Echocardiographic Measurements in a Preclinical Model of Chronic Chagasic Cardiomyopathy in Dogs: Validation and Reproducibility

Abstract

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.

DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi

“…Despite the presence of hypertrophic cardiomyopathy, fibrosis in myocardial tissue was not observed when performing the histological analysis, which is characteristic of many chronic diseases, including Chagas disease [70]. There were differences in the diastolic and systolic diameters when comparing the infected/SS mock-treated group and healthy group; and these results are not consistent with similar measurements performed by others who used young mongrel dogs infected with VL-10 strain of T. cruzi and did not find differences in the end-diastolic and end-systolic volumes when comparing infected and noninfected dogs [71]. On the other hand, diastolic and systolic diameters were in accordance with our previous study, in which the use of these recombinant plasmids used as a prophylactic treatment also had a protective effect based on similar parameter values found in both vaccinated and healthy control dogs with the exception of the empty vector (unpublished data).…”

Cardiac diagnostic test results and outcomes in 44 dogs naturally infected with Trypanosoma cruzi

“…Echocardiographic abnormalities described with T. cruzi infection include chamber enlargement and ventricular myocardial dysfunction. 5 , 11 , 12 In humans with Chagas disease, diastolic dysfunction, left atrial enlargement, left and right ventricular systolic dysfunction and ventricular tachycardia are associated with a higher risk of cardiac mortality. 36 In experimental infections in dogs, a reduction in left ventricular fractional shortening occurred over time and the degree of reduction was variable and included hypokinetic wall motion.…”

“…5 , 11 In an experimental model of Chagas disease, 25/78 (32%) dogs inoculated with T. cruzi organisms died 1 to 6 months after infection, and 13 of the 46 (28%) infected dogs that remained alive and had echocardiographic imaging had a variable reduction in left ventricular ejection fraction that occurred 6 to 9 months after infection. 11 Beagles monitored approximately every 10 days after inoculation developed evidence of acute and chronic Chagas disease that included atrioventricular block (AVB), ventricular arrhythmias, segmental thinning and wall motion abnormalities, global systolic dysfunction and biventricular failure over nearly a 10 month period. 6 However normal left ventricular function was also present in dogs with severe myocarditis documented at necropsy.…”

Cardiac Manifestations of Trypanosoma cruzi Infection in a Domestic Dog

“…Chronic infection with T cruzi results in clinical abnormalities in approximately 20% to 30% of infected humans and dogs over the course of months to years in the form of a chronic, progressive myocarditis affecting any of the four cardiac chambers and the conduction system. 10,11 Manifestations of chronic Chagas myocarditis in humans often initially include conduction abnormalities (RBBB or left anterior fascicular block) and ventricular wall motion abnormalities. 1,10 Conduction abnormalities can also affect wall motion, and this may have been a contributing factor in the echocardiographic appearance of the ventricular septum of the dog reported here.…”