Skip to main content
SpringerLink
Log in

Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). We explored genetic determinants of pharmacodynamic effects of B-type NP (BNP) and changes in plasma cyclic guanosine monophosphate (cGMP) and blood pressure (BP). HF patients (n = 135) received recombinant human BNP (nesiritide) at standard doses, and plasma cGMP levels were measured at baseline and during infusion. We tested the association of 119 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NPR1, NPR2, NPR3, and membrane metallo-endopeptidase (MME)) with the change in cGMP and BP. Gene-based testing for association of genetic variation with endpoints was significant only for MME. Upon individual SNP testing, two loci in MME were associated with ΔcGMP; another (rs16824656) showed association with BP change. In summary, the pharmacodynamic effects of BNP vary substantially in HF patients and are associated with genetic variation in MME. MME genetic variation may be an important determinant of NP-mediated effects in humans.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

BP:

Blood pressure

BPM:

Beats per minute

BNP:

B-type natriuretic peptide

cGMP:

Cyclic guanosine monophosphate

DBP:

Diastolic blood pressure

GMP:

Guanosine monophosphate

HF:

Heart failure

MME:

Membrane metallo-endopeptidase

NEP:

Neutral endopeptidase

NP:

Natriuretic peptide

NPR:

Natriuretic peptide receptor

NPRC:

Natriuretic peptide receptor C

PGBNP:

Pharmacogenetics of N-type natriuretic peptide

SBP:

Systolic blood pressure

SNP:

Single nucleotide polymorphism

References

  1. Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Borden, W. B., et al. (2013). Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation, 127(1), e6–e245. doi:10.1161/CIR.0b013e31828124ad.

    Article  PubMed  Google Scholar 

  2. O'Connor, C. M., Starling, R. C., Hernandez, A. F., Armstrong, P. W., Dickstein, K., Hasselblad, V., et al. (2011). Effect of nesiritide in patients with acute decompensated heart failure. New England Journal of Medicine, 365(1), 32–43. doi:10.1056/NEJMoa1100171.

    Article  PubMed  Google Scholar 

  3. Sackner-Bernstein, J. D., Kowalski, M., Fox, M., & Aaronson, K. (2005). Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA, 293(15), 1900–5.

    Article  CAS  PubMed  Google Scholar 

  4. Sackner-Bernstein, J. D., Skopicki, H. A., & Aaronson, K. D. (2005). Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation, 111(12), 1487–91.

    Article  CAS  PubMed  Google Scholar 

  5. Choudhary, R., Iqbal, N., Khusro, F., Higginbotham, E., Green, E., & Maisel, A. (2013). Heart failure biomarkers. Journal of Cardiovascular Translational Research, 6(4), 471–84. doi:10.1007/s12265-013-9465-0.

    Article  PubMed  Google Scholar 

  6. Egom, E. E. (2015). BNP and heart failure: preclinical and clinical trial data. Journal of Cardiovascular Translational Research, 8(3), 149–57. doi:10.1007/s12265-015-9619-3.

    Article  PubMed  Google Scholar 

  7. Lanfear, D. E., Chow, S., Padhukasahasram, B., Li, J., Langholz, D., Tang, W. H., et al. (2014). Genetic and nongenetic factors influencing pharmacokinetics of B-type natriuretic peptide. Journal of Cardiac Failure, 20(9), 662–8. doi:10.1016/j.cardfail.2014.06.357.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Publication Committee for the VMAC Investigators. (2002). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA, 287(12), 1531–40.

    Google Scholar 

  9. Wang, T. J., Larson, M. G., Levy, D., Benjamin, E. J., Corey, D., Leip, E. P., et al. (2003). Heritability and genetic linkage of plasma natriuretic peptide levels. Circulation, 108(1), 13–6.

