Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics

  • Matthew T. Wheeler
  • Michael Ho
  • Joshua W. Knowles
  • Aleks Pavlovic
  • Euan A. Ashley
Article

Abstract

Heart failure is a significant medical problem affecting more than five million people in the USA alone. Although clinical trials of pharmacological agents have demonstrated significant reductions in the relative risk of mortality across populations, absolute mortality remains high. In addition, individual variation in response is great. Some of this variation may be explained by genetic polymorphism. In this paper, we review the key studies to date in heart failure pharmacogenetics, setting this against a background of recent progress in the genetics of warfarin metabolism. Several polymorphisms that have supporting molecular and clinical data in the heart failure literature are reviewed, among them the β1-adrenergic receptor variant Arg389Gly and the angiotensin converting enzyme gene insertion/deletion polymorphism. These variants and others are responsible for a fraction of the total variation seen in the treatment response to heart failure. With the dawn of the genomic age, further pharmacogenetic and new pharmacogenomic studies will advance our ability to tailor the treatment of heart failure.

Keywords

Pharmacogenetics Pharmacogenomics Heart Failure Beta Blockers ACE Inhibitors Warfarin Aldosterone ADRB1 ADRB2 ADRA2C VKORC1 CYP11B2 CYP2C9 

References

  1. 1.
    Rosamond W., Flegal K., Friday G., Furie K., Go A., Greenlund K., et al. (2007). Update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 115(5), e69–e171, (February 6).PubMedCrossRefGoogle Scholar
  2. 2.
    Lloyd-Jones D. M., Larson M. G., LeipE. P., Beiser A., D’Agostino R. B., Kannel W. B., et al. (2002). Lifetime risk for developing congestive heart failure: The Framingham Heart Study. Circulation, 106(24), 3068–243072, (Dec 10).PubMedCrossRefGoogle Scholar
  3. 3.
    Pitt B., Zannad F., Remme W. J., Cody R., Castaigne A., Perez A., et al. (1999). The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine, 341(10), 709–717, (Sep 2).PubMedCrossRefGoogle Scholar
  4. 4.
    Packer M., Fowler M. B., Roecker E. B., Coats A. J., Katus H. A., Krum H., et al. (2002). Effect of carvedilol on the morbidity of patients with severe chronic heart failure: Results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation, 106(17), 2194–2199, (Oct 22).PubMedCrossRefGoogle Scholar
  5. 5.
    Hjalmarson A., Goldstein S., Fagerberg B., Wedel H., Waagstein F., Kjekshus J., et al. (2000). Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: The Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA, 283(10), 1295–101302, (Mar 8).PubMedCrossRefGoogle Scholar
  6. 6.
    Konstam M. A., Rousseau M. F., Kronenberg M. W., Udelson J. E., Melin J., Stewart D., et al. (1992). Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators. Circulation, 86(2), 431–438, (Aug).PubMedGoogle Scholar
  7. 7.
    Investigators T. S. (1991). Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine, 325(5), 293–302, (Aug 1).CrossRefGoogle Scholar
  8. 8.
    Roger V. L., Weston S. A., Redfield M. M., Hellermann-Homan J. P., Killian J., Yawn B. P., et al. (2004). Trends in heart failure incidence and survival in a community-based population. JAMA, 292(3), 344–350, (Jul 21).PubMedCrossRefGoogle Scholar
  9. 9.
    Thomas K. L., East M. A., Velazquez E. J., Tuttle R. H., Shaw L. K., O'Connor C. M., et al. (2005). Outcomes by race and etiology of patients with left ventricular systolic dysfunction. American Journal of Cardiology, 96(7), 956–963. (Oct 1).PubMedCrossRefGoogle Scholar
  10. 10.
    Follath F., Cleland J. G., Klein W., Murphy R. (1998). Etiology and response to drug treatment in heart failure. Journal of the American College of Cardiology, 32(5), 1167–1172, (Nov).PubMedCrossRefGoogle Scholar
  11. 11.
