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Review
. 2024 May 10;134(10):1379-1397.
doi: 10.1161/CIRCRESAHA.124.324507. Epub 2024 May 9.

Arrhythmogenic Manifestations of Chagas Disease: Perspectives From the Bench to Bedside

Danilo Roman-Campos  1 , José Antonio Marin-Neto  2 , Artur Santos-Miranda  3 , Nathan Kong, André D'Avila, Anis Rassi Jr  4
Affiliations
Review

Arrhythmogenic Manifestations of Chagas Disease: Perspectives From the Bench to Bedside

Danilo Roman-Campos et al. Circ Res. .

Abstract

Chagas cardiomyopathy caused by infection with the intracellular parasite Trypanosoma cruzi is the most common and severe expression of human Chagas disease. Heart failure, systemic and pulmonary thromboembolism, arrhythmia, and sudden cardiac death are the principal clinical manifestations of Chagas cardiomyopathy. Ventricular arrhythmias contribute significantly to morbidity and mortality and are the major cause of sudden cardiac death. Significant gaps still exist in the understanding of the pathogenesis mechanisms underlying the arrhythmogenic manifestations of Chagas cardiomyopathy. This article will review the data from experimental studies and translate those findings to draw hypotheses about clinical observations. Human- and animal-based studies at molecular, cellular, tissue, and organ levels suggest 5 main pillars of remodeling caused by the interaction of host and parasite: immunologic, electrical, autonomic, microvascular, and contractile. Integrating these 5 remodeling processes will bring insights into the current knowledge in the field, highlighting some key features for future management of this arrhythmogenic disease.

Keywords: Chagas cardiomyopathy; Chagas disease; Trypanosoma cruzi; arrhythmias, cardiac; cardiovascular system; myocytes, cardiac; ventricular remodeling.

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Conflict of interest statement

Disclosures None.

