Background variability in standard clinical pathology biomarkers in beagle dogs instrumented with chronic indwelling telemetry devices.

INTRODUCTION: Contemporary best practice recommendations in preclinical cardiovascular safety assessment promote 3Rs principles. This includes the employment of within-subjects experimental designs to evaluate discrete, acute doses of investigational new drugs, as well as the maintenance of stock colonies of appropriate large animal test systems. Such colony species are often tested repeatedly on independent studies with provision of appropriate recovery periods and requisite health status evaluations (e.g., physical examinations, electrocardiographic assessments, clinical pathology evaluations). METHODS: To investigate the utility of the often reiterative process of pre- or inter-study clinical pathology testing to help ascertain health status of non-naïve, telemetered canines (beagle dogs), the present study collated the results of a randomly selected set of animals approximately every three months for a period of three years. RESULTS: Although occasionally a few routine hematology or clinical chemistry endpoints did demonstrate evidence of systematic trending over time, none of the observed fluctuations fell outside the range of expected biological variability, nor would have prevented assignment of any given animal to study. DISCUSSION: The present findings illustrate a high degree of consistency in routinely assessed clinical pathology parameters during the course of chronic telemetry instrumentation in the canine, including relative to historical control data in healthy, experimentally naïve animals of the same species and source, maintained under analogous laboratory conditions. The data suggest that routine assessment of such parameters for the purposes of facilitating judgments concerning suitability for study may represent a pursuit of little overall value, and which may be reasonably accomplished based on alternative, observation-based screening procedures.

Effects of telemetric epicardial leads and ventricular catheters on arrhythmia incidence in cynomolgus monkeys.

INTRODUCTION: Utilization of implantable bio-telemetry devices represents a common approach to contemporary cardiovascular safety assessment. Depending on the specific needs of the study design, and corresponding surgical methodologies employed, application of telemetry devices may have more or less liability to interact with ongoing physiology. The potential for intrathoracic procedures (epicardial/intracardiac ECG lead arrangements, left ventricular catheterization) to influence baseline cardiovascular function, and particularly arrhythmia status is currently an important topic of consideration. METHODS: Two experiments were performed to assess the post-surgical incidence of ventricular arrhythmias in cynomolgus monkeys instrumented with telemetry devices with 1) left ventricular pressure (LVP) transducers and epicardial lead array (N=67), and 2) epicardial lead array without LVP catheter placement (N=55). A third experiment (N=18) was performed to prospectively, and definitively, investigate the effect of chronic left ventricular catheterization on the observed incidences of arrhythmias by means of multiple (pre- and post-surgery) electrocardiographic evaluations conducted on ~24h of data per interval assessed up to ~12months post-implantation. RESULTS: The diversity and number of ventricular rhythm variants was considerably greater in animals instrumented with left ventricular catheters (62/67; 93%) compared to animals instrumented with epicardial leads only (21/55; 38.2%), and surgically naïve animals (9/18; 50%). Prior to surgery, the average frequency of all definitively characterized arrhythmias among experimentally naïve animals was 0.19/h; following surgical implantation of the telemetry device with epicardial leads and ventricular pressure catheter, the overall frequency of arrhythmia increased approximately 40-fold, to 7.19/h. DISCUSSION: Similar to prior investigations in canines, the present results confirm an increased incidence in the rate and variety of ventricular arrhythmias in cynomolgus monkeys when instrumented with telemetry devices equipped with LVP catheters. Instrumentation with epicardial leads was not associated with an increase in arrhythmias above that expected as a function of normal biological variation in experimentally naïve animals of this species.