    Article  PubMed  Google Scholar 

  10. Costello-Boerrigter LC, G., Ameenuddin, S., Mahoney, D. W., Slusser, J. P., Heublein, D. M., et al. (2011). The effect of the brain-type natriuretic peptide single-nucleotide polymorphism rs198389 on test characteristics of common assays. Mayo Clinic Proceedings, 86(3), 210–8. doi:10.4065/mcp.2010.0708.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Lanfear, D. E., Stolker, J. M., Marsh, S., Rich, M. W., & McLeod, H. L. (2007). Genetic variation in the B-type natriuretic peptide pathway affects BNP levels. Cardiovascular Drugs and Therapy, 21(1), 55–62. doi:10.1007/s10557-007-6007-5.

    Article  CAS  PubMed  Google Scholar 

  12. Newton-Cheh, C., Larson, M. G., Vasan, R. S., Levy, D., Bloch, K. D., Surti, A., et al. (2009). Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nature Genetics, 41(3), 348–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Kosuge, K., Soma, M., Nakayama, T., Aoi, N., Sato, M., Izumi, Y., et al. (2007). A novel variable number of tandem repeat of the natriuretic peptide precursor B gene’s 5'-flanking region is associated with essential hypertension among Japanese females. International Journal of Medical Sciences, 4(3), 146–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Rubattu, S., Bigatti, G., Evangelista, A., Lanzani, C., Stanzione, R., Zagato, L., et al. (2006). Association of atrial natriuretic peptide and type a natriuretic peptide receptor gene polymorphisms with left ventricular mass in human essential hypertension. Journal of the American College of Cardiology, 48(3), 499–505.

    Article  CAS  PubMed  Google Scholar 

  15. Nakayama, T., Soma, M., Mizutani, Y., Xinjuan, X., Honye, J., Kaneko, Y., et al. (2002). A novel missense mutation of exon 3 in the type A human natriuretic peptide receptor gene: possible association with essential hypertension. Hypertension Research, 25(3), 395–401.

    Article  CAS  PubMed  Google Scholar 

  16. Stoupakis, G., & Klapholz, M. (2003). Natriuretic peptides: biochemistry, physiology, and therapeutic role in heart failure. Heart Disease, 5(3), 215–23.

    Article  CAS  PubMed  Google Scholar 

  17. Lanfear, D. E. (2010). Genetic variation in the natriuretic peptide system and heart failure. Heart Failure Reviews, 15(3), 219–28. doi:10.1007/s10741-008-9113-y.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Nakayama, T. (2005). The genetic contribution of the natriuretic peptide system to cardiovascular diseases. Endocrine Journal, 52(1), 11–21.

    Article  CAS  PubMed  Google Scholar 

  19. Chow, S. L., O'Barr, S. A., Peng, J., Chew, E., Pak, F., Quist, R., et al. (2011). Modulation of novel cardiorenal and inflammatory biomarkers by intravenous nitroglycerin and nesiritide in acute decompensated heart failure: an exploratory study. Circulation. Heart Failure, 4(4), 450–5. doi:10.1161/CIRCHEARTFAILURE.110.958066.

    Article  CAS  PubMed  Google Scholar 

  20. Chow, S. L., O'Barr, S. A., Peng, J., Chew, E., Pak, F., Quist, R., et al. (2011). Renal function and neurohormonal changes following intravenous infusions of nitroglycerin versus nesiritide in patients with acute decompensated heart failure. Journal of Cardiac Failure, 17(3), 181–7. doi:10.1016/j.cardfail.2010.10.005.

    Article  CAS  PubMed  Google Scholar 

  21. Cochran, W. G. (1950). The comparison of percentages in matched samples. Biometrika, 37(3-4), 256–66.

    Article  CAS  PubMed  Google Scholar 

  22. DerSimonian, R., & Laird, N. (1986). Meta-analysis in clinical trials. Controlled Clinical Trials, 7(3), 177–88.

    Article  CAS  PubMed  Google Scholar 

  23. Li, M. X., Gui, H. S., Kwan, J. S., & Sham, P. C. (2011). GATES: a rapid and powerful gene-based association test using extended Simes procedure. American Journal of Human Genetics, 88(3), 283–93. doi:10.1016/j.ajhg.2011.01.019.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Benjamini, Y., Drai, D., Elmer, G., Kafkafi, N., & Golani, I. (2001). Controlling the false discovery rate in behavior genetics research. Behavioural Brain Research, 125(1-2), 279–84.