Figures

Figure 1.
Figure 1.
The clinical course of Trypanosoma cruzi (T. cruzi) infection and influential factors in the pathogenesis and progression of Chagas disease. *The overall mortality rate for acute Chagas disease, encompassing both asymptomatic and symptomatic cases, ranges from 1 in 100 to 1 in 200 cases.
Figure 2.
Figure 2.
Chagas cardiomyopathy (CCM): a quintet of interrelated remodeling processes. The progression of Chagas disease from the indeterminate (asymptomatic) form to CCM, which occurs in up to 40% of infected individuals, is guided by 5 intimately linked remodeling processes. These processes collectively shape the pathophysiological landscape of the disease. Central to the pathogenesis of CCM is the interplay among ongoing parasite infection, Trypanosoma cruzi strain, the patient’s genetic vulnerability, and their immune system’s reaction, influencing the clinical progression of the disease into its major syndromes: arrhythmias, heart failure, and thromboembolism.
Figure 3.
Figure 3.
RASSI score. This illustration presents the RASSI score, comprising 6 independent all-cause mortality predictors, with their associated points inside the circles. It shows the division into 3 risk categories and displays both the 5- and 10-year overall mortality rates, alongside the Kaplan-Meier survival curves for each risk subgroup. Of note, all these variables were also strong predictors of the risk of cardiovascular deaths and sudden cardiac deaths, except for the male sex, which was of borderline significance for the prediction of cardiovascular death, and low QRS voltage, which was of borderline significance for the prediction of sudden cardiac death. HR indicates heart rate; NSVT, nonsustained ventricular tachycardia; NYHA, New York Heart Association; and WMA, wall motion abnormality. *Cardiothoracic ratio >0.50. †≥3 beats and duration <30 s (HR >100 bpm). ‡≤ 0.5 mV in all limb leads.
Figure 4.
Figure 4.
Electrical remodeling and arrhythmogenic mechanisms in Chagas cardiomyopathy (CCM). The infection with Trypanosoma cruzi (T. cruzi) initiates a complex sequence of alterations in cardiac myocytes that significantly disrupts the heart’s rhythm and contractile function. CCM is characterized by a cascade of events that include impaired calcium influx through attenuated L-type calcium channels (ICa-L), which is essential for triggering the release of calcium from the sarcoplasmic reticulum (SR) through the RyR2 (ryanodine receptor type 2). This disruption leads to insufficient release of calcium ions during systole, affecting myocardial contractility. Concurrently, the reuptake of calcium by the SR during diastole, mediated by a dysfunctional SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) pump, causes a harmful cytosolic calcium overload. Additionally, disruptions in the function of potassium channels have also been observed. There is a marked attenuation of the transient outward potassium current (Ito) and the delayed rectifier potassium current (Ik) that are essential for the repolarization phase of the cardiac action potential (AP). This dysfunction results in a prolonged AP duration, creating a favorable environment for early afterdepolarizations (EADs). In parallel, the heart’s electrical connectivity is impaired due to a reduction in Cx43 (connexin-43) expression, disrupting the spread of electrical impulses and leading to disordered anisotropic conduction and desynchronized myocardial contractions. The compromised ionic balance triggers the activation of compensatory mechanisms, such as the sodium-calcium exchanger (NCX), which acts to expel excess calcium from the cell. This compensatory increase, depicted as enhanced transient inward current (Iti) in the diagram, may inadvertently become counterproductive, potentially precipitating additional electrical irregularities that can provoke delayed afterdepolarizations (DADs) during the heart diastolic phase. Oxidative stress further aggravates the situation, with increased levels of reactive oxygen species (ROS) and NO promoting the hyperactivation of CaMKII (Ca2+/calmodulin-dependent protein kinase II). This enzyme, when overstimulated, can modify the function of ion channels and calcium-handling proteins, further promoting the development of arrhythmias. In summary, arrhythmogenesis in CCM is characterized by calcium mishandling, ionic current imbalances, reduced intercellular communication, and oxidative stress. This comprehensive depiction of electrical remodeling may provide insights into the potential therapeutic targets for mitigating the progression of cardiac arrhythmias and myocardial dysfunction in CCM.
Figure 5.
Figure 5.
Multifaceted cardiac remodeling in Chagas cardiomyopathy (CCM). The clinical course of CCM is characterized by a complex cascade of pathological remodeling processes that encompasses 5 distinct but interrelated phenomena: immunologic, electrical, structural, autonomic, and microvascular. The initial immune response to Trypanosoma cruzi (T. cruzi) infection is a combination of innate and adaptive mechanisms. Innate immunity involves dendritic cells (DCs), natural killer (NK) cells and macrophages, releasing a cascade of inflammatory cytokines such as IFN-γ (interferon gamma), TNF-α (tumor necrosis factor-alpha), IL (interleukin)-1β, TGF-β (transforming growth factor-beta), IL-12 and IL-10, while the adaptive immune response involves T cells and B cells. Although the immune response aims to control the infection, it also induces a state of persistent inflammation and oxidative stress, potentially leading to myocardial injury. Concurrently, the heart undergoes electrical remodeling. This is characterized by a disruption in ion channels’ function and gap junction connectivity, along with aberrant calcium handling, culminating in electrical instability. The consequence is an increased susceptibility to various forms of arrhythmias, ranging from benign premature ventricular contractions (PVCs) to serious ventricular arrhythmias, which can precipitate sudden cardiac death. As the heart faces persistent inflammation and imbalanced immune responses, structural changes ensue. On a microscopic level, there is an accumulation of myocardial fibrosis, scarring, and apoptosis of cardiac cells. Macroscopically, these changes manifest as segmental wall motion abnormalities (WMA) and dilatation of the left ventricle (LV) and right ventricle (RV). The autonomic nervous system is equally affected, undergoing early functional remodeling. The cardiac autonomic innervation, pivotal in modulating heart rate and rhythm, is disrupted through parasympathetic and sympathetic denervation, increasing the propensity for arrhythmogenesis and exacerbating the progression of cardiac dysfunction. Finally, the microcirculations are not spared in this pathogenic odyssey. Microvascular remodeling is characterized by ischemia in watershed zones between the main coronary arteries, leading to the formation of the characteristic aneurysmatic lesions at 2 principal sites of the left ventricle: the apex and the inferolateral wall. In summary, this figure succinctly captures the intricate and interconnected nature of cardiac remodeling induced by CCM, emphasizing the sequential development of ventricular arrhythmias as a hallmark of the disease. Yet, it is critical to acknowledge that ventricular arrhythmias do not always follow a predictable pattern in relation to myocardial changes, indicating a need for nuanced understanding in clinical assessment and management. This multidimensional model underscores the critical points for potential therapeutic intervention and highlights the necessity of a comprehensive approach to mitigate the adverse outcomes associated with CCM. NSVT indicates nonsustained ventricular tachycardia; ROS, reactive oxygen species; SVT, sustained ventricular tachycardia, and VF, ventricular fibrillation.
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