    Owan T. E., Hodge D. O., Herges R. M., Jacobsen S. J., Roger V. L., Redfield M. M. (2006). Trends in prevalence and outcome of heart failure with preserved ejection fraction. New England Journal of Medicine, 355(3), 251–259, (Jul 20).PubMedCrossRefGoogle Scholar
  12. 12.
    Tabibiazar R., Wagner R. A., Deng A., Tsao P. S., Quertermous T. (2006). Proteomic profiles of serum inflammatory markers accurately predict atherosclerosis in mice. Physiological Genomics, 25(2), 194–202, (Apr 13).PubMedCrossRefGoogle Scholar
  13. 13.
    King J. Y., Ferrara R., Tabibiazar R., Spin J. M., Chen M. M., Kuchinsky A., et al. (2005). Pathway analysis of coronary atherosclerosis. Physiological Genomics, 23(1), 103–118, (Sep 21).PubMedCrossRefGoogle Scholar
  14. 14.
    Alizadeh A. A., Eisen M. B., Davis R. E., Ma C., Lossos I. S., Rosenwald A., et al. (2000). Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature, 403(6769), 503–511, (Feb 3).PubMedCrossRefGoogle Scholar
  15. 15.
    Arnett D. K., Baird A. E., Barkley R. A., Basson C. T., Boerwinkle E., Ganesh S. K., et al. (2007). Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: A scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation, 115(22), 2878–2901, (Jun 5).PubMedCrossRefGoogle Scholar
  16. 16.
    Davies, S. M. (2006). Pharmacogenetics, pharmacogenomics and personalized medicine: Are we there yet? Hematology Am Soc Hematol Educ Program, pp. 111–117.Google Scholar
  17. 17.
    Consortium I. H. G. S. (2004). Finishing the euchromatic sequence of the human genome. Nature, 431(7011), 931–945, (Oct 21).CrossRefGoogle Scholar
  18. 18.
    Lander E. S., Linton L. M., Birren B., Nusbaum C., Zody M. C., Baldwin J., et al. (2001). Initial sequencing and analysis of the human genome. Nature, 409(6822), 860–921, (Feb 15).PubMedCrossRefGoogle Scholar
  19. 19.
    Frazer K. A., Ballinger D. G., Cox D. R., Hinds D. A., Stuve L. L., Gibbs R. A., et al. (2007). A second generation human haplotype map of over 3.1 million SNPs. Nature, 449(7164), 851–861, (Oct 18).PubMedCrossRefGoogle Scholar
  20. 20.
    Cupples L. A., Arruda H. T., Benjamin E. J., D'Agostino R. B. Sr., Demissie S., DeStefano A. L., et al. (2007). The Framingham heart study 100K SNP genome-wide association study resource: Overview of 17 phenotype working group reports. BMC Medical Genetics, 8, Suppl 1S1.PubMedCrossRefGoogle Scholar
  21. 21.
    Saxena R., Voight B. F., Lyssenko V., Burtt N. P., de Bakker P. I., Chen H., et al. (2007). Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science, 316(5829), 1331–1336, (Jun 1).PubMedCrossRefGoogle Scholar
  22. 22.
    Gudbjartsson D. F., Arnar D. O., Helgadottir A., Gretarsdottir S., Holm H., Sigurdsson A., et al. (2007) Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature, 448(7151), 353–357, (Jul 19).PubMedCrossRefGoogle Scholar
  23. 23.
    Horne B. D., Carlquist J. F., Muhlestein J. B., Nicholas Z. P., Anderson J. L. (2007) Associations with myocardial infarction of six polymorphisms selected from a three-stage genome-wide association study. American Heart Journal, 154(5), 969–975, (Nov).PubMedCrossRefGoogle Scholar
  24. 24.
    Higashi M. K., Veenstra D. L., Kondo L. M., Wittkowsky A. K., Srinouanprachanh S. L., Farin F. M., et al. (2002). Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA, 287(13), 1690–1698, (Apr 3).PubMedCrossRefGoogle Scholar
  25. 25.
    Sanderson S., Emery J., Higgins J. (2005). CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet systematic review and meta-analysis. Genetics in Medicine, 7(2), 97–104, (Feb).PubMedCrossRefGoogle Scholar
  26. 26.
    Li T., Chang C. Y., Jin D. Y., Lin P. J., Khvorova A., Stafford D. W. (2004) Identification of the gene for vitamin K epoxide reductase. Nature, 427(6974), 541–544, (Feb 5).PubMedCrossRefGoogle Scholar
  27. 27.
    Rost S., Fregin A., Ivaskevicius V., Conzelmann E., Hortnagel K., Pelz H. J., et al. (2004). Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature, 427(6974), 537–541, (Feb 5).PubMedCrossRefGoogle Scholar
  28. 28.
    Rieder M. J., Reiner A. P., Gage B. F., Nickerson D. A., Eby C. S., McLeod H. L., et al. (2005). Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. New England Journal of Medicine, 352(22), 2285–2293, (Jun 2).PubMedCrossRefGoogle Scholar
  29. 29.
    Takahashi H., Wilkinson G. R., Nutescu E. A., Morita T., Ritchie M. D., Scordo M. G., et al. (2006). Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenetics & Genomics, 16(2), 101–110, (Feb).CrossRefGoogle Scholar
  30. 30.
    Aquilante C. L., Langaee T. Y., Lopez L. M., Yarandi H. N., Tromberg J. S., Mohuczy D., Gaston K. L., et al. (2006). Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clinical Pharmacology and Therapeutics, 79(4), 291–302, (Apr).PubMedCrossRefGoogle Scholar
  31. 31.
    Carlquist J. F., Horne B. D., Muhlestein J. B., Lappe D. L., Whiting B. M., Kolek M. J. (2006). Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: A prospective study. Journal of Thrombosis and Thrombolysis, 22(3), 191–197, (Dec).PubMedCrossRefGoogle Scholar
  32. 32.
    Kimura R., Miyashita K., Kokubo Y., Akaiwa Y., Otsubo R., Nagatsuka K., et al. (2007). Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thrombosis Research, 120(2), 181–186.PubMedCrossRefGoogle Scholar
  33. 33.
    Herman D., Peternel P., Stegnar M., Breskvar K., Dolzan V., (2006). The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thrombosis and Haemostasis, 95(5), 782–787, (May).PubMedGoogle Scholar
  34. 34.
    Anderson, J. L., Horne, B. D., Stevens, S. M., Grove, A. S., Barton, S., Nicholas, Z. P., et al. (2007). Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation, 116, 2563–2570.Google Scholar
  35. 35.
    Baudhuin L. M., Langman L. J., O'Kane D. J., (2007). Translation of pharmacogenetics into clinically relevant testing modalities. Clinical Pharmacology and Therapeutics, 82(4), 373–376, (Oct).PubMedCrossRefGoogle Scholar
  36. 36.
    Rettie A. E., Tai G., (2006). The pharmocogenomics of warfarin: Closing in on personalized medicine. Molecular Interventions, 6(4), 223–227, (Aug).PubMedCrossRefGoogle Scholar
  37. 37.
    Wadelius M., Pirmohamed M. (2007). Pharmacogenetics of warfarin: Current status and future challenges. Pharmacogenomics Journal, 7(2), 99–111, (Apr).PubMedCrossRefGoogle Scholar
  38. 38.
    Knowles J. W., Assimes T. L., Li J., Quertermous T., Cooke J. P. (2007). Genetic susceptibility to peripheral arterial disease: A dark corner in vascular biology. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(10), 2068–2078, (Oct).PubMedCrossRefGoogle Scholar
  39. 39.
