Serum Natriuretic Peptides as Differential Biomarkers Allowing for the Distinction between Physiologic and Pathologic Left Ventricular Hypertrophy.
Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy.
1 Regeneron Pharmaceuticals, Tarrytown, New York, USA.
Michael E
ME
Dunn
2 Department of Kinesiology, University of Rhode Island, Kingston, Rhode Island, USA.
Thomas G
TG
Manfredi
2 Department of Kinesiology, University of Rhode Island, Kingston, Rhode Island, USA.
Kevin
K
Agostinucci
3 Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana, USA.
Steven K
SK
Engle
4 Millennium: the Takeda Oncology Company, Cambridge, Masschusettes, USA.
Josh
J
Powe
5 Critical Path Institute, Predictive Safety Testing Consortium, Tucson, Arizona, USA.
Nicholas M P
NM
King
6 GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Luis A
LA
Rodriguez
7 Pfizer Inc, Groton, Connecticut, USA.
Kathryn E
KE
Gropp
4 Millennium: the Takeda Oncology Company, Cambridge, Masschusettes, USA.
Matthew
M
Gallacher
8 Department of Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA.
Frederick J
FJ
Vetter
9 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA.
Vijay
V
More
9 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA.
Prajakta
P
Shimpi
9 Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA.
David
D
Serra
6 GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Heidi M
HM
Colton
D000818:Animals; D015415:Biomarkers / Q000097:blood; D066126:Cardiotoxicity; D003937:Diagnosis, Differential; D017379:Hypertrophy, Left Ventricular / Q000097:blood* / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D045265:Natriuretic Peptides / Q000097:blood*; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity; D047495:PPAR gamma / Q000819:agonists; D017207:Rats, Sprague-Dawley; D013550:Swimming / Q000502:physiology; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D016277:Ventricular Function, Left / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
D015415:Biomarkers; D045265:Natriuretic Peptides; D010080:Oxazoles; D047495:PPAR gamma; C422415:farglitazar; D014443:Tyrosine
atrial natriuretic peptide; brain natriuretic peptide; cardiac hypertrophy; cardiotoxicity; natriuretic peptides; nonclinical; rat