title: Translational assessment of cardiac contractility by echocardiography in the telemetered rat.
abstract: BACKGROUND
  Cardiac contractility was evaluated using standard inotropic agents in rats. We compared indices of cardiac contractility, i.e. LV dP/dt max from telemetry while simultaneously collecting EF (ejection fraction) and FS (fractional shortening) measures from echocardiography.
  
  
  METHODS
  Male Wistar rats were instrumented with telemetry devices for measurements of blood pressure and left ventricular pressure. Milrinone (PDE III inhibitor) and verapamil (L-type calcium channel blocker) at doses of 0, 3, 10, and 30 mg/kg were administered orally using a 4 × 4 Latin square crossover study design. Telemetry data were recorded at predose and continuously for 24h post-dose. Echocardiographic evaluations were conducted once at predose and at 1 and 2h after milrinone or verapamil administration, respectively. During the recording of echocardiograms, telemetry data were collected simultaneously. Blood samples were also collected to confirm plasma drug exposure.
  
  
  RESULTS
  As expected, milrinone increased LV dP/dt max, EF and FS while verapamil decreased LV dP/dt max, EF and FS. Linear regression analysis showed a positive correlation between LV dP/dt max and EF or FS (P<0.001) with both test agents. A change in LV dP/dt max of 1000 mmHg/s was found to correspond with a change in EF and FS of 13 and 16%, respectively, in the telemetered rat.
  
  
  CONCLUSIONS
  The correlation between contractility indices assessed by telemetry and echocardiographic methods in rat models has not received much attention to date. Our results with two reference compounds demonstrate that both methods are sensitive to alterations in contractility induced by inotropic agents administered to rats. The high degree of correlation between changes in LV dP/dt max and EF or FS in the rat enables a translational-element of clinical relevance following changes in contractility indices when measured with telemetry devices in preclinical studies.
authors.affiliation: Safety Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, East Hanover, NJ, United States. Electronic address: hai-ming.tang@novartis.com.
authors.forename: Hai-Ming
authors.initials: HM
authors.lastname: Tang
authors.affiliation: Safety Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, East Hanover, NJ, United States.
authors.forename: Haisong
authors.initials: H
authors.lastname: Ju
authors.affiliation: Translational Imaging, BioMarker Development, Translational Medicine, Novartis Institute for Biomedical Research, East Hanover, NJ, United States.
authors.forename: Shufang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Safety Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, East Hanover, NJ, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: LaDuke
authors.affiliation: Safety Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, East Hanover, NJ, United States.
authors.forename: Suzette
authors.initials: S
authors.lastname: Hahn
authors.affiliation: DMPK, Early Bioanalytics and Technology, Novartis Institutes for Biomedical Research, East Hanover, NJ, United States.
authors.forename: James
authors.initials: J
authors.lastname: Glick
authors.affiliation: Safety Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, East Hanover, NJ, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Carey
authors.affiliation: Safety Pharmacology, Preclinical Safety, Novartis Institute for Biomedical Research, East Hanover, NJ, United States.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Friedrichs
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D018592:Cross-Over Studies; D004452:Echocardiography / Q000379:methods; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013686:Telemetry / Q000379:methods; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D014700:Verapamil; D020105:Milrinone
keywords: Cardiac contractility; Echocardiography; Ejection fraction; Fractional shortening; Milrinone; Rat; Telemetry; Verapamil; dP/dt