The fibro-inflammatory remodeling continuum in Chagas cardiomyopathy: from Trypanosoma cruzi persistence and immune signaling to extracellular matrix reorganization and cardiac dysfunction

Chronic Chagas cardiomyopathy is characterized by persistent myocardial inflammation, heterogeneous fibrosis, and progressive electrical and mechanical dysfunction. However, the mechanisms underlying persistent, progressive fibrosis remain poorly understood. This review proposes a fibro-inflammatory remodeling continuum in which persistent Trypanosoma cruzi infection and myocardial injury activate immune and stromal responses that converge on cardiac fibroblasts, extracellular matrix (ECM) remodeling, and potentially altered tissue mechanics. Evidence in chronic Chagas cardiomyopathy demonstrates that fibrosis constitutes a heterogeneous structural substrate associated with ventricular remodeling, conduction abnormalities, ventricular arrhythmias, and adverse clinical outcomes. Experimental studies indicate that T. cruzi and parasite-derived signals can directly activate cardiac fibroblasts, while macrophage-derived matrix metalloproteinases and transforming growth factor beta (TGFβ) represent important inflammatory pathways involved in fibroblast activation. Molecular circuits involving transforming growth factor beta signaling, imbalances between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), matricellular mediators, and microRNA-21 support a network model rather than a single fibrogenic pathway. Additional inflammatory and post-transcriptional regulators have been implicated, although the roles of fibroblast heterogeneity and spatially organized fibrotic niches in chronic Chagas cardiomyopathy remain unresolved. Mechanobiological signaling pathway involving integrins, focal adhesion kinase, mechanosensitive ion channels, and transcriptional regulators may reinforce fibroblast activation through extracellular matrix remodeling. However, this evidence derives primarily from experimental models of cardiac fibrosis and has not yet been directly demonstrated in chronic Chagas cardiomyopathy. The key unresolved question is whether an initially stimulus-dependent fibrotic response becomes partially self-reinforcing as the myocardial microenvironment is remodeled. Clarifying this transition may help explain inter-individual differences in disease progression and reveal mechanistically informed opportunities for earlier intervention.