{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T09:43:13Z","timestamp":1768556593912,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T00:00:00Z","timestamp":1700179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T015969\/1"],"award-info":[{"award-number":["MR\/T015969\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R021430\/1"],"award-info":[{"award-number":["MR\/R021430\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Drugs for Neglected Diseases Initiative (DNDi)","award":["MR\/T015969\/1"],"award-info":[{"award-number":["MR\/T015969\/1"]}]},{"name":"Drugs for Neglected Diseases Initiative (DNDi)","award":["MR\/R021430\/1"],"award-info":[{"award-number":["MR\/R021430\/1"]}]},{"name":"Foreign, Commonwealth &amp; Development Office (FCDO), UK","award":["MR\/T015969\/1"],"award-info":[{"award-number":["MR\/T015969\/1"]}]},{"name":"Foreign, Commonwealth &amp; Development Office (FCDO), UK","award":["MR\/R021430\/1"],"award-info":[{"award-number":["MR\/R021430\/1"]}]},{"name":"Federal Ministry of Education and Research (BMBF) through KfW, Germany","award":["MR\/T015969\/1"],"award-info":[{"award-number":["MR\/T015969\/1"]}]},{"name":"Federal Ministry of Education and Research (BMBF) through KfW, Germany","award":["MR\/R021430\/1"],"award-info":[{"award-number":["MR\/R021430\/1"]}]},{"name":"M\u00e9decins sans Fronti\u00e8res (MSF) International","award":["MR\/T015969\/1"],"award-info":[{"award-number":["MR\/T015969\/1"]}]},{"name":"M\u00e9decins sans Fronti\u00e8res (MSF) International","award":["MR\/R021430\/1"],"award-info":[{"award-number":["MR\/R021430\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Chronic Chagas cardiomyopathy (CCC) results from infection with the protozoan parasite Trypanosoma cruzi and is a prevalent cause of heart disease in endemic countries. We previously found that cardiac fibrosis can vary widely in C3H\/HeN mice chronically infected with T. cruzi JR strain, mirroring the spectrum of heart disease in humans. In this study, we examined functional cardiac abnormalities in this host:parasite combination to determine its potential as an experimental model for CCC. We utilised electrocardiography (ECG) to monitor T. cruzi-infected mice and determine whether ECG markers could be correlated with cardiac function abnormalities. We found that the C3H\/HeN:JR combination frequently displayed early onset CCC indicators, such as sinus bradycardia and right bundle branch block, as well as prolonged PQ, PR, RR, ST, and QT intervals in the acute stage. Our model exhibited high levels of cardiac inflammation and enhanced iNOS expression in the acute stage, but denervation did not appear to have a role in pathology. These results demonstrate the potential of the C3H\/HeN:JR host:parasite combination as a model for CCC that could be used for screening new compounds targeted at cardiac remodelling and for examining the potential of antiparasitic drugs to prevent or alleviate CCC development and progression.<\/jats:p>","DOI":"10.3390\/pathogens12111364","type":"journal-article","created":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T09:10:38Z","timestamp":1700212238000},"page":"1364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cardiac Abnormalities in a Predictive Mouse Model of Chagas Disease"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3475-8130","authenticated-orcid":false,"given":"Amanda Fortes","family":"Francisco","sequence":"first","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0085-3882","authenticated-orcid":false,"given":"Giovane R.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Section on Immunobiology, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mhairi","family":"Vaughan","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, Cancer Institute, Faculty of Medical Sciences, University College London, London WC1E 6DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry","family":"Langston","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Archie","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiromani","family":"Jayawardhana","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4147-0693","authenticated-orcid":false,"given":"Martin C.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9540-3280","authenticated-orcid":false,"given":"Michael D.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Infection Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,17]]},"reference":[{"key":"ref_1","unstructured":"(2023, November 15). World Health Organization (WHO). Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/chagas-disease-(american-trypanosomiasis)."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"510","DOI":"10.2174\/156652408785748004","article-title":"Chagas heart disease pathogenesis: One mechanism or many?","volume":"8","author":"Bonney","year":"2008","journal-title":"Curr. Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0140-6736(17)31612-4","article-title":"Chagas disease","volume":"391","author":"Molina","year":"2018","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1146\/annurev-pathol-020117-043711","article-title":"Pathology and pathogenesis of Chagas heart disease","volume":"24","author":"Bonney","year":"2019","journal-title":"Annu. Rev. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pack, A.D., and Collins, M.H. (2018). Highly competent, non-exhausted CD8+ T cells continue to tightly control pathogen load throughout chronic Trypanosoma cruzi infection. