The evidence compiled in this review underscores a pronounced vulnerability among individuals harboring the T. cruzi parasite, responsible for CD, towards experiencing cerebrovascular incidents. Particularly, those exhibiting the chronic manifestation of the disease manifest an escalated risk for strokes, independent of their cardiac functionality [36]. Notably, among patients encountering a cerebrovascular event, a substantial fraction, up to 30%, tested positive for CD, with this proportion surging to 62.5% in individuals afflicted by both CD and a cerebrovascular incident [37].

This correlation suggests a heightened propensity for stroke development in T. cruzi-infected individuals, particularly within those presenting the chronic form of CD. Predominantly, strokes in these patients are cardioembolic. Literature supports the linkage between CD and embolic-origin strokes, attributing such occurrences to endothelial damage augmentation, diminished blood circulation, and a dysregulation in coagulation factors conducive to thrombus formation [13, 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30, 14, 19, 38].

Corad & Gascon delineated key risk factors for cardioembolic stroke within CD patients, categorizing them into three groups: (1) Cardiomyopathy, including left atrium dilation, progressive heart failure (systolic or diastolic), segmental lesions (left ventricular posterior wall lesion, apical aneurysm); (2) Arrhythmias, specifically right bundle branch block with left anterior hemiblock, advanced atrioventricular block, atrial fibrillation, and sustained ventricular tachycardia; and (3) Mural thrombus. Apical aneurysms (37.23%), left ventricular dilation (23.4%), and mural thrombus (11.7%) are identified as prevalent manifestations [37, 39].

Reports by Barbosa et al. and Calle et al. noted electrocardiogram (EKG) alterations in their cases [11, 13] with approximately 70% of Chagas stroke patients displaying EKG anomalies, including right bundle branch block, left fascicular block, and atrial fibrillation. Such findings, particularly in regions endemic to Chagas, could serve as early warning indicators, enabling healthcare professionals to anticipate and strategize potential stroke interventions and prophylaxis for Chagas patients [40].

Beyond cardioembolic sources, literature also acknowledges non-cardioembolic mechanisms, where chronic inflammation plays a critical role. The infection initiates macrophage activation and iNOS production, infringing upon the vascular endothelium. This cascade, marked by an excessive nitric oxide release due to heightened iNOS activity, potentially suppresses endothelial nitric oxide synthase activity, culminating in vasoconstriction, cerebral microvascular spasms, and ultimately, ischemic strokes. Other implicated causes include large vessel atherothrombosis (8.5%) and small vessel disease (9.6%) [40,41,42].

In patients with CD, four mechanisms implicated in the development of ischemic stroke are identified (Fig. 2): cardioembolisms, microembolisms, chronic inflammation, and watershed infarcts [34].

Mechanisms of Ischemic Stroke Development in Patients with Chagas Disease (CD). This figure delineates the four primary mechanisms implicated in the onset of ischemic stroke in individuals diagnosed with CD: cardioembolisms, microembolisms, chronic inflammation, and watershed infarcts. Each mechanism is a potential pathway through which CD contributes to the increased risk of ischemic stroke, highlighting the complexity of interactions between the disease and cerebrovascular events [34]

Oliveira-Filho, recognizing that existing theories fail to account for the specific nature of brain involvement observed in CD patients, argues for the necessity of a new theoretical framework [34]. He suggests that brain involvement in CD may principally stem from two mechanisms, as depicted in Fig. 3.

Pathways of Increased Ischemic Stroke Risk in Chagas Disease (CD) Patients due to T. cruzi infection. The figure delineates two main mechanisms: structural cardiac alterations by T. cruzi leading to cardioembolic events, and a T. cruzi-triggered immune response causing chronic inflammation that promotes atherosclerosis. Guedes et al. identified an immune imbalance in CD patients—lower regulatory cytokines (GATA-3, FoxP3, IL-10) and higher pro-inflammatory markers (IFN-γ, TNF-α, iNOS)—which correlates with an increased stroke risk and mortality. This immune dysregulation accelerates atherosclerosis, linking CD with ischemic stroke, further evidenced by studies showing a relationship between altered cytokine levels and atherosclerosis progression in CD [34]

The first mechanism involves structural cardiac damage induced by T. cruzi, while the second, a concurrent mechanism, pertains to the immune response to T. cruzi, characterized by chronic inflammation that can accelerate atherosclerosis, thereby increasing the risk of ischemic stroke. Guedes et al. have noted an imbalance in the immune response among CD patients, marked by a predisposition towards stroke and higher mortality rates. This imbalance is characterized by decreased levels of GATA-3, FoxP3, and IL-10, coupled with increased levels of IFN-γ, TNF-α, and iNOS [18]. Further studies have corroborated these findings, indicating that elevated levels of TNF-γ and IFN-γ, alongside reduced levels of IL-10 in individuals with Chagas disease, may hasten the progression of atherosclerosis and subsequently lead to ischemic stroke [43,44,45].

This systematic review is one of first of its kind on this subject. During its execution, we did not find any other systematic reviews published on this topic in the databases used. This review aims to elucidate the complex relationship between stroke and Chagas disease (CD), with the goal of informing and guiding clinical practice and research. Despite the insights gained, numerous aspects of this relationship remain unclear, emphasizing the necessity for further, well-controlled studies to unravel the multifaceted interactions at play. The findings underscore an urgent need for a deeper investigation into the mechanisms underlying stroke in CD, to refine preventative strategies and therapeutic interventions for affected populations.

This systematic review rigorously adheres to PRISMA guidelines but encounters limitations including methodological heterogeneity among included studies, potentially biasing outcomes and affecting generalizability. Language restrictions might have excluded pertinent studies, limiting the evidence base. Additionally, the exclusion of gray literature and studies focusing solely on cardiac complications unrelated to stroke could contribute to publication bias and overlook interconnected cardiovascular insights. The absence of analyses on ethnic, gender and environmental factors further restricts the review’s applicability across diverse populations. Outcome assessment heterogeneity complicates definitive conclusions regarding CD and stroke risk. These factors necessitate cautious interpretation of the findings and underscore the need for further research to address these gaps, standardize outcomes, and enhance our understanding of CD’s impact on stroke, informing clinical and public health practices.