Skip to main content
Download PDF

Sodium excretion as a modulator of genetic influence on arterial stiffness and other cardiovascular phenotypes

Artery Research volume 1, pages 20–25 (2007)Cite this article

Summary

Hypertension is a chronic age-related disorder, affecting nearly 20% of all adult Europeans. This disease entails debilitating cardiovascular complications and is the leading cause for drug prescriptions in Europeans older than 50 years. Intensive research over the past two decades has so far failed to identify common genetic polymorphisms with a major impact on blood pressure or associated cardiovascular phenotypes, suggesting that multiple genes each with a minor impact, along with gene—gene and gene—environment interactions, play a role. The European Project on Genes in Hypertension (EPOGH) is a large-scale, family-based study in which participants from seven different populations were phenotyped and genotyped according to standardized procedures. The EPOGH demonstrated that phenotype–genotype relations strongly depend on host factors such as gender and lifestyle, in particular salt intake as reflected by the 24-h urinary excretion of sodium. Individuals with the same genetic predisposition had different vascular stiffness, left ventricular mass or heart rate variability, depending on whether they ate a high-sodium or a low-sodium diet. The EPOGH therefore highlights the concept that phenotype—genotype relations can only be studied within a defined eco-genetic context.

References

  1. Bronner LL, Kanter DS, Manson JE. Primary prevention of stroke. N Engl J Med 1995;333:1392–400.

    Google Scholar 

  2. Staessen JA, Wang JG, Birkenhäger WH. Outcome beyond blood pressure control? Eur Heart J 2003;24:504–14.

    Google Scholar 

  3. Staessen JA, Wang J, Bianchi G, Birkenhäger WH. Essential hypertension. Lancet 2003;361:1629–41.

    Google Scholar 

  4. Matsukawa T, Ichikawa I. Biological functions of angiotensin and its receptors. Annu Rev Physiol 1997;59:395–412.

    Google Scholar 

  5. Ferrandi M, Salardi S, Tripodi G, Barassi P, Rivera R, Manunta P, et al. Evidence for an interaction between adducin and Na+– K+-ATPase: relation to genetic hypertension. Am J Physiol 1999; 277:H1338–49.

    Google Scholar 

  6. O’Shaughnessy KM, Karet FE. Salt handling and hypertension. J Clin Invest 2004;113:1075–81.

    Google Scholar 

  7. Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Dietary salt intake. A determinant of cardiac involvement in essential hypertension. Circulation 1988;78:951–6.

    Google Scholar 

  8. Safar ME, Thuilliez C, Richard V, Benetos A. Pressure-independent contribution of sodium to large artery structure and function in hypertension. Cardiovasc Res 2000;46:269–76.

    Google Scholar 

  9. Wojciechowska W, Staessen JA, Stolarz K, Nawrot T, Filipovsky J, Ticha M, et al. Association of peripheral and central arterial wave reflections with the CYP11B2 –344C allele and sodium excretion. J Hypertens 2004;22:2311–9.

    Google Scholar 

  10. Takeda Y. Pathophysiological roles of vascular 11 beta-hydrox-ysteroid dehydrogenase and aldosterone. J Steroid Biochem Mol Biol 2003;85:443–7.

    Google Scholar 

  11. Seidlerova J, Staessen JA, Maillard M, Nawrot T, Zhang H, Bochud M, et al. Association between arterial properties and renal sodium handling in a general population. Hypertension 2006;48:609–15.

    Google Scholar 

  12. Dzau VJ. Tissue renin–angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 1993;153:937–42.

    Google Scholar 

  13. Kuznetsova T, Staessen JA, Stolarz K, Ryabikov A, Tikhonoff V, Olszanecka A, et al. Relationship of left ventricular mass and the ACE D/I polymorphism varies according to sodium intake. J Hypertens 2004;22:287–95.

