Factors affecting the degree of QT prolongation with drug challenge in a large cohort of normal volunteers

Background: The degree of QT prolongation by drug is highly variable and related to risk for polymorphic ventricular tachycardia due to drugs.

Objective: The purpose of this study was to determine factors that affect the degree of QT prolongation by drugs.

Methods: QT and QTc were measured before and after administration of the QT-prolonging drug ibutilide in 253 normal volunteers aged 18 to 40 years. Drug effect on QTc prolongation was defined as ΔQTc = QTc after drug minus QTc before drug.

Results: Ibutilide prolonged QT from 396 ± 31 ms to 418 ± 39 ms (P <.001) and QTc from 406 ± 15 ms to 446 ± 33 ms (P <.001). ΔQTc did not correlate with baseline QTc (Pearson correlation 0.016, P = .8). Postdrug QTc was correlated weakly with predrug QTc (Pearson correlation 0.484, P <.001), and strongly with ΔQTc (Pearson correlation 0.882, P <.001). ΔQTc was identical for men and women (39 ± 29 ms vs 39 ± 27 ms, P = .9) but displayed significant differences among body mass index categories (P <.001). Overweight (48 ± 27 ms) and obese (61 ± 31 ms) subjects had significantly more QT prolongation by drug than normal (31 ± 25 ms) or underweight (24 ± 12 ms) subjects.

Conclusion: QT prolongation by ibutilide does not correlate to baseline QTc and does not differ between men and women. Overweight and obese subjects have greater drug effect on QTc than subjects with normal or low body mass index. These findings have implications for drug-induced long QT syndrome.