salardi S, et al. Ouabain-like factor in Milan hypertensive rats. Am J Physiol. 1992;263:F739–48.

    CAS  PubMed  Google Scholar 

  110. Ferrandi M, Manunta P, Balzan S, et al. Ouabain-like factor quantification in human tissues and plasma: comparison of two independent assays. Hypertension. 1997;30:886–96.

    Article  CAS  PubMed  Google Scholar 

  111. Ferrandi M, Molinari I, Barassi P, et al. Organ hypertrophic signalling within caveolae membrane subdomains triggered by ouabain and antagonized by PST2238. J Biol Chem. 2004;279:33306–14.

    Article  CAS  PubMed  Google Scholar 

  112. Ferrari P, Torielli L, Ferrandi M, et al. PST2238: a new antihypertensive compound that antagonizes the long-term pressor effect of ouabain. J Pharmacol Exp Ther. 1998;285:83–94.

    CAS  PubMed  Google Scholar 

  113. Efendiev R, Krmar RT, Ogimoto G, et al. Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na, K-ATPase trafficking in response to GPCR signals and intracellular sodium. Circ Res. 2004;95:1100–8.

    Article  CAS  PubMed  Google Scholar 

  114. Bubien JK. Epithelial Na+ channel (ENaC), hormones, and hypertension. J Biol Chem. 2010;285:23527–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Manunta P, Hamilton BP, Hamlyn JM. Salt intake and depletion increase circulating levels of endogenous ouabain in normal men. Am J Physiol Regul Integr Comp Physiol. 2006;290:R553–9.

    Article  CAS  PubMed  Google Scholar 

  116. Manunta P, Messaggio E, Ballabeni C, et al. Salt sensitivity study group of the Italian Society of Hypertension. Plasma ouabain-like factor during acute and chronic changes in sodium balance in essential hypertension. Hypertension. 2001;38:198–203.

    Article  CAS  PubMed  Google Scholar 

  117. Zhang J, Lee MY, Cavalli M, et al. Sodium pump alpha2 subunits control myogenic tone and blood pressure in mice. J Physiol. 2005;569:243–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kurtz TW, Dominiczak AF, DiCarlo SE, et al. Molecular-based mechanisms of mendelian forms of salt-dependent hypertension: questioning the prevailing theory. Hypertension. 2015;65:932–41.

    Article  CAS  PubMed  Google Scholar 

  119. Warnock DG, Kusche-Vihrog K, Tarjus A, et al. Blood pressure and amiloride-sensitive sodium channels in vascular and renal cells. Nat Rev Nephrol. 2014;10:146–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Liang M, Lee NH, Wang H, et al. Molecular networks in Dahl salt-sensitive hypertension based on transcriptome analysis of a panel of consomicrats. Physiol Genomics. 2008;34:54–64.

    Article  CAS  PubMed  Google Scholar 

  121. Davidson EH. Emerging properties of animal gene regulatory networks. Nature. 2010;468:911–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Erwin DH, Davidson EH. The evolution of hierarchical gene regulatory networks. Nat Rev Genet. 2009;10:141–8.

    Article  CAS  PubMed  Google Scholar 

  123. Gu J, Xuan Z. Inferring the perturbed microRNA regulatory networks in cancer using hierarchical gene co-expression signatures. PLoS ONE. 2013;8:e81032.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Ferrari P, Ferrandi M, Valentini G, Bianchi G. Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+–K+ATPase alterations in ouabain and adducin-dependent hypertension. Am J Physiol Regul Integr Comp Physiol. 2006;290:R529–35.

    Article  CAS  PubMed  Google Scholar 

  125. Ferrari P, Ferrandi M, Tripodi G, et al. PST2238: a new antihypertensive compound that modulates Na+–K+ ATPase in genetic hypertension. J Pharmacol Exp Ther. 1999;288:1074–83.

    CAS  PubMed  Google Scholar 

  126. Heineke J, Molkentin JD. Regulation of cardiac hypertrophy by intracellular signaling pathways. Nat Rev Mol Cell Biol. 2006;7:589–600.

    Article  CAS  PubMed  Google Scholar 

  127. Muslin J. MAPK signaling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci. 2008;115:203–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Staessen JA, Kuznetsova T, Acceto R, et al. OASIS-HT: design of a pharmacogenomic dose-finding study. Pharmacogenomics. 2005;6:755–75.

    Article  CAS  PubMed  Google Scholar 

  129. Lanzani C, Citterio L, Glorioso N, et al. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 2: clinical studies. Sci Transl Med. 2010;2:59ra87.

    Article  CAS  PubMed  Google Scholar 

  130. Staessen JA, Thijs L, Stolarz-Skrzypek K, et al. Main results of the ouabain and adducin for specific intervention on sodium in hypertension trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin. Trials. 2011;12:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290–300.

    Article  PubMed  Google Scholar 

  132. Finucane HK, Bulik-Sullivan B, Gusev A, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet. 2015;47:1228–35.

    Article  CAS  PubMed  Google Scholar 

  133. Zhao B, Tan PH, Li SS, Pei D. Systematic characterization of the specificity of the SH2 domains of cytoplasmic tyrosine kinases. J Proteomics. 2013;81:56–69.

    Article  CAS  PubMed  Google Scholar 

  134. Ferrandi M, Molinari I, Rastaldi MP, et al. Rostafuroxin protects from podocyte injury and proteinuria induced by adducin genetic variants and ouabain. J Pharmacol Exp Ther. 2014;351:278–87.