    Google Scholar 

  14. Kuznetsova T, Staessen JA, Thijs L, Kunath C, Olszanecka A, Ryabikov A, et al. Left ventricular mass in relation to genetic variation in angiotensin II receptors, renin system genes, and sodium excretion. Circulation 2004;110:2644–50.

    Google Scholar 

  15. Kuznetsova T, Staessen JA, Wang JG, Gasowski J, Nikitin Y, Ryabikov A, et al. Antihypertensive treatment modulates the association between the D/I ACE gene polymorphism and left ventricular hypertrophy: a meta-analysis. J Hum Hypertens 2000;14:447–54.

    Google Scholar 

  16. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343–6.

    Google Scholar 

  17. Hiraga H, Oshima T, Watanabe M, Ishida M, Ishida T, Shingu T, et al. Angiotensin I-converting enzyme gene polymorphism and salt sensitivity in essential hypertension. Hypertension 1996;27(Pt 2):569–72.

    Google Scholar 

  18. Poch E, González D, Giner V, Bragulat E, Coca A, de la Sierra A. Molecular basis for salt sensitivity in human hypertension. Evaluation of the renin–angiotensin–aldosterone system gene polymorphisms. Hypertension 2001;38:1204–9.

    Google Scholar 

  19. Schmieder RE, Langenfeld MRW, Friedrich A, Schobel HP, Gatzka CD, Weihprecht H. Angiotensin II related to sodium excretion modulates left ventricular structure in human essential hypertension. Circulation 1996;94:1304–9.

    Google Scholar 

  20. Duncan AM, Scholey JW, Miller JA. Angiotensin II type 1 receptor gene polymorphisms inhumans: physiology and pathophysiology of the genotypes. Curr Opin Nephrol Hypertens 2001;10: 111–6.

    Google Scholar 

  21. Castellano M, Muiesan ML, Beschi M, Rizzoni D, Cinelli A, Salvetti M, et al. Angiotensin II type 1 receptor A/C1166 polymorphism. Relationships with blood pressure and cardiovascular structure. Hypertension 1996;28:1076–80.

    Google Scholar 

  22. Hamon M, Amant C, Bauters C, Richard F, Helbecque N, McFadden E, et al. Association of angiotensin converting enzyme and angiotensin II type 1 receptor genotypes with left ventricular function and mass in patients with angiographically normal coronary arteries. Heart 1997;77:502–5.

    Google Scholar 

  23. Takami S, Katsuya T, Rakugi H, Sato N, Nakata Y, Kamitani A, et al. Angiotensin II type 1 receptor gene polymorphism is associated with increase of left ventricular mass but not with hypertension. Am J Hypertens 1998;11:316–21.

    Google Scholar 

  24. De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000;52:415–72.

    Google Scholar 

  25. Warnecke C, Willich T, Holzmeister J, Bottari SP, Fleck E, Regitz-Zagrosek V. Efficient transcription of the human angio-tensin II type 2 receptor gene requires intronic sequence elements. Biochem J 1999;340:17–24.

    Google Scholar 

  26. Schmieder RE, Erdmann J, Delles C, Jacobi J, Fleck E, Hilgers K, et al. Effect of the angiotensin II type 2-receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol 2001;37:175–82.

    Google Scholar 

  27. Herrmann SM, Nicaud V, Schmidt-Petersen K, Pfeifer J, Erdmann J, McDonagh T, et al. Angiotensin II type 2 receptor genepolymorphism and cardiovascular phenotypes: the GLAECO and GLAOLD studies. Eur J Heart Failure 2002;4:707–12.

    Google Scholar 

  28. Ozono R, Wang ZQ, Moore AF, Inagami T, Siragy HM, Carey RM. Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney. Hypertension 1997;30:1238–46.

    Google Scholar 

  29. Siragy HM, Inagami T, Ichiki T, Carey RM. Sustained hypersensi-tivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci U S A 1999;96:6506–10.

