Circulating MicroRNAs and myocardial involvement severity in chronic Chagas cardiomyopathy

Abstract

BackgroundChronic Chagas Cardiomyopathy (CCM) is characterized by a unique pathophysiology in which inflammatory, microvascular and neuroendocrine processes coalesce in the development of one of the most severe cardiomyopathies affecting humans. Despite significant advances in understanding the molecular mechanisms involved in this disease, scarce information is available regarding microRNAs and clinical parameters of disease severity. We aimed to evaluate the association between circulating levels of six microRNAs with markers of myocardial injury and prognosis in this population.MethodsPatients with CCM and reduced ejection fraction were included in a prospective exploratory cohort study. We assessed the association of natural log-transformed values of six circulating microRNAs (miR-34a-5p, miR-208a-5p, miR-185-5p, miR-223-5p, let-7d-5p, and miR-454-5p) with NT-proBNP levels and echocardiographic variables using linear regression models adjusted for potential confounders. By using Cox Proportional Hazard models, we examined whether levels of microRNAs could predict a composite outcome (CO), including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD). Finally, for mRNAs showing significant associations, we predicted the target genes and performed pathway analyses using Targetscan and Reactome Pathway Browser.ResultsSeventy-four patients were included (59% males, median age: 64 years). After adjustment for age, sex, body mass index, and heart failure medications, only increasing miR-223-5p relative expression levels were significantly associated with better myocardial function markers, including left atrium area (Coef. -10.2; 95% CI -16.35; -4.09), end-systolic (Coef. -45.3; 95% CI -74.06; -16.61) and end-diastolic volumes (Coef. -46.1; 95% CI -81.99; -10.26) of the left ventricle. Moreover, we observed that higher miR-223-5p levels were associated with better left-ventricle ejection fraction and lower NT-proBNP levels. No associations were observed between the six microRNAs and the composite outcome. A total of 123 target genes for miR-223-5p were obtained. From these, several target pathways mainly related to signaling by receptor tyrosine kinases were identified.ConclusionsThe present study found an association between miR-223-5p and clinical parameters of CCM, with signaling pathways related to receptor tyrosine kinases as a potential mechanism linking low levels of miR-223-5p with CCM worsening.

Unraveling the role of miRNAs as biomarkers in Chagas cardiomyopathy: Insights into molecular pathophysiology

“…Further, although the exact mechanism by which miRNAs are involved in ChCM pathophysiology remains unclear, studies have revealed that the biogenesis of miRNAs implicated in cardiac physiology is affected by T . cruzi infection, and thus miRNAs could potentially serve as prospective biomarkers for ChCM [ 11 – 14 , 20 – 22 ].…”

“…In the context of ChCM, various studies have explored miRNAs’ expression profiles in patients and identified specific miRNAs that are dysregulated in cardiac tissues [ 11 – 14 ]. These findings suggest that miRNAs could be potential biomarkers for diagnosing ChCM and monitoring disease progression [ 12 , 20 ].…”

microRNAs: Critical Players during Helminth Infections

“…Since miRNA expression changes during pathogen infection, they have been proposed as a tool for the prevention, diagnosis, prognosis, treatment, and control of parasitic diseases [ 16 , 22 , 23 , 24 ]. In addition, several miRNAs have been suggested as biomarkers of some parasitic diseases’ different phases and severity [ 24 , 25 , 26 ].…”

Blood DNA methylation marks discriminate Chagas cardiomyopathy disease clinical forms

“…BNP and NT-proBNP, well-known markers be associated with cardiac dysfunction ( 14 ), have been associated to Chagas cardiomyopathy ( 15 , 16 ), but are not specific to this pathology. Others markers, including miRNAs ( 17 , 18 ), cytokines ( 19 ) or metalloproteinases ( 20 ) have been proposed as biomarkers for CCC, but no confirmation has been made in a test cohort at this time. The only diagnosis of CCC currently in place is a clinical diagnosis, which is difficult to access for the most remote populations.…”