Detection of left ventricular hypertrophy in rats administered a peroxisome proliferator-activated receptor alpha/gamma dual agonist using natriuretic peptides and imaging.
Chronic treatment with suprapharmacologic doses of peroxisome proliferator-activated receptor (PPAR) agonists has a known potential for causing left ventricular hypertrophy (LVH). The mechanism by which LVH develops is not well understood nor are biomarkers of it well characterized. Natriuretic peptides are important regulators of cardiac growth, blood volume, and arterial pressure and may be useful biomarkers of LVH and hemodynamic changes that precede it. We measured amino-terminal pro-atrial natriuretic peptide (NTproANP), amino-terminal pro-brain natriuretic peptide (NTproBNP), and cardiac troponin I (cTnI) concentrations in serum and plasma, as well as transcripts in left ventricular heart tissue for atrial natriuretic peptide precursor (Nppa), brain natriuretic peptide precursor (Nppb), and myosin heavy chain-beta (Myh7) as potential biomarkers of LVH induced by a PPARalpha/gamma dual agonist in Sprague-Dawley rats. We used magnetic resonance imaging, echocardiography, and hemodynamics to identify structural and functional cardiovascular changes related to the biomarkers. Heart-to-brain weight ratios (HW:BrW) were correlated with NTproANP, NTproBNP, and cTnI concentrations in serum as well as fold change in expression of Nppa and Nppb. LVH was characterized by increased left ventricular wall thickness and inner diameter, increased cardiac output, decreased arterial blood pressure, and increased heart rate. In these studies, each end point contributed to the early detection of LVH, the ability to monitor its progression, and demonstrated the ability of NTproANP concentration in serum to predict LVH and hemodynamic changes.
Engle
Steven K
SK
Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Solter
Philip F
PF
Credille
Kelly M
KM
Bull
Christopher M
CM
Adams
Stephanie
S
Berna
Michael J
MJ
Schultze
Albert E
AE
Rothstein
Emily C
EC
Cockman
Michael D
MD
Pritt
Michael L
ML
Liu
Hong
H
Lu
Yuefeng
Y
Chiang
Alan Y
AY
Watson
David E
DE
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002317:Cardiovascular Agents / Q000633:toxicity*; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010666:Phenylpropionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013876:Thiophenes / Q000633:toxicity*; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
C486784:2-methyl-3-(4-(2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy)phenyl)-2-phenoxypropionic acid; D015415:Biomarkers; D002317:Cardiovascular Agents; D047493:PPAR alpha; D047495:PPAR gamma; D010446:Peptide Fragments; D010666:Phenylpropionates; D013876:Thiophenes; D020107:Troponin T; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor