Table_2_Echocardiographic Measurements in a Preclinical Model of Chronic Chagasic Cardiomyopathy in Dogs: Validation and Reproducibility.docx

Background: The failure to translate preclinical results to the clinical setting is the rule, not the exception. One reason that is frequently overlooked is whether the animal model reproduces distinctive features of human disease. Another is the reproducibility of the method used to measure treatment effects in preclinical studies. Left ventricular (LV) function improvement is the most common endpoint in preclinical cardiovascular disease studies, while echocardiography is the most frequently used method to evaluate LV function. In this work, we conducted a robust echocardiographic evaluation of LV size and function in dogs chronically infected by Trypanosoma cruzi.Methods and Results: Echocardiography was performed blindly by two distinct observers in mongrel dogs before and between 6 and 9 months post infection. Parameters analyzed included end-systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF), and fractional shortening (FS). We observed a significant LVEF and FS reduction in infected animals compared to controls, with no significant variation in volumes. However, the effect of chronic infection in systolic function was quite variable, with EF ranging from 17 to 66%. Using the cut-off value of EF ≤ 40%, established for dilated cardiomyopathy (DCM) in dogs, only 28% of the infected dogs were affected by the chronic infection.Conclusions: The canine model of CCC mimics human disease, reproducing the percentage of individuals that develop heart failure during the chronic infection. It is thus mandatory to establish inclusion criteria in the experimental design of canine preclinical studies to account for the variable effect that chronic infection has on systolic function.

背景：将临床前研究结果转化为临床环境的情况，通常是常态而非例外。其中，常被忽视的一个原因是动物模型是否能够重现人类疾病的独特特征。另一个原因是临床前研究中用于测量治疗效果的方法的可重复性。在临床前心血管疾病研究中，左心室功能改善是最常见的终点指标，而超声心动图是评估左心功能最常用的方法。在本研究中，我们对感染克氏锥虫的犬只进行了稳健的超声心动图评估，以检测其左心室的大小和功能。方法与结果：超声心动图由两位不同的观察者在感染后6至9个月对混血犬进行盲法检查。分析的参数包括射血期末容积（ESV）、舒张期末容积（EDV）、射血分数（EF）和缩短分数（FS）。我们发现，与对照犬相比，感染犬只的左心射血分数（LVEF）和缩短分数（FS）显著降低，而容积方面则没有显著变化。然而，慢性感染对收缩功能的影响差异很大，射血分数（EF）范围在17%至66%之间。使用为犬只扩张型心肌病（DCM）设定的EF ≤ 40%的截止值，只有28%的感染犬只受到慢性感染的影响。结论：犬只的慢性心肌炎模型模拟了人类疾病，重现了慢性感染期间发展心脏衰竭的个体比例。因此，在犬只临床前研究的实验设计中，必须建立纳入标准，以考虑慢性感染对收缩功能的可变影响。