    Article  PubMed  CAS  Google Scholar 

  135. Duboule D, Wilkins AS. The evolution of ‘bricolage’. Trends Genet. 1998;14:54–9.

    Article  CAS  PubMed  Google Scholar 

  136. Citterio L, Ferrandi M, Delli Carpini S, et al. cGMP-dependent protein kinase 1 polymorphisms underlie renal sodium handling impairment. Hypertension. 2013;62:1027–33.

    Article  CAS  PubMed  Google Scholar 

  137. Kuznetsova T, Citterio L, Zagato L, et al. Left ventricular radial function associated with genetic variation in the cGMP-dependent protein kinase. Hypertension. 2013;62:1034–9.

    Article  CAS  PubMed  Google Scholar 

  138. Kuznetsova T, Citterio L, Herbots L, et al. Effects of genetic variation in adducin on left ventricular diastolic function as assessed by tissue Doppler imaging in a Flemish population. J Hypertens. 2008;26:1229–36.

    Article  CAS  PubMed  Google Scholar 

  139. Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet. 2002;3:165–75.

    Article  CAS  PubMed  Google Scholar 

  140. Hamlyn JM, Laredo J, Shah JR, et al. 11-hydroxylation in the biosynthesis of endogenous ouabain: multiple implications. Ann N Y Acad Sci. 2003;986:685–93.

    Article  CAS  PubMed  Google Scholar 

  141. Pitzalis MV, Hamlyn JM, Messaggio E, et al. Independent and incremental prognostic value of endogenous ouabain in idiopathic dilated cardiomyopathy. Eur J Heart Fail. 2006;8:179–86.

    Article  CAS  PubMed  Google Scholar 

  142. Jacobs BE, Liu Y, Pulina MV, et al. Normal pregnancy: mechanisms underlying the paradox of a ouabain-resistant state with elevated endogenous ouabain, suppressed arterial sodium calcium exchange, and low blood pressure. Am J Physiol Heart Circ Physiol. 2012;302:H1317–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Robertson JI. Dietary salt and hypertension: a scientific issue or a matter of faith? J Eval Clin Pract. 2003;9:1–22.

    Article  PubMed  Google Scholar 

  144. Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005;95:144s–50. This is a very thorough discussion on the difficulty to demonstrate causation of a given factor (either genetic or environmental) within the complex interactions among the various modifiers factors (either genetic or environmental).

    Article  Google Scholar 

  145. Stolarz-Skrzypek K, Kuznetsova T, Thijs L, et al. Fatal and nonfatal outcomes, incidence of hypertension, and blood pressure changes in relation to urinary sodium excretion. JAMA. 2011;305:1777–85.

    Article  CAS  PubMed  Google Scholar 

  146. Nelson RM, Pettersson ME, Carlborg Ö. A century after fisher: time for a new paradigm in quantitative genetics. Trends Genet. 2013;29:669–76. The present analysis paradigms in genetics are at its limits in regards to unraveling complex traits with GWAS.

  147. Mackay TF. Epistatis and quantitative traits: using model organisms to study gene-gene interactions. Nat Rev Genet. 2014;15:22–33. Carrying out tests for about 18 million possible pairwise interactions remains a practical impossibility even in a tractable model system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wei WH, Hemani G, Haley CS. Detecting epistasis in human complex traits. Nat Rev Genet. 2014;15:722–33. Testing interactions with GWAS data based on SNPs that have been grouped into genes or functional modules can markedly reduce the multiple test burden, particular when one of this functional module has a very strong experimental and clinical support.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

P. Manunta’s research is supported by Ministero della Salute Italiano (RF-2011-02347356 and RF-2011-02346988) and by CVie Therapeutics Limited, Taipei.

J. Staessen’s research is currently supported by the European Union (HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-F7-305507 HOMAGE, the European Research Council Advanced Researcher Grant-2011-294713-EPLORE) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.088013).

Author information

Authors and Affiliations

  1. Università Vita Salute San Raffaele, Chair of Nephrology; IRCCS San Raffaele Scientific Institute, Genomics of Renal Disease and Hypertension Unit, Via Olgettina 60, 20132, Milan, Italy

    Paolo Manunta & Giuseppe Bianchi

  2. CVie Therapeutics Limited, Taipei, Taiwan

    Mara Ferrandi, Patrizia Ferrari & Giuseppe Bianchi

  3. Italian National Centre of Research, Institute of Biomedical Technologies, Segrate, Milan, Italy

    Daniele Cusi

  4. Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium

    Jan Staessen

  5. R&D Group VitaK, Maastricht University, Maastricht, The Netherlands

    Jan Staessen

Authors
  1. Paolo Manunta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mara Ferrandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniele Cusi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrizia Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan Staessen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giuseppe Bianchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giuseppe Bianchi.

Ethics declarations

Conflict of Interest

Drs. Bianchi and Ferrari are consultants to CVie Therapeutic Limited, Taipei, Taiwan. Dr. Ferrendi is an employee of CVie. Dr. Manunta received research support from CVie. Drs. Cusi and Staessen declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Novel Treatments for Hypertension

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Manunta, P., Ferrandi, M., Cusi, D. et al. Personalized Therapy of Hypertension: the Past and the Future. Curr Hypertens Rep 18, 24 (2016). https://doi.org/10.1007/s11906-016-0632-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-016-0632-y

Keywords

Search

Navigation