Aim: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure. Materials & methods: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%. Results: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022). Conclusion:AGTR1 1166C carriers may experience a greater long-term compensatory renin–angiotensin–aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation.

Clinicaltrials.gov: NCT00400582

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1 Unger T, Li J. The role of the renin-angiotensin-aldosterone system in heart failure. J. Renin Angiotensin Aldosterone Syst. 5(Suppl. 1), S7–S10 (2004).
Medline CASGoogle Scholar
2 Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ. Res. 66(4), 883–890 (1990).
Medline CASGoogle Scholar
3 Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N. Engl. J. Med. 345(23), 1667–1675 (2001).
Medline CASGoogle Scholar
4 Pfeffer MA, Swedberg K, Granger CB et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 362(9386), 759–766 (2003).
Medline CASGoogle Scholar
5 Vinck WJ, Fagard RH, Vlietinck R, Lijnen P. Heritability of plasma renin activity and plasma concentration of angiotensinogen and angiotensin-converting enzyme. J. Hum. Hypertens. 16(6), 417–422 (2002).
Medline CASGoogle Scholar
6 Rice GI, Jones AL, Grant PJ, Carter AM, Turner AJ, Hooper NM. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 48(5), 914–920 (2006).
Medline CASGoogle Scholar
7 Newton-Cheh C, Guo CY, Gona P et al. Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample. Hypertension 49(4), 846–856 (2007).
Medline CASGoogle Scholar
8 Johnson T, Gaunt TR, Newhouse SJ et al. Blood pressure loci identified with a gene-centric array. Am. J. Hum. Genet. 89(6), 688–700 (2011).
Medline CASGoogle Scholar
9 Newton-Cheh C, Johnson T, Gateva V et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41(6), 666–776 (2009).
Medline CASGoogle Scholar
10 Liu D-X, Zhang Y-Q, Hu B, Zhang J, Zhao Q. Association of AT1R polymorphism with hypertension risk: an update meta-analysis based on 28,952 subjects. J. Renin Angiotensin Aldosterone Syst. 16(4), 898–909 (2015).
Medline CASGoogle Scholar
11 Nordestgaard BG, Kontula K, Benn M et al. Effect of ACE insertion/deletion and 12 other polymorphisms on clinical outcomes and response to treatment in the LIFE study. Pharmacogenet. Genomics 20(2), 77–85 (2010).
Medline CASGoogle Scholar
12 Spiering W, Kroon AA, Fuss-Lejeune MJ, de Leeuw PW. Genetic contribution to the acute effects of angiotensin II type 1 receptor blockade. J. Hypertens. 23(4), 753–758 (2005).
Medline CASGoogle Scholar
13 Hallberg P, Lind L, Michaelsson K et al. B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. J. Hypertens. 21(3), 621–624 (2003).
Medline CASGoogle Scholar
14 Kurland L, Melhus H, Karlsson J et al. Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. Am. J. Hypertens. 15(5), 389–393 (2002).
Medline CASGoogle Scholar
15 Kurland L, Melhus H, Karlsson J et al. Angiotensin-converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients. J. Hypertens. 19(10), 1783–1787 (2001).
Medline CASGoogle Scholar
16 Brugts JJ, Isaacs A, Boersma E et al. Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease. Eur. Heart J. 31(15), 1854–1864 (2010).
Medline CASGoogle Scholar
17 Kurland L, Melhus H, Karlsson J et al. Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. J. Hypertens. 20(4), 657–663 (2002).
Medline CASGoogle Scholar
18 de Denus S, Zakrzewski-Jakubiak M, Dube MP et al. Effects of AGTR1 A1166C gene polymorphism in patients with heart failure treated with candesartan. Ann. Pharmacother. 42(7), 925–932 (2008).
Medline CASGoogle Scholar
19 White M, Lepage S, Lavoie J et al. Effects of combined candesartan and ACE inhibitors on BNP, markers of inflammation and oxidative stress, and glucose regulation in patients with symptomatic heart failure. J. Cardiac. Fail. 13(2), 86–94 (2007).
Medline CASGoogle Scholar
20 McMurray JJ, Ostergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting enzyme inhibitors: the CHARM-Added trial. Lancet 362(9386), 767–771 (2003). •• Results of a large, multicenter study demonstrating the benefit of candesartan in patients with symptomatic heart failure.
Medline CASGoogle Scholar
21 Hemmelgarn BR, McAlister FA, Grover S et al. The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: part I – blood pressure measurement, diagnosis and assessment of risk. Can. J. Cardiol. 22(7), 573–581 (2006).
Medline CASGoogle Scholar
22 Lachance K, Barhdadi A, Mongrain I et al. PRKCB is associated with calcineurin inhibitor-induced renal dysfunction in heart transplant recipients. Pharmacogenet. Genomics 22(5), 336–343 (2012).
Medline CASGoogle Scholar
23 Lemieux Perreault LP, Provost S, Legault MA, Barhdadi A, Dube MP. pyGenClean: efficient tool for genetic data clean up before association testing. Bioinformatics 29(13), 1704–1705 (2013).
Medline CASGoogle Scholar
24 Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X. Rare-variant association testing for sequencing data with the sequence kernel association test. Am. J. Hum. Genet. 89(1), 82–93 (2011).
Medline CASGoogle Scholar
25 Gao X, Starmer J, Martin ER. A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet. Epidemiol. 32(4), 361–369 (2008).
MedlineGoogle Scholar
26 Purcell S, Neale B, Todd-Brown K et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81(3), 559–575 (2007).
