Measurement and interpretation of electrocardiographic QT intervals in murine hearts

Abstract

Alterations in ECG QT intervals correlate with the risk of potentially fatal arrhythmias, for which transgenic murine hearts are becoming increasingly useful experimental models. However, QT intervals are poorly defined in murine ECGs. As a consequence, several different techniques have been used to measure murine QT intervals. The present work develops a consistent measure of the murine QT interval that correlates with changes in the duration of ventricular myocyte action potentials (APs). Volume-conducted ECGs were compared with simultaneously recorded APs, obtained using floating intracellular microelectrodes in Langendorff-perfused mouse hearts. QT intervals were measured from the onset of the QRS complex. The interval, Q-APR90, measured to the time at 90% AP recovery, was compared with two measures of the QT interval. QT1 was measured to the recovery of the ECG trace to the isoelectric baseline for entirely positive T-waves or to the trough of any negative T-wave undershoot. QT2—used extensively in previous studies—was measured to the return of any ECG trough to the isoelectric baseline. QT1, but not QT2, closely correlated with changes in Q-APR90. These findings were confirmed over a range of pacing rates, in low K+ concentration solutions, and in Scn5a+/ΔKPQ hearts used to model human long QT syndrome. Application of this method in whole anesthetized mice similarly demonstrated a prolonged corrected QT (QTc) in Scn5a+/ΔKPQ hearts. We therefore describe a robust method for the determination of QT and QTc intervals that correlate with the duration of ventricular myocyte APs in murine hearts.

Age‐dependent electrocardiographic changes in Pgc‐1β deficient murine hearts

“…These findings parallel the reduced conduction velocities reported in other arrhythmic genetic models. These had accompanied either fibrotic change or reduced Na + currents resulting from Nav1.5 deficiency in Scn5a +/ − 32, 33, 45 and Scn5a +/ΔKPQ ,21 or secondary to Ca 2+ handling abnormalities in RyR2‐P2328S hearts 44, 46, 47. These findings are also compatible with reports that mitochondrial abnormalities could alter I K and therefore result in current‐load mismatch 6, 30…”

“…ECG deflections related to ventricular activation and recovery confirmed previous reports that murine ECGs lack well‐defined ST segments 17, 44. The murine ECG shows a R' wave deflection, immediately following the S wave not seen in the human ECG.…”

“…A number of authors have suggested that the late component of the R' wave or the R' wave in totality is in fact part of ventricular repolarisation 16, 18, 44. Others suggested that inclusion of the R' wave may lead to systematic overestimation of ventricular activation, whilst its exclusion in genetically modified mouse models, such as that of the Brugada syndrome, which displays slowed conduction, may lead to underestimation of ventricular activation times 18…”

Electrophysiology and metabolism of caveolin-3-overexpressing mice

“…Indeed, when the channel protein expression differences measured in Cav-3 OE mice were used to scale whole-cell ion channel conductances in a mouse ventricular myocyte mode, the APD was shortened. APD 90 and QTc are closely related [68], and the reduction in APD 90 from the model (12% at 6 Hz pacing) was similar to the reduction in QTc measured with telemetry (13%). These results suggest that the increase in K v channel expression is sufficient to explain the QTc decrease in Cav-3 OE mice.…”

“…Continuous telemetry recordings were monitored for 72 hours using Dataquest ART software (Data Sciences International, Inc., St. Paul, MN) and analyzed with the programs default mouse parameters. QTc was measured using previously published derived equations for conscious mice, QTc=QT/SQRT(RR/100) [32, 68]. …”