title: Quantitative MRI biomarkers to characterize regional left ventricular perfusion and function in nonhuman primates during dobutamine-induced stress: A reproducibility and reliability study.
abstract: To identify reproducible and reliable noninvasive regional imaging biomarkers of cardiac function and perfusion at rest and under stress in healthy nonhuman primates (NHPs) that may be used in the future for the early characterization of preclinical heart failure models, to evaluate therapy, and for clinical translation.
  
  
  
  Seven naive cynomolgus macaques underwent test-retest 3T cardiac MRI tagging and dual-bolus perfusion experiments. Regional cardiac function biomarkers, such as peak circumferential strain (CS), average diastolic strain-rate (DSR), contractile reserve (CR), diastolic reserve, peak torsion, and torsion reserve were quantified. Further, regional myocardial blood flow (MBF), myocardial perfusion reserve (MPR), and myocardial perfusion reserve-to-contractile reserve (MPR/CR) were also derived. Inter- and intraobserver reproducibility and test-retest reliability analyses were conducted using the reliability and generalizability coefficients including correlation coefficient (CC) and intraclass correlation coefficient (ICC).
  
  
  
  Overall, peak CS, DSR, and MBF are robust biomarkers at both rest and stress with moderate-good inter- and intraobserver reproducibility and test-retest reliability. At rest: intra-/interobserver reproducibility (CC): peak CS (0.81/0.81), DSR (0.81/0.81), MBF (0.72/0.57), peak torsion (0.79/0.79); test-retest reliability: (CC/ICC): peak CS (0.62/0.75), DSR (0.24/0.55), MBF (0.66/0.62), and peak torsion (0.79/0.78). Under stress: intra-/interobserver reproducibility (CC): peak CS (0.61/0.60), DSR (0.50/0.50), MBF (0.63/0.61), MPR (0.43/0.43), and peak torsion (0.38/0.38); test-retest reliability: (CC/ICC): peak CS (0.58/0.58), DSR (0.24/0.43), MBF (0.58/0.58), MPR (0.43/0.38), and peak torsion (0.38/0.38).
  
  
  
  We demonstrated the feasibility of using cardiac MRI to characterize left ventricular functional and perfusion responses to stress in an NHP species, and specific robust biomarkers such as peak CS, DSR, MBF, diastolic reserve, and MPR have been identified for clinical translation and drug research.
  
  
  
  1 J. Magn. Reson. Imaging 2017;45:556-569.
authors.affiliation: Translational Biomarkers, Merck Research Laboratories, MSD, Singapore.
authors.forename: Smita
authors.initials: S
authors.lastname: Sampath
authors.affiliation: Translational Biomarkers, Merck Research Laboratories, MSD, Singapore.
authors.forename: Annamalai Sarayu
authors.initials: AS
authors.lastname: Parimal
authors.affiliation: Biometric Research, Biostatistics and Research Decision Sciences, Merck Research Laboratories, Merck & Co. Inc., Rahway, New Jersey, USA.
authors.forename: Dai
authors.initials: D
authors.lastname: Feng
authors.affiliation: Translational Biomarkers, Merck Research Laboratories, MSD, Singapore.
authors.forename: Miko May Lee
authors.initials: MM
authors.lastname: Chang
authors.affiliation: Biometric Research, Biostatistics and Research Decision Sciences, Merck Research Laboratories, Merck & Co. Inc., Rahway, New Jersey, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: Translational Biomarkers, Merck Research Laboratories, Merck & Co. Inc., West Point, Pennsylvania, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Klimas
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, MSD, Singapore.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Jacobsen
authors.affiliation: Imaging, Maccine Pte. Ltd., Singapore.
authors.forename: Elaine
authors.initials: E
authors.lastname: Manigbas
authors.affiliation: Imaging, Maccine Pte. Ltd., Singapore.
authors.forename: Willy
authors.initials: W
authors.lastname: Gsell
authors.affiliation: Translational Biomarkers, Merck Research Laboratories, Merck & Co. Inc., West Point, Pennsylvania, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
authors.affiliation: Translational Biomarkers, Merck Research Laboratories, MSD, Singapore.
authors.forename: Chih-Liang
authors.initials: CL
authors.lastname: Chin
mesh_terms: D000818:Animals; D015415:Biomarkers; D001783:Blood Flow Velocity / Q000502:physiology*; D003326:Coronary Circulation / Q000502:physiology*; D004280:Dobutamine; D005080:Exercise Test / Q000379:methods*; D006352:Heart Ventricles / Q000000981:diagnostic imaging*; D006801:Humans; D008252:Macaca fascicularis; D018810:Magnetic Resonance Angiography / Q000379:methods; D019028:Magnetic Resonance Imaging, Cine / Q000379:methods*; D008297:Male; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D015415:Biomarkers; D004280:Dobutamine
keywords: MRI; cardiac stress; dobutamine; imaging biomarker; myocardial blood flow; nonhuman primate; perfusion reserve; tagging