Does B-type Natriuretic Peptide or Its Gene Polymorphism Predict Patient Outcome after Coronary Artery Bypass Graft Surgery?
Fox, Amanda A. M.D.*; Collard, Charles D. M.D.; Shernan, Stanton K. M.D.; Seidman, Christine E. M.D.; Seidman, Jonathan G. Ph.D.; Liu, Kuang-Yu Ph.D.; Muehlschlegel, Jochen D. M.D.; Perry, Tjorvi E. M.D.; Aranki, Sary F. M.D.; Lange, Christoph Ph.D.; Herman, Daniel S.; Meitinger, Thomas M.D.; Lichtner, Peter Ph.D.; Body, Simon C. M.B.Ch.B., M.P.H.
We appreciate the interest of Dr. Yu et al.
in our April 2009 publication in which we describe significant associations between single nucleotide polymorphisms (SNPs) within the natriuretic peptide NPPA
, and NPR3
genes and the occurrence of ventricular dysfunction (VnD) after primary coronary artery bypass graft surgery.1
We agree that assessing natriuretic peptide system gene SNPs for association with perioperative plasma B-type natriuretic peptide (BNP) levels may improve understanding of the underlying biology linking these SNPs to postoperative VnD, and we are currently conducting these analyses.
Although we agree with Dr. Yu et al.
that the association between natriuretic peptide SNPs and perioperative BNP concentrations should be assessed, the biologic mechanisms for the association between these SNPs and postoperative VnD may be more complex than the pathway that they propose, i.e.
, that natriuretic peptide system gene variants predict perioperative plasma BNP levels, which in turn predict postoperative VnD. As Dr. Yu et al.
rightly point out, increased plasma BNP is an established biomarker for heart failure. Indeed, we have previously reported that postoperative plasma BNP is significantly increased in patients who develop in-hospital VnD after coronary artery bypass graft surgery versus
those who do not.2
Despite the fact that circulating plasma BNP is known to be increased in heart failure, we are aware of at least four studies of outpatient, noncardiac cohorts that report that one or more of the NPPA
SNP alleles that we found associated with decreased VnD associate with increased plasma BNP levels (approximately 10-pg/ml increase in plasma BNP for each copy of the minor allele).3–6
One hypothesis to explain the seeming conundrum of why plasma BNP may be modestly increased in ambulatory patients who carry NPPA
SNP alleles that are associated with decreased VnD may be that these SNPs code for qualitative as well as quantitative changes in circulating BNP. Indeed, recent studies have shown that there is functional heterogeneity in circulating forms of plasma BNP, with heart failure patients tending to have higher plasma ratios of biologically inactive precursor pro-BNP compared with subjects without heart failure.7,8
Certain natriuretic peptide SNPs may be associated with increased production of biologically inactive BNP. Furthermore, there is evidence that natriuretic peptides have both autocrine and paracrine influences on ventricular myocardium.9
Therefore, we can postulate that even though a natriuretic peptide gene SNP may associate with increased BNP levels, the qualitative nature of the BNP produced may mitigate the development of postoperative VnD through its direct effects on the myocardium.
In summary, we appreciate the comments of Dr. Yu et al. and fully agree that further study of natriuretic peptide system genes, circulating natriuretic peptides, and natriuretic peptide tissue effects are needed to tease out mechanisms for our observed associations between NPPA/NPPB and NPR3 gene variants and development of VnD after coronary artery bypass graft surgery.
Amanda A. Fox, M.D. *
Charles D. Collard, M.D.
Stanton K. Shernan, M.D.
Christine E. Seidman, M.D.
Jonathan G. Seidman, Ph.D.
Kuang-Yu. Liu, Ph.D.
Jochen D. Muehlschlegel, M.D.
Tjorvi E. Perry, M.D.
Sary F. Aranki, M.D.
Christoph. Lange, Ph.D.
Daniel S. Herman
Thomas. Meitinger, M.D.
Peter. Lichtner, Ph.D.
Simon C. Body, M.B.Ch.B., M.P.H.
*Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. firstname.lastname@example.org
1. Fox AA, Collard CD, Shernan SK, Seidman CE, Seidman JG, Liu KY, Muehlschlegel JD, Perry TE, Aranki SF, Lange C, Herman DS, Meitinger T, Lichtner P, Body SC: Natriuretic peptide system gene variants are associated with ventricular dysfunction after coronary artery bypass grafting. Anesthesiology 2009; 110:738–47
2. Fox AA, Shernan SK, Collard CD, Liu KY, Aranki SF, DeSantis SM, Jarolim P, Body SC: Preoperative B-type natriuretic peptide is as independent predictor of ventricular dysfunction and mortality after primary coronary artery bypass grafting. J Thorac Cardiovasc Surg 2008; 136:452–61
3. Newton-Cheh C, Larson MG, Vasan RS, Levy D, Bloch KD, Surti A, Guiducci C, Kathiresan S, Benjamin EJ, Struck J, Morgenthaler NG, Bergmann A, Blankenberg S, Kee F, Nilsson P, Yin X, Peltonen L, Vartiainen E, Salomaa V, Hirschhorn JN, Melander O, Wang TJ: Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet 2009; 41:348–53
4. Takeishi Y, Toriyama S, Takabatake N, Shibata Y, Konta T, Emi M, Kato T, Kawata S, Kubota I: Linkage disequilibrium analyses of natriuretic peptide precursor B locus reveal risk haplotype conferring high plasma BNP levels. Biochem Biophys Res Commun 2007; 362:480–4
5. Lajer M, Tarnow L, Jorsal A, Parving HH: Polymorphisms in the B-type natriuretic peptide (BNP) gene are associated with NT-proBNP levels but not with diabetic nephropathy or mortality in type 1 diabetic patients. Nephrol Dial Transplant 2007; 22:3235–9
6. Lanfear DE, Stolker JM, Marsh S, Rich MW, McLeod HL: Genetic variation in the B-type natriuretic peptide pathway affects BNP levels. Cardiovasc Drugs Ther 2007; 21:55–62
7. Liang F, O'Rear J, Schellenberger U, Tai L, Lasecki M, Schreiner GF, Apple FS, Maisel AS, Pollitt NS, Protter AA: Evidence for functional heterogeneity of circulating B-type natriuretic peptide. J Am Coll Cardiol 2007; 49:1071–8
8. Lam CS, Burnett JC Jr, Costello-Boerrigter L, Rodeheffer RJ, Redfield MM: Alternate circulating pro-B-type natriuretic peptide and B-type natriuretic peptide forms in the general population. J Am Coll Cardiol 2007; 49:1193–202
9. D'Souza SP, Davis M, Baxter GF: Autocrine and paracrine actions of natriuretic peptides in the heart. Pharmacol Ther 2004; 101:113–29
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