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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.

SUBMITTER: Carvalho EB

PROVIDER: S-EPMC6768978 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Carvalho Eduardo B EB Ramos Isalira P R IPR Nascimento Alvaro F S AFS Brasil Guilherme V GV Mello Debora B DB Oti Martin M Sammeth Michael M Bahia Maria T MT Campos de Carvalho Antonio C AC Carvalho Adriana B AB

Frontiers in cellular and infection microbiology 20190924

<b>Background:</b> 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 frequ ...[more]

PMID: 31616643

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Project description:Background Chronic chagasic cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, is an important public health problem attributable to progressive cardiomyopathy in patients, for which there is no cure. Chronic chagasic cardiomyopathy is characterized by myocarditis and cardiac fibrosis, which leads to life-threatening arrhythmogenic and circulatory abnormalities. This study aimed to investigate cardiac fibrosis progression in a mouse model of chronic chagasic cardiomyopathy. Methods and Results Cardiac cells infected with T cruzi produced significantly higher concentrations of transforming growth factor-β (TGF-β), connective tissue growth factor, endothelin-1, and platelet-derived growth factor-D than noninfected controls. Female Balb/c mice infected with T cruzi were compared with naïve mice. TGF-β genes and other TGF-β superfamily genes, as well as connective tissue growth factor, endothelin-1, and platelet-derived growth factor, were upregulated in infected mouse hearts. Serum concentrations of TGF-β, connective tissue growth factor, and platelet-derived growth factor-D were higher in infected mice and correlated with cardiac fibrosis. Strain analysis performed on magnetic resonance images at 111 and 140 days postinfection and echocardiography images at 212 days postinfection revealed significantly elevated left ventricular strain and cardiac fibrosis and concomitantly significantly decreased cardiac output in infected mice. Conclusions TGF-β, connective tissue growth factor and platelet-derived growth factor-D are potentially useful biomarkers of cardiac fibrosis, as they correlate with cardiac fibrosis. Strain analysis allows for use of noninvasive methods to measure fibrosis in the chronic stages of chagasic cardiomyopathy in a mouse model. These findings can be applied as noninvasive tools to study the effects of interventions and/or therapeutics on cardiac fibrosis development when using a mouse model of chronic chagasic cardiomyopathy.

Project description:Clinical trials often rely on echocardiographic measures of left ventricular size and function as surrogate end points. However, the quantitative impact of factors that affect the reproducibility of these measures is unknown. To address this issue, the National Heart, Lung, and Blood Institute-funded Pediatric Heart Network designed a longitudinal observational study of children with known or suspected dilated cardiomyopathy aged 0 to 22 years from eight pediatric clinical centers.Clinical data were collected together with 150 echocardiographic indices of left ventricular size and function. Separate observers performed duplicate echocardiographic imaging. Multiple observers performed measurements from three cardiac cycles to enable assessment of intraobserver and interobserver variability. The impacts of beat averaging (BA), observer type (local vs core), and variable type (areas, calculations, dimensions, slopes, time intervals, and velocities) on measurement reproducibility were studied. The outcome measure was percentage error (100 × difference/mean).Of 173 enrolled subjects, 131 met criteria for dilated cardiomyopathy. BA, variable type and observer type all influenced percentage error (P < .0001). Core interobserver percentage error (medians, 11.4%, 10.2%, and 9.3% for BA using one, two, and three beats, respectively) was approximately twice the intraobserver percentage error (medians, 6.3%, 4.9%, and 4.2% for BA using one, two, and three beats, respectively). Slopes and calculated variables exhibited high percentage error despite BA. Chamber dimensions, areas, velocities, and time intervals exhibited low percentage error.This comprehensive evaluation of quantitative echocardiographic methods will provide a valuable resource for the design of future pediatric studies. BA and a single core lab observer improve the reproducibility of echocardiographic measurements in children with dilated cardiomyopathy. Certain measurements are highly reproducible, while others, despite BA, are poorly reproducible.

Project description:BackgroundChagasic cardiomyopathy (CCM) caused by Trypanosoma cruzi (Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM.Methods and resultsC57BL/6 mice were infected with Tc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks. Mice were monitored at 150 days post-infection corresponding to chronic disease phase. The cGMP/PKG activity was decreased by 2-fold and PDE5 expression was increased by 1.4-fold and 100% at RNA and protein levels, respectively, in chagasic myocardium. Transthoracic echocardiography showed the left ventricular (LV) systolic function, i.e., stroke volume, cardiac output, and ejection fraction, were significantly decreased in chagasic mice. Sildenafil treatment resulted in normal levels of PDE5 and cGMP/PKG activity and preserved the LV function in chagasic mice. The cardioprotective effects of SIL were provided through inhibition of cardiac collagenosis and chronic inflammation that otherwise were pronounced in CCM. Further, mtDNA-encoded gene expression and ADP-coupled mitochondrial respiration were decreased and mitochondrial oxidative stress and cellular oxidative damage (lipid hydroperoxides and protein carbonyls) were increased in chagasic myocardium. SIL treatment restored the mtDNA-encoded gene expression and complex I (but not complex II) dependent ADP-coupled respiration, and established the oxidant/antioxidant balance in chagasic myocardium. In vitro studies in cardiomyocytes verified that SIL conserved the redox metabolic state and cellular health via maintaining the antioxidant status that otherwise was compromised in response to Tc infection.ConclusionSIL therapy was useful in controlling the LV dysfunction and chronic pathology in CCM.

Dataset Information

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

Publications

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

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