    Arnett D. K., (2007). Summary of the American Heart Association’s scientific statement on the relevance of genetics and genomics for prevention and treatment of cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 27(8), 1682–1686, (Aug).PubMedCrossRefGoogle Scholar
  40. 40.
    Wang W. Y., Barratt B. J., Clayton D. G., Todd J. A. (2005). Genome-wide association studies: Theoretical and practical concerns. Nature Reviews. Genetics, 6(2), 109–118, (Feb).PubMedCrossRefGoogle Scholar
  41. 41.
    Klein T. E., Chang J. T., Cho M. K., Easton K. L., Fergerson R., Hewett M., et al. (2001). Integrating genotype and phenotype information: An overview of the PharmGKB project. Pharmacogenetics Research Network and Knowledge Base. Pharmacogenomics Journal, 1(3), 167–170.PubMedGoogle Scholar
  42. 42.
    Patsopoulos N. A., Tatsioni A., Ioannidis J. P. (2007). Claims of sex differences: an empirical assessment in genetic associations. JAMA, 298(8), 880–893.PubMedCrossRefGoogle Scholar
  43. 43.
    Ioannidis J. P., (2007). Non-replication and inconsistency in the genome-wide association setting. Human Heredity, 64(4), 203–213.PubMedCrossRefGoogle Scholar
  44. 44.
    Takekuma Y., Takenaka T., Kiyokawa M., Yamazaki K., Okamoto H., Kitabatake A., et al. (2007). Evaluation of effects of polymorphism for metabolic enzymes on pharmacokinetics of carvedilol by population pharmacokinetic analysis. Biological & Pharmaceutical Bulletin, 30(3), 537–542, (Mar).CrossRefGoogle Scholar
  45. 45.
    Ismail R., Teh L. K., (2006). The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients. Journal of Clinical Pharmacy and Therapeutics, 31(1), 99–109, (Feb).PubMedCrossRefGoogle Scholar
  46. 46.
    Kirchheiner J., Heesch C., Bauer S., Meisel C., Seringer A., Goldammer M., et al. (2004). Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics. Clinical Pharmacology and Therapeutics, 76(4), 302–312, (Oct).PubMedGoogle Scholar
  47. 47.
    Cascorbi I., Paul M., Kroemer H. K., (2004). Pharmacogenomics of heart failure—focus on drug disposition and action. Cardiovascular Research, 64(1), 32–39, (Oct 1).PubMedCrossRefGoogle Scholar
  48. 48.
    Kolek M. J., Carlquist J. F., Thaneemit-Chen S., Lazzeroni L. C., Whiting B. M., Horne B. D., et al. (2005) The role of a common adenosine monophosphate deaminase (AMPD)-1 polymorphism in outcomes of ischemic and nonischemic heart failure. Journal of Cardiac Failure, 11(9), 677–683, (Dec).PubMedCrossRefGoogle Scholar
  49. 49.
    Yazaki Y., Muhlestein J. B., Carlquist J. F., Bair T. L., Horne B. D., Renlund D. G., (2004). A common variant of the AMPD1 gene predicts improved survival in patients with ischemic left ventricular dysfunction. Journal of Cardiac Failure, 10(4), 316–320, (Aug).PubMedCrossRefGoogle Scholar
  50. 50.
    de Groote P., Lamblin N., Helbecque N., Mouquet F., Hermant X., et al. (2006). The impact of the AMPD1 gene polymorphism on exercise capacity, other prognostic parameters, and survival in patients with stable congestive heart failure: A study in 686 consecutive patients. American Heart Journal, 152(4), 736–741, (Oct).PubMedCrossRefGoogle Scholar
  51. 51.