Medline CASGoogle Scholar
27 Spiering W, Kroon AA, Fuss-Lejeune MM, Daemen MJ, de Leeuw PW. Angiotensin II sensitivity is associated with the angiotensin II type 1 receptor A(1166)C polymorphism in essential hypertensives on a high sodium diet. Hypertension 36(3), 411–416 (2000).
Medline CASGoogle Scholar
28 Baudin B. Polymorphism in angiotensin II receptor genes and hypertension. Exp. Physiol. 90(3), 277–282 (2005).
Medline CASGoogle Scholar
29 Haas U, Sczakiel G, Laufer SD. microRNA-mediated regulation of gene expression is affected by disease-associated SNPs within the 3′-UTR via altered RNA structure. RNA Biol. 9(6), 924–937 (2012).
Medline CASGoogle Scholar
30 Sethupathy P, Borel C, Gagnebin M et al. Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single nucleotide polymorphisms related to phenotypes. Am. J. Hum. Genet. 81(2), 405–413 (2007).
Medline CASGoogle Scholar
31 Mialet Perez J, Rathz DA, Petrashevskaya NN et al. Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat. Med. 9(10), 1300–1305 (2003).
MedlineGoogle Scholar
32 Liggett SB, Mialet-Perez J, Thaneemit-Chen S et al. A polymorphism within a conserved β1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc. Natl Acad. Sci. USA 103(30), 11288–11293 (2006). •• Large pharmacogenomic substudy suggesting that the benefit of bucindolol is modulated by a genetic variant in the adrenergic system.
Medline CASGoogle Scholar
33 Anand IS, Fisher LD, Chiang YT et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 107(9), 1278–1283 (2003).
Medline CASGoogle Scholar
34 Daniels LB, Maisel AS. Natriuretic peptides. J. Am. Coll. Cardiol. 50(25), 2357–2368 (2007).
Medline CASGoogle Scholar
35 de Denus S, Pharand C, Williamson DR. Brain natriuretic peptide in the management of heart failure: the versatile neurohormone. Chest 125(2), 652–668 (2004).
Medline CASGoogle Scholar
36 Latini R, Masson S, Anand I et al. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation 106(19), 2454–2458 (2002).
Medline CASGoogle Scholar
37 van Veldhuisen DJ, Genth-Zotz S, Brouwer J et al. High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril. J. Am. Coll. Cardiol. 32(7), 1811–1818 (1998).
Medline CASGoogle Scholar
38 Riegger GAJ, Bouzo H, Petr P et al. Improvement in exercise tolerance and symptoms of congestive heart failure during treatment with candesartan cilexetil. Circulation 100(22), 2224–2230 (1999).
Medline CASGoogle Scholar
39 Mitrovic V, Willenbrock R, Miric M et al. Acute and 3-month treatment effects of candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure. Am. Heart J. 145(3), E14 (2003).
Medline CASGoogle Scholar
40 McKelvie RS, Yusuf S, Pericak D et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 100(10), 1056–1064 (1999).
Medline CASGoogle Scholar
41 Cohn JN, Anand IS, Latini R, Masson S, Chiang YT, Glazer R. Sustained reduction of aldosterone in response to the angiotensin receptor blocker valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial. Circulation 108(11), 1306–1309 (2003).
Medline CASGoogle Scholar
42 Oemrawsingh RM, Akkerhuis KM, Van Vark LC et al. Individualized angiotensin-converting enzyme (ACE)-inhibitor therapy in stable coronary artery disease based on clinical and pharmacogenetic determinants: the PERindopril GENEtic (PERGENE) Risk Model. J. Am. Heart. Assoc. 5(3), e002688 (2016).
MedlineGoogle Scholar
43 van der Leeuw J, Oemrawsingh RM, van der Graaf Y et al. Prediction of absolute risk reduction of cardiovascular events with perindopril for individual patients with stable coronary artery disease – results from EUROPA. Int. J. Cardiol. 182, 194–199 (2015).
MedlineGoogle Scholar
44 Sprint Research Group; Wright JT Jr, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med. 373(22), 2103–2116 (2015).
MedlineGoogle Scholar
45 Thanassoulis G, Williams K, Ye K et al. Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin therapy: a meta-analysis of randomized trials. J. Am. Heart Assoc. 3(2), e000759 (2014).
MedlineGoogle Scholar
46 McCullough PA, Duc P, Omland T et al. B-type natriuretic peptide and renal function in the diagnosis of heart failure: an analysis from the Breathing Not Properly Multinational Study. Am. J. Kidney Dis. 41(3), 571–579 (2003).
Medline CASGoogle Scholar
47 Anand IS, Rector TS, Kuskowski M, Thomas S, Holwerda NJ, Cohn JN. Effect of baseline and changes in systolic blood pressure over time on the effectiveness of valsartan in the Valsartan Heart Failure Trial. Circ. Heart Fail. 1(1), 34–42 (2008).
Medline CASGoogle Scholar
48 Lesogor A, Cohn JN, Latini R et al. Interaction between baseline and early worsening of renal function and efficacy of renin-angiotensin-aldosterone system blockade in patients with heart failure: insights from the Val-HeFT study. Eur. J. Heart Fail. 15(11), 1236–1244 (2013).
Medline CASGoogle Scholar
49 Young JB, Dunlap ME, Pfeffer MA et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM Low-Left Ventricular Ejection Fraction Trials. Circulation 110(17), 2618–2626 (2004).
Medline CASGoogle Scholar
50 Zannad F, McMurray JJ, Krum H et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med. 364(1), 11–21 (2011).
Medline CASGoogle Scholar
51 McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 371(11), 993–1004 (2014).
MedlineGoogle Scholar

Vol. 19, No. 7

Supplemental Materials

Metrics

Downloaded 201 times

History

Received 10 January 2018

Accepted 8 March 2018

Published online 27 April 2018

Published in print May 2018

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: https://www.futuremedicine.com/doi/suppl/10.2217/pgs-2018-0004

Acknowledgements

This study was supported by AstraZeneca Canada. S de Denus holds the Université de Montréal Beaulieu-Saucier Chair in Pharmacogenomics.

Financial & competing interests disclosure

S de Denus reports receiving research grants from Pfizer, Astra-Zeneca, Roche, Dalcor and Novartis, and consulting fees from Servier, Pfizer and Novartis. J-C Tardif has received research support from Amarin, Astra-Zeneca, DalCor, EliLilly, Esperion, Merck, Pfizer, Sanofi and Servier; honoraria from DalCor, Pfizer, Sanofi and Servier; and holds equity in DalCor. He is also mentioned as an author of a patent on pharmacogenomic determinants of responses to CETP inhibitors. M-P Dubé has an equity interest in DalCor, has received honoraria from Illumina and Dalcor and has also received research support (via institution) from Astra-Zeneca, DalCor, Pfizer and Servier. J-L Rouleau served as a Consultant for Novartis. M White reports receiving research grants from Astra-Zeneca and he is also a Speaker for Astra-Zeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical considerations

The protocol and the informed consent document were approved by all local Institutional Review Boards (IRBs) and all patients provided a written consent to participate in the study. This study was conducted in accordance with the Declaration of Helsinki with Good Clinical Practice.

PDF download