    Google Scholar 

  30. Huang Y, Wang DH. Role of AT1 and AT2 receptor subtypes in salt-sensitive hypertension induced by sensory nerve degeneration. J Hypertens 2001;19:1841–6.

    Google Scholar 

  31. DiBona GF. Nervous kidney. Interaction between renal sympathetic nerves and the renin–angiotensin system in the control of renal function. Hypertension 2000;36:1083–8.

    Google Scholar 

  32. Stolarz K, Staessen JA, Kawecka-Jaszcz K, Brand E, Bianchi G, Kuznetsova T, et al. Genetic variation in CYP11B2 and ATR1 influences heart rate variability conditional on sodium excretion. Hypertension 2004;44:156–62.

    Google Scholar 

  33. Veglio F, Melchio R, Rabbia F, Molino P, Martini G, Chiandussi L. Spectral characteristicsofheart rate and blood pressurevariabil-ity in primary aldosteronism. Am J Hypertens 1995;8:479–86.

    Google Scholar 

  34. Spinelli L, Petretta M, Marciano F, Testa G, Rao MA, Volpe M, et al. Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy. Am J Physiol 1999;277:H1361–8.

    Google Scholar 

  35. Beretta-Piccoli C, Weidmann P, Brown JJ, Davies DL, Lever AF, Robertson JIS. Body sodium and blood volume state in essential hypertension: abnormal relation of exchangeable sodium to age and blood pressure in male patients. J Cardiovasc Pharmacol 1984;6(Suppl. 1):S134–42.

    Google Scholar 

  36. Strehlow K, Nickenig G, Roeling J, Wassmann S, Zolk O, Knorr A, et al. AT1 receptor regulation in salt-sensitive hypertension. Am J Physiol 1999; 277:H1701–7.

    Google Scholar 

Download references

Author information

Author notes

  1. Katarzyna Stolarz, Tatiana Kuznetsova, Wiktoria Wojciechowska, Jitka Seidlerova, Edoardo Casiglia, Jan Filipovský, Jan Peleška, Yuri Nikitin, Jan A. Staessen & Kalina Kawecka-Jaszcz

    Present address: Artery 6, Athens, Greece

Authors and Affiliations

  1. First Department of Cardiology and Hypertension, Medical College, Jagiellonian University, Kopernika 17, 31-501, Cracow, Poland

    Katarzyna Stolarz, Wiktoria Wojciechowska & Kalina Kawecka-Jaszcz

  2. Study Coordinating Centre, Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium

    Tatiana Kuznetsova & Jan A. Staessen

  3. Department of Clinical and Experimental Medicine, University of Padova, Italy

    Edoardo Casiglia

  4. Charles University, Pilsen, Czech Republic

    Jitka Seidlerova & Jan Filipovský

  5. General Faculty Hospital, Prague, Czech Republic

    Jan Peleška

  6. Institute of Internal Medicine, Novosibirsk, Russian Federation

    Tatiana Kuznetsova & Yuri Nikitin

Authors
  1. Katarzyna Stolarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatiana Kuznetsova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wiktoria Wojciechowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jitka Seidlerova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edoardo Casiglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Filipovský
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jan Peleška
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuri Nikitin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jan A. Staessen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kalina Kawecka-Jaszcz
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the European Project On Genes in Hypertension (EPOGH) Investigators

Corresponding author

Correspondence to Katarzyna Stolarz.

Rights and permissions

This is an open access article distributed under the CC BY-NC license. https://doi.org/creativecommons.org/licenses/by/4.0/

Reprints and permissions

About this article

Cite this article

Stolarz, K., Kuznetsova, T., Wojciechowska, W. et al. Sodium excretion as a modulator of genetic influence on arterial stiffness and other cardiovascular phenotypes. Artery Res 1, 20–25 (2007). https://doi.org/10.1016/j.artres.2007.03.002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.artres.2007.03.002

Keywords

Artery Research

ISSN: 1876-4401

Contact us