Left ventricular pressure, contractility and dP/dt(max) in nonclinical drug safety assessment studies.
Increasing or decreasing cardiac contractility is an undesirable property of drugs being developed for noncardiovascular 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 2× 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.
Data Sciences International, 119 14th St NW, Suite 100. St. Paul, MN 55112, USA. dsarazan@datasci.com
R Dustan
RD
Sarazan
John P
JP
Kroehle
Bradley W
BW
Main
D000818:Animals; D000830:Animals, Laboratory; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000502:physiology; D017725:Ventricular Pressure / Q000187:drug effects* / Q000502:physiology