Diurnal differences in common electrocardiographic indices of arrhythmic liability in normal telemetered dogs and telemetered dogs with failing hearts: Implications for safety pharmacology and veterinary cardiology.

摘要

The assessment of the electrocardiogram (ECG) liabilities is a key component in both clinical medicine and safety-pharmacology. However, despite the known circadian dependence of both pro-arrhythmic substrates and prevalence of arrhythmias, the optimal time for the ECG evaluation remains undetermined. In fact the time of day of the recording is seldom considered in the interpretation. This study assessed circadian changes in ECG parameters in a well-defined telemetered canine model. Diurnal differences were sought between normal dogs and dogs with failing hearts (i.e., with reduced ejection fraction and elevated NTproBNP) but not in heart failure (i.e., asymptomatic). Methods of analyzing ECGs from (the relatively few) dogs with clinical heart failure are not of great concern, since dogs so afflicted have clear echocardiographic and other clinical evidence of disease. So this study was directed more at (the much greater number of) dogs with subclinical disease, where standard methods are more equivocal, difficult to perform, and expensive.;Healthy male dogs (n = 9) and male dogs with failing hearts (n=10) were instrumented for telemetered ECG recordings at rest (1-hour epochs) during periods of low (2AM) and high autonomic activation (6PM and 6AM); heart rates (HR), indices of cardiac conduction (PQ, QRS) and repolarization duration (QT, QTcF) as well as heart rate variability (RRSD), repolarization instability (QTSTV) and steepness of restitution (QT/TQ) were evaluated at each time-point. Data are mean +/- SD and were compared (ANOVA). The number of dogs entered into this study was determined a priori to produce a power of ∼0.8 to detect 15% differences in parameters having coefficients of variation of 25% with an alpha of 0.05.;In both groups, at 2 AM, heart rates were slower and more variable while the PQ interval was longer, indicating strong parasympathetic control. No notable circadian differences in ventricular conduction (QRS duration) were found in either normal dogs or dogs with failing hearts. For normal dogs, no notable differences were found in ventricular repolarization (QT, QTcF) or repolarization variability (QTSD, QT-STV). Though in normal dogs, ventricular restitution (QT: TQ) showed some differences, these are not considered to be of clinical relevance. For dogs with failing heart, no notable differences were found in repolarization variability (QTSD, QT-STV) or ventricular restitution (QT: TQ). The QT-interval was longer at night, but rate-corrected QT duration did not change.;These data strongly indicate lack of notable diurnal differences in ECG markers of arrhythmic liability and their underlying physiology between normal dogs and dogs with failing hearts but no clinical signs of cardiac disease. Dogs with failing hearts had significantly longer QTc(F) and higher short term variability in QT, both indicators of a potential for a torsadomorphic ventricular arrhythmia. Furthermore, TQ interval was significantly shorter for dogs with failing hearts, but QT only had a tendency to prolong, thus the QT: TQ only had a tendency to prolong. This is an indicator for a non-torsadomorphic, reentrant ventricular arrhythmia, which is known to develop in more severe heart failure. It may be postulated, then, that millions of dogs with failing hearts may develop a risk for ventricular arrhythmia, and may be candidates to receive compounds (e.g., beta-blockers, ACE inhibitors) prophylactic against the development. Although there were no differences of significance in parameters of HRV between normal dogs and dogs with failing hearts, dogs with failing hearts tended to have: higher heart rates at 2 AM and 6 AM, and had higher coefficients of variation of almost all parameters. This finding, also, might indicate value for prophylaxis against the pathophysiology that occurs with more advanced heart disease and leads to morbidity and mortality.