Original article Evaluation of a method to correct the contractility index LVdP/dt max for changes in heart rate Michael Markert a, ⁎, Thomas Trautmann a , Marcus Groß b , Anja Ege a , Karin Mayer a , Brian Guth a a Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany b Humboldt Universität zu Berlin, Unter den Linden 6, Berlin, Germany abstract article info Article history: Received 22 February 2012 Accepted 12 April 2012 Keywords: Contractility Dog Heart rate Inotropy Method Telemetry Introduction: In order to differentiate heart rate (HR)‐induced changes from drug-induced positive or negative inotropic effects, HR-dependent effects need to be taken into account. Left ventricular (LV)dP/dt max , the maximal value of the first derivative of a left ventricular pressure signal, is a convenient index for LV contractile state. The objective of this study was to define the normal relationship between left ventricular LVdP/dt max and HR in chronically instrumented, conscious dogs, primates and minipigs in our laboratory and then to use these data as the basis for developing a LVdP/dt max –HR-correction formula for each species. Methods: Trained Labrador-mix dogs, cynomolgus monkeys and minipigs (Goettinger) were equipped with a fully implantable radiotelemetry-based system (ITS, Maryland, USA) for the measurement of aortic pressure (AP), left ventricular pressure (LVP), ECG (lead II) and body temperature. The contractility index LVdP/dt max was derived from the LV pressure signal. Notocord HEM 4.2 software was used for data acquisition. For each species the relationship between LVdP/dt max and HR was evaluated using spontaneous HRs throughout the observation period (8–24 h) without pharmacological intervention. The formulae for the LVdP/dt max –HR relationships were generated using the R-script software for statistical evaluations and then used as the basis for an automated software for data analysis. Additionally, two different validation compounds (1 negative inotrope and 1 positive inotrope) were then used to investigate the impact of these compounds on the LVdP/dt max –HR relation- ship. Results and Discussion: There was a direct and reproducible LVdP/dt max –HR relationship in all animals tested and formulae were derived to describe this relationship in each species. Inotropic agents (both positive and negative) demonstrated the expected shifts of this relationship. Using the formulae found for each species describing the LVdP/dt max –HR dependency, one can assess the inotropic effects of drugs independently from simultaneous changes in HR. © 2012 Elsevier Inc. All rights reserved. 1. Introduction The safety assessment of all new pharmacological agents includes an evaluation using safety pharmacology models, covering as a minimum requirement a group of “core battery” studies that includes respiratory, central nervous system and cardiovascular effects (Friedrichs, Patmore, & Bass, 2005; Pugsley & Curtis, 2006). The cardiovascular evaluation typically includes potential drug-induced effects on arterial blood pressure, HR and the electrocardiogram. The value of including an assessment of possible effects on myocardial contractility has recently been pointed out indicating an interest in integrating such measure- ments in the cardiovascular safety pharmacology evaluation (Markert et al., 2007; Sarazan et al., 2011; Templeton et al., 2007). Whereas the evaluation of myocardial contractility in the whole animal, (particularly in conscious animals which are preferred for use in safety pharmacol- ogy studies) may be challenging, the increased use of the first derivative of the left ventricular pressure signal (LVdP/dt max ) provides a viable approach for generating data useful for this assessment. Whereas the general experience has been that the parameter LVdP/dt max (the maximal value of LVdP/dt during systole) is highly sensitive to changes in myocardial contractile state, it is also well recognized that this parameter is influenced importantly by factors other than the contractile state of the heart. In particular, the loading conditions of the left ventricle, including both preload (typically measured using the end-diastolic left ventricular pressure) and afterload (measured using the aortic pressure) as well as the HR. To take this into account it was proposed in a recent work (Hamlin & Del Rio, 2012) to use “barinometry” as a possibly more appropriate term for what LVdP/dt max represents. The effect of the rate of contraction on contractile force is well established and was shown in isolated muscle preparations (Endoh, 2004; Gabel, Bihler, & Dresel, 1966; Schildberg, Fleckenstein, & Klek, 1965) as well as in vivo, and has been referred to as the “force– frequency relationship”. This relationship also appears to become increasingly important with enhanced sympathetic tone (Miura, Miyazaki, Guth, Indolfi, & Ross, 1994). Thus, the parameter LVdP/ Journal of Pharmacological and Toxicological Methods 66 (2012) 98–105 ⁎ Corresponding author at: Boehringer Ingelheim Pharma GmbH & Co KG, J91 UG, Birkendorferstr.65, 88397 Biberach, Germany. E-mail address: michael.markert@boehringer-ingelheim.com (M. Markert). 1056-8719/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.vascn.2012.04.005 Contents lists available at SciVerse ScienceDirect Journal of Pharmacological and Toxicological Methods journal homepage: www.elsevier.com/locate/jpharmtox