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007410"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s00281-015-0481-9","article-title":"CD8+ T cells in Trypanosoma cruzi infection","volume":"37","author":"Tarleton","year":"2015","journal-title":"Semin. Immunopathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1002\/clc.22421","article-title":"The Epidemiology, Clinical manifestations, and management of Chagas heart disease","volume":"38","author":"Malik","year":"2015","journal-title":"Clin. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nrcardio.2012.109","article-title":"Diagnosis and management of Chagas disease and cardiomyopathy","volume":"9","author":"Ribeiro","year":"2012","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Rojas, L.Z., and Glisic, M. (2018). Electrocardiographic abnormalities in Chagas disease in the general population: A systematic review and meta-analysis. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006567"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1590\/0037-8682-0184-2018","article-title":"Electrocardiogram in Chagas disease","volume":"51","author":"Brito","year":"2018","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e014176","DOI":"10.1161\/JAHA.119.014176","article-title":"Risk score for predicting 2-Year mortality in patients with Chagas cardiomyopathy from endemic areas: SaMi-Trop Cohort Study","volume":"9","author":"Nunes","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1007\/s10554-021-02508-5","article-title":"Longitudinal strain by speckle tracking and echocardiographic parameters as predictors of adverse cardiovascular outcomes in chronic Chagas cardiomyopathy","volume":"38","author":"Rojas","year":"2022","journal-title":"Int. J. Cardiovasc. Imaging."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1620\/tjem.240.243","article-title":"Chagas Disease in Mexico: Report of 14 Cases of Chagasic Cardiomyopathy in Children","volume":"240","year":"2016","journal-title":"Tohoku. J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.actatropica.2014.07.005","article-title":"Trypanosoma cruzi strains cause different myocarditis patterns in infected mice","volume":"139","author":"Rodriguez","year":"2014","journal-title":"Acta Trop."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Queiroga, T.B.D., and Pereira, N.S. (2021). Virulence of Trypanosoma cruzi strains is related to the differential expression of innate immune receptors in the heart. Front Cell Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.696719"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1111\/cmi.12584","article-title":"Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy","volume":"18","author":"Lewis","year":"2016","journal-title":"Cell Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.actatropica.2016.12.015","article-title":"Host genetics background influence in the intragastric Trypanosoma cruzi infection","volume":"167","author":"Caldas","year":"2017","journal-title":"Acta Trop."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00832-18","DOI":"10.1128\/AAC.00832-18","article-title":"Assessing the effectiveness of curative benznidazole treatment in preventing chronic cardiac pathology in experimental models of Chagas disease","volume":"62","author":"Francisco","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.1073\/pnas.94.8.3932","article-title":"\u201cAutoimmune rejection\u201d of neonatal heart transplants in experimental Chagas disease is a parasite-specific response to infected host tissue","volume":"94","author":"Tarleton","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1016\/j.ajpath.2014.12.023","article-title":"Autoimmune pathogenesis of Chagas heart disease: Looking back, looking ahead","volume":"185","author":"Bonney","year":"2015","journal-title":"Amer. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1111\/cmi.12297","article-title":"Bioluminescence imaging of chronic Trypanosoma cruzi infections reveals tissue-specific parasite dynamics and heart disease in the absence of locally persistent infection","volume":"16","author":"Lewis","year":"2014","journal-title":"Cell Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.pt.2016.08.009","article-title":"Putting Trypanosoma cruzi dynamics at the heart of Chagas disease","volume":"32","author":"Lewis","year":"2016","journal-title":"Trends. Parasitol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1177\/1087057114552623","article-title":"A new experimental model for assessing drug efficacy against Trypanosoma cruzi infection based on highly sensitive in vivo imaging","volume":"20","author":"Lewis","year":"2015","journal-title":"J. Biomolec. Screen."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.ab.2009.09.009","article-title":"Red-emitting luciferases for bioluminescence reporter and imaging applications","volume":"396","author":"Branchini","year":"2010","journal-title":"Anal. