Animations

Overestimated QTc Prolongation Revealed by QTbtb Analysis: 

Nitroprusside-Induced Reflex Tachycardia: Demonstration of a False-Positive QT Prolongation in a Drug Not Associated with Arrhythmia Liability

Effect of Physiologic Reflex Tachycardia on QT in Humans: Demonstration of a False-Positive QT Prolongation by Conventional QTc Analysis 

Underestimated QTc Prolongation Revealed by QTbtb Analysis: 

Phenylephrine-Induced Reflex Bradycardia:Demonstration of Underestimation of QT Prolongation by Conventional QTc Analysis

Concordance between QTbtb and QTc Analysis in Cases of Direct Repolarization Inhibition:  

Delayed Repolarization Induced by E-403: Demonstration of QT Prolongation Due to Delayed Cardiac Repolarization

Effect of Delayed Cardiac Repolarization on QT Interval in Human Study – Sotalol 

Animation 1: Nitroprusside-Induced Reflex Tachycardia: Demonstration of a False-Positive QT Prolongation in a Drug Not Associated with Arrhythmia Liability

Click to view Dog Nitroprusside

Experiment: In this experiment dogs trained to lie quietly in slings in isolated rooms to ensure no gross cardiac arrhythmias or behavioral irregularities were continuously monitored via telemetry. Each animal was monitored at baseline and during a nitroprusside infusion. Nitroprusside is a drug known to produce an acute drop in blood pressure and increase in heart rate, but has no association with drug-induced arrhythmias. This drug was selected to demonstrate and model the effect of reflex tachycardia on QTc measurements and compare them with the QTbtb measurements.

QT measurements were derived for QTbtb analysis as the boot-strap sampled uncorrected QT values of each of five individual dog’s “QT-RR cloud”. To provide consistent comparison with the QTc methods, the same beats were included in the QTc analyses, corrected using QTcB or QTcF respectively.

Results: The following table summarizes the results of this experiment:

By 2 to 3 min after infusion, the QTbtb had decreased -43 ms from the original baseline. This result is consistent with the dynamic visualization of the data (see animation one). These same beats corrected using the Bazett or Fridericia formulas were interpreted as a prolongation of QTcB (+55 ms) and QTcF (+16 ms), both qualitatively opposing the interpretation from QTbtb and exceeding the threshold of regulatory concern of 10 ms. This experiment demonstrates the breakdown of the conventional QTc method in a situation when a drug causes reflex tachycardia. The sudden drop in BP caused a rapid reduction in RR and QT intervals that resulted in a dramatic divergence from the Bazett and Fridericia HR corrected relationships.

Movie Annotation: Nitroprusside infusion produced a drop in BP with a subsequent reflex tachycardia initiated in all dogs by 1 min and peaked by 3 to 4 min. After nitroprusside, there was no statistically significant increase in the number of outlier beats beyond the upper 95% confidence bounds of the QT-RR interval relationship established at baseline indicating no increased arrhythmia risk. The beats moved downward and to the left due to decrease in QT duration and increase in the heart rate. The return to baseline values followed a different path (upward and to the right) consistent with the physiologic reflex tachycardia loop.  

Animation 2: Phenylephrine-Induced Reflex Bradycardia:Demonstration of Underestimation of QT Prolongation by Conventional QTc Analysis

Click to view Dog Phenylephrine

Experiment: In this experiment dogs trained to lie quietly in slings in isolated rooms to ensure no gross cardiac arrhythmias or behavioral irregularities were continuously monitored via telemetry. Each animal was monitored at baseline and during a phenylephrine infusion. Phenylephrine is a drug known to produce an increase in blood pressure and decrease in heart rate (reflex bradycardia). Phenylephrine is contraindicated in patients with Long QT Syndrome due to elevated arrhythmia risk in this population. This drug was selected to demonstrate and model the effect of reflex bradycardia induced changes in QT and compare the QTbtb analysis with the conventional QTc analyses (QT Bazett and Fridericia).