    Kalsi K. K., Yuen A. H., Rybakowska I. M., Johnson P. H., Slominska E., Birks E. J., (2003). Decreased cardiac activity of AMP deaminase in subjects with the AMPD1 mutation—a potential mechanism of protection in heart failure. Cardiovascular Research, 59(3), 678–684, (Sep 1).PubMedCrossRefGoogle Scholar
  52. 52.
    McNamara D. M., Holubkov R., Postava L., Ramani R., Janosko K., Mathier M., et al. (2003). Effect of the Asp298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure. Circulation, 107(12), 1598–1602, (Apr 1).PubMedCrossRefGoogle Scholar
  53. 53.
    dbSNP. (2007). dbSNP accession: rs180252, rs1801253, rs1042711, rs17858183, rs 17859732, rs1800888.Google Scholar
  54. 54.
    Maqbool A., Hall A. S., Ball S. G., Balmforth A. J., (1999). Common polymorphisms of beta1-adrenoceptor: identification and rapid screening assay. Lancet, 353(9156), 897, (Mar 13).PubMedCrossRefGoogle Scholar
  55. 55.
    Mialet Perez J., Rathz D. A., Petrashevskaya N. N., Hahn H. S., Wagoner L. E., Schwartz A., et al. (2003). Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Natural Medicines, 9(10), 1300–1305, (Oct).CrossRefGoogle Scholar
  56. 56.
    Rochais F., Vilardaga J. P., Nikolaev V. O., Bunemann M., Lohse M. J., Engelhardt S., (2007). Real-time optical recording of beta1-adrenergic receptor activation reveals supersensitivity of the Arg389 variant to carvedilol. Journal of Clinical Investigation, 117(1), 229–235, (Jan).PubMedCrossRefGoogle Scholar
  57. 57.
    Wagoner L. E., Craft L. L., Zengel P., McGuire N., Rathz D. A., Dorn G. W. 2nd, et al. (2002). Polymorphisms of the beta1-adrenergic receptor predict exercise capacity in heart failure. American Heart Journal, 144(5), 840–846, (Nov).PubMedGoogle Scholar
  58. 58.
    White H. L., de Boer R. A., Maqbool A., Greenwood D., van Veldhuisen D. J., Cuthbert R., et al. (2003). An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: A MERIT-HF sub-study. European Journal of Heart Failure, 5(4), 463–468, (Aug).PubMedCrossRefGoogle Scholar
  59. 59.
    Liggett S. B., Mialet-Perez J., Thaneemit-Chen S., Weber S. A., Greene S. M., Hodne D., (2006). A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proceedings of the National Academy of Sciences of the United States of America, 103(30), 11288–11293, (Jul 25).PubMedCrossRefGoogle Scholar
  60. 60.
    Liggett S. B., Wagoner L. E., Craft L. L., Hornung R. W., Hoit B. D., McIntosh T. C., et al. (1998). The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. Journal of Clinical Investigation, 102(8), 1534–1539.PubMedCrossRefGoogle Scholar
  61. 61.
    Leineweber K., Tenderich G., Wolf C., Wagner S., Zittermann A., Elter-Schulz M., et al. (2006). Is there a role of the Thr164Ile-beta(2)-adrenoceptor polymorphism for the outcome of chronic heart failure?. Basic Research in Cardiology, 101(6), 479–484, (Nov).PubMedCrossRefGoogle Scholar
  62. 62.
    Kaye D. M., Smirk B., Williams C., Jennings G., Esler M., Holst D., (2003). Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics, 13(7), 379–382, (Jul).PubMedCrossRefGoogle Scholar
  63. 63.
    Forleo C., Resta N., Sorrentino S., Guida P., Manghisi A., De Luca V., et al. (2004). Association of beta-adrenergic receptor polymorphisms and progression to heart failure in patients with idiopathic dilated cardiomyopathy. American Journal of Medicine, 117(7), 451–458, (Oct 1).PubMedCrossRefGoogle Scholar
  64. 64.
