A translational assessment of preclinical versus clinical tools for the measurement of cardiac contractility: comparison of LV dP/dt(max) with echocardiography in telemetry implanted beagle dogs

Frank Cools; Deborah Dhuyvetter; Annik Vanlommel; Sigrid Janssens; Herman Borghys; Helena Geys; David J Gallacher

doi:10.1016/j.vascn.2013.10.003

A translational assessment of preclinical versus clinical tools for the measurement of cardiac contractility: comparison of LV dP/dt(max) with echocardiography in telemetry implanted beagle dogs

J Pharmacol Toxicol Methods. 2014 Jan-Feb;69(1):17-23. doi: 10.1016/j.vascn.2013.10.003. Epub 2013 Oct 16.

Authors

Frank Cools¹, Deborah Dhuyvetter², Annik Vanlommel², Sigrid Janssens², Herman Borghys², Helena Geys³, David J Gallacher²

Affiliations

¹ Translational Sciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium. Electronic address: fcools@its.jnj.com.
² Translational Sciences, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
³ Nonclinical Statistics and Computing, Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.

PMID: 24140387
DOI: 10.1016/j.vascn.2013.10.003

Abstract

Introduction: Regarding evaluation of drug-induced changes in left ventricular contractility in safety pharmacology there is still a gap in knowledge between preclinically and clinically used measurements.

Methods: As a step towards translation of preclinical to clinical outcomes, this study in telemetered dogs was initiated to compare indexes of contractility, such as LV dP/dt(max) (contractility measured as the maximum raise of pressure in the left ventricle) and LV dP/dt(max)/P (contractility measured as the maximum raise of pressure in the left ventricle, corrected for pressure) (telemetry; both commonly preclinically used) and EF (ejection fraction) and FS (fractional shortening) (echocardiography; both commonly clinically used). Different inotropic states were induced by minoxidil, milrinone, isoprenaline, clonidine, atenolol and verapamil.

Results: Both techniques demonstrated reproducible changes in contractility which showed a clear linear association. A change in LV dP/dt(max) of 1000 mmHg/s (in the range of 2500 to 7500 mmHg/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of approximately 6%. A change of 10/s LV dP/dt(max)/P (in the range of 35 to 85/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of 7%.

Discussion: The correlation found in this study could potentially enable a better--translational--assessment of the clinical relevance of changes in contractility indices measured with telemetry devices in preclinical safety studies.

Keywords: Beagle dog; C(max); Contractility; EF; Echocardiography; Ejection fraction; FS; Fractional shortening; LV dP/dt(max); LV dP/dt(max)/P; LVP; M-mode; Methods; T(max); TdP; Torsades de pointes; contractility measured as the maximum raise of pressure in the left ventricle; contractility measured as the maximum raise of pressure in the left ventricle, corrected for pressure; ejection fraction; fractional shortening; left ventricular pressure; maximum plasma concentration; motion mode of echo-cardiography; time point of maximum plasma concentration.

MeSH terms

Animals
Cardiotonic Agents / pharmacology*
Dogs
Echocardiography / methods
Female
Heart / drug effects*
Heart Ventricles / drug effects
Myocardial Contraction / drug effects*
Telemetry / methods
Ventricular Function, Left / drug effects*
Ventricular Pressure / drug effects

Substances

Cardiotonic Agents