Results: The following table summarizes the results of this experiment:

By 2 to 3 min after infusion, the QTbtb had increased by 6 ms from the original baseline. This result is consistent with the dynamic visualization of the data (see movie from this experiment). These same beats corrected using the Bazett or Fridericia formulae were interpreted as a shortening of QTcB (-14 ms) and QTcF (-7 ms), qualitatively opposing the interpretation from QTbtb. In addition, the beat-to-beat analysis showed three of the five dogs had a statistically significant increase in the number of outlier beats above the baseline 95% confidence bounds for the QT-RR interval relationship indicating some arrhythmia liability. Conventional QTc analysis in this case significantly underestimated arrhythmia risk associated with the drug. This experiment demonstrates the breakdown of the conventional QTc method in a situation when a drug causes reflex bradycardia.

Movie Annotation: Phenylephrine infusion produced a reflex bradycaria of 12 bpm almost immediately after the infusion. The beats moved to the right and slightly upward consistent with the slowdown of the heart rate, and indicating small but significant delay in cardiac repolarization.  

Animation 3: Delayed Repolarization Induced by E-4031: Demonstration of QT Prolongation Due to Delayed Cardiac Repolarization

Click to view E4031 Dog Fast

Experiment: In this experiment dogs trained to lie quietly in slings in isolated rooms to ensure no gross cardiac arrhythmias or behavioral irregularities were continuously monitored via telemetry. Each animal was monitored at baseline and during an E-4031 infusion. E-4031, a Class 3 anti-arrhythmic, and a known torsadogenic agent was used as a positive control to demonstrate the effect of a drug that causes QT prolongation directly by delayed cardiac repolarization.

Results: The following table summarizes the results of this experiment:

In this experiment both methods (QTbtb and QTc) are in agreement qualitatively. QTbtb appears to be more sensitive in measuring the QT prolongation compared to QTc. It is important to note that according to the conventional QTcB method, nitroprusside appears to be far more arrhythmogenic than the Class 3 anti-arrhythmic E-4031 – a gross misrepresentation of the arrhythmia liability associated with these two agents. Movie Annotation: As E-4031 was infused, mean decreases of 5 to 8 bpm in HR or 4 to 7 mm Hg in BP occurred, and the QTbtb interval was increased 27 ms by 2-3 min post infusion. All four dogs showed a vertical shift of the QT-RR cloud as measured by an increase in the number of outlier beats above the upper confidence bounds of their normal QT-RR interval relationship.  

Animation 4: Effect of Physiologic Reflex Tachycardia on QT in Humans: Demonstration of a False-Positive QT Prolongation by Conventional QTc Analysis

Click to view Standing

Dynamic QTbtb Method in Humans: 

Experiment: In this study, six male volunteers were Holter monitored for beat-to-beat analyses of ECG intervals and T-wave morphologies. Changes were assessed with several autonomic challenges including a rapid standing from supine position (Schellong test). Tests were conducted during a 2-hour period after a morning baseline of 30 minutes on Day 1 then compared to the same protocol performed on a separate day (Day 2). After each autonomic challenge session, subjects were monitored by Holter for the remainder of the approximate 20-hr of normal unstressed-ambulatory activity (eating, sleeping, etc).

Results: The following table summarizes the results of the Rapid Standing experiment in humans:

Dynamic QTbtb measures obtained during autonomic challenge showed substantial differences from traditional measures of QTcB and QTcF. During standing the beat-to-beat measure of QT interval (QTbtb) shows a 2 ms decrease in QT, consistent with the dynamic visualization of the standing experiment, as opposed to 11 to 26 ms prolongation obtained by the two conventional QTc correction methods. The conventional QTc method has significantly over-estimated the QT prolongation in this experiment.  

Animation 5: Effect of Delayed Cardiac Repolarization on QT Interval in Human Study – Sotalol

Animation Coming Soon!

Experiment: In this study data was obtained from 24-hr Holter recording in healthy normal male volunteers at baseline and on 320 mg of sotalol. Sotalol is a known inhibitor of cardiac repolarization and is associated with significant decrease in heart rate. Sotalol has been associated with an increased risk of torsades de pointes (TdP) arrhythmia.

Results: The following table summarizes the results of the Sotalol study in humans:

This experiment demonstrated the conventional QTc analysis under-estimated the prolongation of the QT interval caused by sotalol. While both methods clearly detected the prolongation, the QTcB showed prolongation of only half of that detected by QTbtb. QTbtb result was consistent with the QT prolongation observed in the dynamic visualization of the 24hr on-drug dataset.  

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