King Andrew, Bailie Marc, Olivier N Bari
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
Ann Noninvasive Electrocardiol. 2006 Oct;11(4):289-98. doi: 10.1111/j.1542-474X.2006.00120.x.
Accurate detection of drug-induced QT interval changes is often confounded by concurrent heart rate changes. Application of heart rate correction formulas has been the traditional approach to account for heart rate-induced QT interval changes, and thereby identify the direct effect of the test article on cardiac repolarization. Despite numerous recent studies identifying the imprecision of these formulas they continue to be applied.
Using a chronic atrioventricular dissociated His-paced canine model, heart rate correction methods were evaluated for their ability to generate a corrected QT interval independent of original heart rate. Additionally, His bundle pacing at a heart rate of 60 beats/min allowed calculation of the magnitude of error introduced by application of heart rate correction formulas.
Of the fixed parameter heart rate correction formulas, only Van de Water was able to predict corrected QT values independent of the original heart rate. The magnitude of error discovered by application of heart rate correction formulas varied, but in many cases was very large. Bazett's formula was associated with a mean overcorrection of 67.9 ms; Fridericia's 28.7 ms. Van de Water was the best fixed parameter formula with a mean error of 10.8 ms. As expected, group and individual corrections derived from linear regression of the HR-QT data offered improvement over the traditional formulas. Both were able to predict QTc values independent of the heart rate. However, errors of the magnitude of 10 and 6 ms, respectively, were still introduced.
Van de Water and linear regression correction methods were superior to others in this study, but all methods generated QTc errors equal to or much greater than the magnitude of interest for drug safety evaluation.
药物诱导的QT间期变化的准确检测常常因同时发生的心率变化而混淆。应用心率校正公式一直是解释心率引起的QT间期变化从而确定受试物对心脏复极化直接作用的传统方法。尽管最近有大量研究指出这些公式不准确，但它们仍在被应用。
使用慢性房室分离的希氏束起搏犬模型，评估心率校正方法生成独立于原始心率的校正QT间期的能力。此外，以60次/分钟的心率进行希氏束起搏可计算应用心率校正公式引入的误差大小。
在固定参数心率校正公式中，只有范德沃特公式能够预测独立于原始心率的校正QT值。应用心率校正公式发现的误差大小各不相同，但在许多情况下非常大。巴泽特公式的平均过度校正为67.9毫秒；弗里德里西亚公式为28.7毫秒。范德沃特公式是最佳的固定参数公式，平均误差为10.8毫秒。正如预期的那样，从HR-QT数据的线性回归得出的组校正和个体校正比传统公式有所改进。两者都能够预测独立于心率的QTc值。然而，分别仍引入了10毫秒和6毫秒大小的误差。
在本研究中，范德沃特公式和线性回归校正方法优于其他方法，但所有方法产生的QTc误差等于或远大于药物安全性评估所关注的大小。