    Forleo C., Sorrentino S., Guida P., Romito R., De Tommasi E., Iacoviello M., et al. (2007). Beta1- and beta2-adrenergic receptor polymorphisms affect susceptibility to idiopathic dilated cardiomyopathy. Journal of Cardiovascular Medicine (Hagerstown), 8(8), 589–595, (Aug).CrossRefGoogle Scholar
  65. 65.
    de Groote P., Lamblin N., Helbecque N., Mouquet F., Mc Fadden E., Hermant X., et al. (2005). The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. European Journal of Heart Failure, 7(6), 966–973.PubMedCrossRefGoogle Scholar
  66. 66.
    de Groote P., Helbecque N., Lamblin N., Hermant X., Mc Fadden E., Foucher-Hossein C., et al. (2005). Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenetics & Genomics, 15(3), 137–142, (Mar).Google Scholar
  67. 67.
    Small K. M., Wagoner L. E., Levin A. M., Kardia S. L., Liggett S. B., (2002). Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure. New England Journal of Medicine, 347(15), 1135–1142, (Oct 10).PubMedCrossRefGoogle Scholar
  68. 68.
    Regitz-Zagrosek V., Hocher B., Bettmann M., Brede M., Hadame kK., Gerstner C., et al. (2006). Alpha2C-adrenoceptor polymorphism is associated with improved event-free survival in patients with dilated cardiomyopathy. European Heart Journal, 27(4), 454–459, (Feb).PubMedCrossRefGoogle Scholar
  69. 69.
    Hasimu B., Nakayama T., Mizutani Y., Izumi Y., Asai S., Soma M., et al. (2003). Haplotype analysis of the human renin gene and essential hypertension. Hypertension, 41(2), 308–312, (Feb).PubMedCrossRefGoogle Scholar
  70. 70.
    Goldbergova M., Spinarova L., Spinar J., Toman J., Vasku A., Vacha J., (2003). Association of two angiotensinogen gene polymorphisms, M235T and G(-6)A, with chronic heart failure. International Journal of Cardiology, 89(2–3), 267–272, (Jun).PubMedGoogle Scholar
  71. 71.
    Diez J., Laviades C., Orbe J., Zalba G., Lopez B., Gonzalez A., et al. (2003). The A1166C polymorphism of the AT1 receptor gene is associated with collagen type I synthesis and myocardial stiffness in hypertensives. Journal De Lhypertension, 21(11), 2085–2092, (Nov).CrossRefGoogle Scholar
  72. 72.
    Cameron V. A., Mocatta T. J., Pilbrow A. P., Frampton C. M., Troughton R. W., Richards A. M., et al. (2006). Angiotensin type-1 receptor A1166C gene polymorphism correlates with oxidative stress levels in human heart failure. Hypertension, 47(6), 1155–1161, (Jun).PubMedCrossRefGoogle Scholar
  73. 73.
    Hindorff L. A., Heckbert S. R., Tracy R., Tang Z., Psaty B. M., Edwards K. L., et al. (2002). Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events. American Journal of Hypertension, 15(12), 1050–1056, (Dec).PubMedCrossRefGoogle Scholar
  74. 74.
    Pitt B., Remme W., Zannad F., Neaton J., Martinez F., Roniker B., et al. (2003). Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. New England Journal of Medicine, 348(14), 1309–1321, (Apr 3).PubMedCrossRefGoogle Scholar
  75. 75.
    McNamara D. M., Tam S. W., Sabolinski M. L., Tobelmann P., Janosko K., Taylor A. L., (2006). Aldosterone synthase promoter polymorphism predicts outcome in African Americans with heart failure: Results from the A-HeFT Trial. Journal of the American College of Cardiology, 48(6), 1277–1282, (Sep 19).PubMedCrossRefGoogle Scholar
  76. 76.
