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.

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.

ECG arrhythmias in non-implanted vs. telemetry-implanted dogs: need for screening before and sufficient recovery time after implantation.

INTRODUCTION: The purpose of this study was: (1) to characterize and assess the incidence of spontaneous arrhythmias in totally naive Beagle dogs (n=51; 10 males+41 females): (2) to study the effects of permanent ECG- and LVP-probe telemetry implants both acutely and up to 233days after surgery in a subset of 11 female Beagle dogs. METHODS: Naive ECG assessments were conducted by means of 6 external telemetry leads in jacketed dogs. Telemetry ECG recordings were captured by means of implanted telemetry devices suitable for ECG, LVP and aortic blood pressure recording. Experienced laboratory personnel visually evaluated all 22h ECG recordings at different time points after implantation and evaluated the incidence and type of arrhythmia. RESULTS: The 51 healthy and totally naive Beagle dogs showed a prevalence of: 49.0% 2°AVB; 58.8% single atrial premature complexes; 17.6% junctional tachycardia; 27.5% ventricular complexes; 13.7% ventricular escape complexes; 21.6% ventricular premature complexes; 3.9% runs of ventricular complexes; 3.9% runs of ventricular escape complexes. As such, a high percentage of clinically normal Beagle dogs showed different types of arrhythmias when ECG's obtained by external telemetry leads were fully evaluated for a 22h period. The chronic implantation of a ventricular probe through the apex of the heart in 11 dogs only, resulted in higher incidences and frequencies of ventricular episodes, which (in some dogs) extended up to 8weeks. Eight months after surgery none of the implanted dogs showed ventricular tachycardia and only 10% had single ventricular or ventricular premature complexes at low frequencies. DISCUSSION: A thorough evaluation of the ECG's of Beagle dogs selected for telemetry implantation can help to avoid inherent arrhythmia-burdened dogs being implanted and used in studies where these arrhythmias will confound drug assessment by increasing the number of potential false positives.