    Article  CAS  PubMed  Google Scholar 

  25. Hao, K., Bosse, Y., Nickle, D. C., Pare, P. D., Postma, D. S., Laviolette, M., et al. (2012). Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genetics, 8(11), e1003029. doi:10.1371/journal.pgen.1003029.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Lanfear, D. E., Sunkara, B., Li, J., Rastogi, S., Gupta, R. C., Padhukasahasram, B., et al. (2013). Association of genetic variation with gene expression and protein abundance within the natriuretic peptide pathway. Journal of Cardiovascular Translational Research, 6(5), 826–33. doi:10.1007/s12265-013-9491-y.

    Article  PubMed Central  PubMed  Google Scholar 

  27. McMurray, J. J., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M., Rizkala, A. R., et al. (2014). Baseline characteristics and treatment of patients in Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). European Journal of Heart Failure, 16(7), 817–25. doi:10.1002/ejhf.115.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Heart and Vascular Institute, Henry Ford Hospital, Detroit, MI, USA

    David E. Lanfear, Ramesh C. Gupta & Hani N. Sabbah

  2. Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA

    David E. Lanfear, Raza Abbas, Ramesh C. Gupta, L. Keoki Williams & Hani N. Sabbah

  3. Center for Health Policy and Health Services Research, Henry Ford Hospital, Detroit, MI, USA

    David E. Lanfear, Badri Padhukasahasram & L. Keoki Williams

  4. Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA

    Jia Li & Ricoung She

  5. Spectrum Health System, Grand Rapids, MI, USA

    David Langholz

  6. Heart and Vascular Institute and Center for Clinical Genomics, Cleveland Clinic Foundation, Cleveland, OH, USA

    W. H. Wilson Tang

  7. Western University of Health Sciences, Pomona, CA, USA

    Sheryl L. Chow

Authors
  1. David E. Lanfear
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raza Abbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ricoung She
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Badri Padhukasahasram
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ramesh C. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Langholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W. H. Wilson Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L. Keoki Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hani N. Sabbah
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sheryl L. Chow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David E. Lanfear.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 [5].

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Funding

This research was supported by the National Heart, Lung, and Blood Institute (Lanfear K23HL085124, R01HL103871; Williams R01HL079055, R01HL118267; Sabbah PO1HL074237), the National Institute of Allergy and Infectious Diseases (Williams R01AI079139, R01AI061774), and the National Institute of Diabetes and Digestive and Kidney Diseases (Williams R01DK064695).

Additional information

Associate Editor Enrique Lara-Pezzi oversaw the review of this article

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplemental Table 1

Change in BP genotype associations (DOC 46 kb)

Supplemental Figure 1

cGMP = cyclic guanosine monophosphate SBP = systolic blood pressure DBP = diastolic blood pressure (DOCX 444 kb)

Supplemental Figure 2

Forest Plot of Regression Models for rs9829347. ABCHF = Assessment of Biomarkers and Cardiorenal Syndrome Heart Failure Trial PGBNP = Pharmacogenetics of BNP study (DOCX 18 kb)

Supplemental Figure 3

Linkage Plot and Heat Map of MME showing Phenotype SNPs Associated in Previous Studies and highlighting pairs with LD of possible interest. Red rectangle = SNP associated with pharmacokinetics of BNP Orange rectangle = SNP associated with expression Black circle = linkage disequilibrium between pharmacodynamics SNP and expression SNP Green circle = longer range LD between 5’ and 3’ blocks (DOCX 2671 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lanfear, D.E., Li, J., Abbas, R. et al. Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients. J. of Cardiovasc. Trans. Res. 8, 545–553 (2015). https://doi.org/10.1007/s12265-015-9660-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-015-9660-2

Keywords

Search

Navigation