    Tiago A. D., Badenhorst D., Skudicky D., Woodiwiss A. J., Candy G. P., BrooksbankR., et al. (2002). An aldosterone synthase gene variant is associated with improvement in left ventricular ejection fraction in dilated cardiomyopathy. Cardiovascular Research, 54(3), 584–589, (Jun).PubMedCrossRefGoogle Scholar
  77. 77.
    Montgomery H. E., Keeling P. J., Goldman J. H., Humphries S. E., Talmud P. J., McKenna W. J., (1995). Lack of association between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and idiopathic dilated cardiomyopathy. Journal of the American College of Cardiology, 25(7), 1627–1631, (Jun).PubMedCrossRefGoogle Scholar
  78. 78.
    Andersson B., Sylven C., (1996). The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure. Journal of the American College of Cardiology, 28(1), 162–167, (Jul).PubMedCrossRefGoogle Scholar
  79. 79.
    Covolo L., Gelatti U., Metra M., Donato F., Nodari S., Pezzali N., et al. (2003). Angiotensin-converting-enzyme gene polymorphism and heart failure: A case-control study. Biomarkers, 8(5), 429–436, (Sep–Oct).PubMedCrossRefGoogle Scholar
  80. 80.
    Schut A. F., Bleumink G. S., Stricker B. H., Hofman A., Witteman J. C., PolsH. A., (2004). Angiotensin converting enzyme insertion/deletion polymorphism and the risk of heart failure in hypertensive subjects. European Heart Journal, 25(23), 2143–2148, (Dec).PubMedCrossRefGoogle Scholar
  81. 81.
    Cicoira M., Zanolla L., Rossi A., Golia G., Franceschini L., Cabrini G., et al. (2001). Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. Journal of the American College of Cardiology, 37(7), 1808–1812, (Jun 1).PubMedCrossRefGoogle Scholar
  82. 82.
    Tang W. H., Vagelos R. H., Yee Y. G., Fowler M. B., (2004). Impact of angiotensin-converting enzyme gene polymorphism on neurohormonal responses to high- versus low-dose enalapril in advanced heart failure. American Heart Journal, 148(5), 889–894, (Nov).PubMedCrossRefGoogle Scholar
  83. 83.
    McNamara D. M., Holubkov R., Postava L., Janosko K., MacGowan G. A., Mathier M., et al. (2004). Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Journal of the American College of Cardiology, 44(10), 2019–2026, (Nov 16).PubMedCrossRefGoogle Scholar
  84. 84.
    Cicoira M., Rossi A., Bonapace S., Zanolla L., Perrot A., FrancisD. P., (2004). Effects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure. American Journal of Medicine, 116(10), 657–661, (May 15).PubMedCrossRefGoogle Scholar
  85. 85.
    McNamara D. M., Holubkov R., Janosko K., Palmer A., Wang J. J., MacGowan G. A., et al. (2001). Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. Circulation, 103(12), 1644–1648, (Mar 27).PubMedGoogle Scholar
  86. 86.
    de Groote P., Helbecque N., Lamblin N., Hermant X., Amouyel P., Bauters C., et al. (2004). Beta-adrenergic receptor blockade and the angiotensin-converting enzyme deletion polymorphism in patients with chronic heart failure. European Journal of Heart Failure, 6(1), 17–21, (Jan).PubMedCrossRefGoogle Scholar
  87. 87.
    Danser A. H., Batenburg W. W., van den Meiracker A. H., Danilov S. M. (2007). ACE phenotyping as a first step toward personalized medicine for ACE inhibitors. Why does ACE genotyping not predict the therapeutic efficacy of ACE inhibition?. Pharmacology & Therapeutics, 113(3), 607–618, (Mar).CrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Matthew T. Wheeler
    • 1
  • Michael Ho
    • 1
  • Joshua W. Knowles
    • 1
  • Aleks Pavlovic
    • 1
  • Euan A. Ashley
    • 1
  1. 1.Division of Cardiovascular Medicine, Department of MedicineStanford UniversityStanfordUSA

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