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1073\/pnas.0305284101","article-title":"Electrocardiographic and other cardiac anomalies in beta-glucuronidase-null mice corrected by nonablative neonatal marrow transplantation","volume":"101","author":"Schuldt","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/cvr\/cvp029","article-title":"Structural and functional cardiac cholinergic deficits in adult neurturin knockout mice","volume":"82","author":"Mabe","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"H1907","DOI":"10.1152\/ajpheart.00681.2008","article-title":"Genetic influence on electrocardiogram time intervals and heart rate in aging mice","volume":"296","author":"Xing","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1016\/S0002-9440(10)63222-1","article-title":"Interferon-gamma-induced nitric oxide causes intrinsic intestinal denervation in Trypanosoma cruzi-infected mice","volume":"164","author":"Arantes","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1645\/GE-2396.1","article-title":"ECG detection of murine chagasic cardiomyopathy","volume":"96","author":"Eickhoff","year":"2010","journal-title":"J. Parasitol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1016\/j.ijcard.2012.09.020","article-title":"Novel insights into the development of chagasic cardiomyopathy: Role of PI3Kinase\/NO axis","volume":"167","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Navarro, I.C., and Ferreira, F.M. (2015). MicroRNA transcriptome profiling in heart of Trypanosoma cruzi-infected mice: Parasitological and cardiological outcomes. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003828"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Vilar-Pereira, G., and Carneiro, V.C. (2016). Resveratrol reverses functional Chagas heart disease in mice. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005947"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Carbajosa, S., and Rodr\u00edguez-Angulo, H.O. (2018). L-arginine supplementation reduces mortality and improves disease outcome in mice infected with Trypanosoma cruzi. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006179"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Santos-Miranda, A., and Joviano-Santos, J.V. (2020). Reactive oxygen species and nitric oxide imbalances lead to in vivo and in vitro arrhythmogenic phenotype in acute phase of experimental Chagas disease. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1009049"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/B978-0-12-385895-5.00009-8","article-title":"Neurodegeneration and neuroregeneration in Chagas disease","volume":"76","author":"Chuenkova","year":"2011","journal-title":"Adv. Parasitol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1113\/jphysiol.2013.270306","article-title":"Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology","volume":"592","author":"Zhang","year":"2014","journal-title":"J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1161\/CIRCULATIONAHA.108.846402","article-title":"Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice","volume":"120","author":"Burger","year":"2009","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1083\/jcb.200110134","article-title":"MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction","volume":"158","author":"Harada","year":"2002","journal-title":"J. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.nbd.2006.09.003","article-title":"Interferon-gamma induced nitric oxide mediates in vitro neuronal damage by Trypanosoma cruzi-infected macrophages","volume":"25","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e01242-20","DOI":"10.1128\/mBio.01242-20","article-title":"In vivo analysis of Trypanosoma cruzi persistence foci at single-cell resolution","volume":"11","author":"Ward","year":"2020","journal-title":"mBio"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1126\/science.1200708","article-title":"Transient regenerative potential of the neonatal mouse heart","volume":"331","author":"Porrello","year":"2011","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1002\/clc.4960231205","article-title":"Chagas\u2019 heart disease","volume":"23","author":"Rassi","year":"2000","journal-title":"Clin. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1161\/CIRCULATIONAHA.112.123612","article-title":"Ten-year incidence of Chagas cardiomyopathy among asymptomatic Trypanosoma cruzi-seropositive former blood donors","volume":"127","author":"Sabino","year":"2013","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hevia-Montiel, N., and Perez-Gonzalez, J. (2022). Machine Learning-Based Feature Selection and Classification for the Experimental Diagnosis of Trypanosoma cruzi. Electronics, 11.","DOI":"10.3390\/electronics11050785"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.bjid.2020.08.007","article-title":"Role of FAK signaling in chagasic cardiac hypertrophy","volume":"24","author":"Tucci","year":"2020","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"495","DOI":"10.4269\/ajtmh.2007.77.495","article-title":"Electrocardiographic characteristics in a population with high rates of seropositivity for Trypanosoma cruzi infection","volume":"77","author":"Magalhaes","year":"2007","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Khan, A.A., and Langston, H.C. (2021). Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale. PLoS Pathogens., 17.","DOI":"10.1101\/2021.03.09.434577"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Haro, P., and Hevia-Montiel, N. (2023). ECG marker evaluation for the machine-learning-based classification of acute and chronic phases of Trypanosoma cruzi infection in a murine model. Trop. Med. Infect. Dis., 8.","DOI":"10.3390\/tropicalmed8030157"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/11\/1364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:24:31Z","timestamp":1760131471000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/11\/1364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,17]]},"references-count":49,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["pathogens12111364"],"URL":"https:\/\/doi.org\/10.3390\/pathogens12111364","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,17]]}}}