Left ventricular pressure, contractility and dP/dtmax in nonclinical drug safety assessment studies
Left ventricular pressure, contractility and dP/dtmax in nonclinical drug safety assessment studies
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DOI：
10.1016/j.vascn.2012.05.009
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发表时间：
2012-09-01
影响因子：
1.9
通讯作者：
Main, Bradley W.
中科院分区：
文献类型：
--
作者：
Sarazan, R. Dustan;Kroehle, John P.;Main, Bradley W.
增加或降低心肌收缩能力是正在开发的用于非心血管适应症的药物的不良特性。国际协调会议(ICH)主题S7A和S7B指南只要求在非临床体内安全性药理学研究中评估心率、血压和心电图。仅建议将药物对收缩功能影响的评估作为一项可选的后续研究。然而，这些非临床安全性评估研究可以检测到这些影响，如果使用适当的器械进行适当的设计和实施。左心室dp/dt是左心室压力的一阶导数，由软件算法通过微积分计算得到。如果控制好前负荷、后负荷和心率等实验参数，其峰值dp/dt(Max)是反映心脏收缩能力变化的常见、可靠和敏感的指标。为了保证实验动物收缩性能测量的准确性和避免误差，必须对压力传感系统的频率响应和数据采集系统的采样率进行优化。对于狗、非人灵长类动物和血压正常的大鼠来说，左心室压力信号中的所有重要信息都可以通过一个频率响应为100赫兹的系统来捕获。虽然可以使用频率响应高得多的系统来测量左心室压力，但必须对这些设备的输出进行滤波，以允许采集的频率不高于采集系统采样率的一半。相反地，采集系统的采样率必须至少是信号中包含的最高频率的2倍。未能遵循这些原则可能会导致不正确的结果，这是由于来自高频噪声的测量伪影，这些伪影可能存在，但调查者无法检测到。这份手稿是为没有高级物理学和/或工程学知识的生物学家撰写的，因此与工程学文献中的内容相比，技术含量较低，而且更简单。(C)2012 Elsevier Inc.保留所有权利。
Increasing or decreasing cardiac contractility is an undesirable property of drugs being developed for non-cardiovascular indications. The International Conference on Harmonization (ICH) Topic S7A and S7B guidelines only require the assessment of heart rate, blood pressure and the electrocardiogram in nonclinical in vivo safety pharmacology studies. Assessment of drug effects on contractility is only suggested as an optional follow-up study. However, these nonclinical safety assessment studies can detect these effects if properly designed and conducted using appropriate instrumentation. Left ventricular dP/dt is the first derivative of left ventricular pressure, which is computed by software algorithms by using calculus. Its peak value, dP/dt(max), is a common, robust and sensitive indicator of changes in cardiac contractility if experimental parameters such as preload, afterload and heart rate are well controlled. In order to ensure accuracy and avoid errors in the measurement of contractility in experimental animals, the frequency response of the pressure sensing system and the sample rate of the data acquisition system must be optimized for the signal. For dogs, nonhuman primates, and normotensive rats, all important information in a left ventricular pressure signal can be captured with a system with a frequency response of 100 Hz. Although systems with much higher frequency response can be used to measure left ventricular pressure, the output of these devices must be filtered to allow no frequencies to be acquired that are higher than one-half the sample rate of the acquisition system. Stated conversely, the sample rate of the acquisition system must be at least 2x the highest frequency contained in the signal. Failure to follow these principals can lead to incorrect results due to measurement artifacts from high frequency noise, which could be present but not detectable by the investigator. This manuscript has been written for biologists who do not have advanced knowledge of physics and/or engineering and is therefore less technical and more simplified than what would be found in the engineering literature. (C) 2012 Elsevier Inc. All rights reserved.