The predictive ability of the QT response in supine-standing test for drug induced QT prolongation

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: None. INTRODUCTION: A significant cause of sudden cardiac death is arrhythmias induced by QT prolongation. The acquired long QT syndrome is much more common than the congenital form. A major cause of acquired long QT prolongation is drug exposure. Drug-induced QT prolongation is common when taking cardiac drugs such as antiarrhythmics but also common with other medication groups such as antibiotics, antihistamines, and psychiatric drugs. These medications prolong QT by inhibiting the HERG channel which controls the rectifier potassium current (IKr) and prolong depolarization. As HERG inhibition is multifactorial an individual’s effect of medications on QT is difficult to predict and thus leaving many patients with significant risk once they initiate treatment with such medications. In the last decade, tests that measure the QT reaction to sudden changes in heart rate while changing position for supine to standing have shown usefulness in assessing the possibility of congenital long QT in patients with equivocal QT interval, probably by measuring the repolarization reserve which is deficient in patients with congenital long QT syndrome. Lol PURPOSE: We sought to identify whether the same tests can be useful in prediction of acquired QT prolongation after exposure to HERG potassium channel suppressing medications. METHODS: Fifty four healthy volunteers undergone a supine-standing test where QT changes: QT stretching, and QT stunning were examined after brisk standing. Afterward the volunteers received one 400 mg dose of moxifloxacin, a drug known to prolong QT by affecting the HERG channel. Results of the standing test were compared to the drug effects on QTc and predictive ability was assessed. RESULTS: There was no significant correlation between the maximal drug evoked QTc prolongation and either change in QTc during the stretching or stunning phase (R=0.090, p= 0.538 and R=0.224, p=0.176 accordingly). Both stunning and stretching tests results did not differ significantly between patient with a significant (>20msecs) QT prolongation in response to drugs and no such prolongation (p> 0.361). The area under the ROC curves of the QTc prolongation during both phases stunning phase did not show usefulness in predicting substantial QTc prolongation (>20msec) during drug therapy with an AUCs of 0.593 (95% CI 0.418-0.769) and 0.617 (95%CI 0.375-0.859) accordingly. CONCLUSIONS: Repolarization reserve assessment using a simple brisk standing test did not efficiently aid in predict QT drug response in patients treated with HERG inhibiting drugs. [Figure: see text] [Figure: see text]