Ventricular repolarization can be affected by direct ion channel inhibition as well as through changes in the autonomic state (heart rate, blood pressure, sleep, etc.). Some drugs cause QT interval prolongation directly. Others may affect the QT interval indirectly by changing autonomic state. Still others trigger a combination of the two. Accurate interpretation of the QT interval, therefore, is critical to prevent beneficial medicines from being terminated in development due to over-estimation of the QT interval prolongation (Nitroprusside Animation: QT Over-estimation), as well as to prevent underestimation of pathophysiological QT (Phenylephrine Animation: QT under-estimation) prolongation. Methods to normalize the QT interval for changes in heart rate have been described since early last century but these linear approaches have significant limitations when applied in drug safety evaluation.

iCardiac’s Dynamic QT btb analysis overcomes the limitations of standard QT heart rate correction methodologies. It provides a more physiologically sound assessment of drug effect on cardiac repolarization because it addresses the dynamicity of the QT-RR relationship.

The conventional formulae for heart rate correction (QTc Bazett’s, Fridericia, individualized, etc.) work well only when the subject’s heart rate does not significantly deviate from approximately 60 beats per minute. These linear correction methods utilize averaged sampled data from several time points. While this averaging simplifies computation, it also has a significant potential to distort the representation of the true physiologic phenomena observed in a 24 hour Holter dataset. Moreover, linear correction methods do not address subject-specific differences in QT-RR dynamics.

Drugs that affect the autonomic state by lowering blood pressure and inducing reflex tachycardia have a very high probability of a false positive or overestimated QTc prolongation finding. Conversely, drugs that increase blood pressure and induce reflex bradycardia have the potential – albeit small -- of causing a false negative or underestimated QTc prolongation finding. Linear correction methods should be supplemented with methods that address the dynamic nature of the QT-RR relationship and ensure an accurate assessment of the drug’s effect on the QT interval.

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