title: Evaluation of a method to correct the contractility index LVdP/dt(max) for changes in heart rate.
abstract: BACKGROUND
  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 relationship.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. michael.markert@boehringer-ingelheim.com
authors.forename: Michael
authors.initials: M
authors.lastname: Markert
authors.forename: Thomas
authors.initials: T
authors.lastname: Trautmann
authors.forename: Marcus
authors.initials: M
authors.lastname: Groß
authors.forename: Anja
authors.initials: A
authors.lastname: Ege
authors.forename: Karin
authors.initials: K
authors.lastname: Mayer
authors.forename: Brian
authors.initials: B
authors.lastname: Guth
mesh_terms: D000818:Animals; D000830:Animals, Laboratory; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008252:Macaca fascicularis / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D015203:Reproducibility of Results; D013552:Swine; D013556:Swine, Miniature / Q000502:physiology; D013686:Telemetry; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents