It is well-known that the heart is the most frequently affected organ during chronic Chagas disease [20], although cardiac affectations can also be detected in the acute phase. The complexity of the T. cruzi life cycle, which involves four distinct morphologically and biochemically well-characterized forms [20], is reflected in the complexity of the infection, which is a pathological condition with many variables including both the parasite and the host and its immune system.

In the acute phase of heart Chagas disease of mammals, the process initiates with the inoculation of the parasite. T. cruzi metacyclic trypomastigotes located in the perianal region of the triatomine vector are released in the feces or urine of the vector after feeding on the host’s blood. These forms can infect the mammalian host through two routes, by contact with mucosa or by penetrating through localized wounds in the epithelium. Once inside the host, the parasite rapidly invades a wide variety of nucleated mammalian cells, including myocytes, endothelial cells, neurons, fibroblasts and adipocytes. These cells are the ones that reside or are recruited into that tissue next to the wound skin [11,19] (Figure 1).

As previously mentioned, the most common DTU of T. cruzi found in Mexico has a marked tropism towards cardiac muscle, specifically to striated cardiac myofibrils. Despite its very rare occurrence (<1%), apparent myocarditis developed during the acute phase has been observed [21], in which myocardial inflammation is similar to those presented by other forms of myocarditis, including those caused by other infectious agents, cardiotoxins and radiation [22]. Once the parasite has infected heart tissue, a fulminant intracardiac replication can occur, with high numbers of amastigote forming amastigote nests, which may lead to myonecrosis, myocytolysis, myofibrils degeneration and intense vasculitis. This will depend largely on the genetic and immunological variants of the parasite and on the host, whose defense system could trigger an intense inflammatory response, which consists primarily of leukocytes, including eosinophils, lymphocytes, macrophages and mast cells, accompanied by increased expression of inflammatory mediators such as cytokines, chemokines and nitric oxide synthase that also complement activation, antibody production and opsonization [20,22,23]. As the disease continues its course, leaving the acute phase and also giving rise to the adaptive immunity, the number of parasitized cells and the inflammatory response decrease considerably, bringing the myocardial tissue to a near-normal state and leaving possible abnormalities such as scarring (interstitial fibrosis), myofiber hypertrophy and continuous minimal inflammation [21]; the whole process usually takes two to four months [20]. In general terms, the characteristics of the acute-phase Chagas cardiomyopathy can range from minimal changes in the heart muscle to dilation of the atria and ventricles in the most severe cases (cardiomegaly); there may also be bundle branch block, diffuse changes of segment ST and T wave, prolonged PR interval and sinus tachycardia [22].

The next step in the course of the disease is chronicity, where the CCC is developed. While this review focuses mainly on heart disorders, it is important to remember that there is another relevant chronic disorder, digestive, which is not so common in Mexico. In chronic phase, many people can live their whole life without any symptoms, most of them without knowing about their infection that probably happened in their childhood.

Once the infection has been present for a few decades, a slow process of inflammation and scarring of the myocardium begins, leading to general changes of heart morphology in approximately 20–30% of infected individuals [21]. These patients may or may not present ventricular failure, a process that is currently classified into five stages according to international recommendations based on ventricular dysfunction [22]. In stage A, which is the only within the chronic indeterminate form, positive serology for Chagas is detected, but no structural heart disease, neither symptoms of heart failure, the electrocardiogram and X-ray are both normal. The stage B includes patients with structural heart disease but who have never had signs or symptoms of heart failure; this phase is divided into two: B1, patients with abnormalities in the electrocardiogram or echocardiography but still without ventricular dysfunction or heart failure, and B2, also with structural heart disease, without signs or symptoms of heart failure, but with a global ventricular dysfunction. Stage C is characterized by ventricular dysfunction and signs or symptoms of heart failure. Finally, stage D encompasses advanced heart failure at rest, despite optimal medical treatment and will therefore require specialized interventions [17,22]. Hearts of patients with chronic Chagas disease are usually fully enlarged, with a dilation of the chamber that predominates over hypertrophy, giving a globular shape; in approximately half of the people who develop chronic disease, the heart shows an unusual thinning of the ventricular wall, which protrudes in the form of an aneurysm [20]. The most frequent and general pathological features of the CCC include low-grade myocarditis associated with myocytolysis, myofiber hypertrophy and interstitial fibrosis [18]. In contrast to the acute phase, in the chronic phase usually only focal areas of inflammation are found that are mainly composed of T cells and macrophages, with a few eosinophils, plasma cells and mast cells; moreover, parasites are rarely observed by conventional microscopic analysis of cardiac biopsy samples [21]. In the final stage of this phase, after suffering severe damage, some patients may need a heart transplantation. The first transplant to end-stage CCC patient was performed in 1985 at the Heart Institute in São Paulo, Brazil [24]. Although initially, it seems that a transplant would resolve the cardiac damage by T. cruzi, the risk of reactivation is quite high and common. The reactivation phenomenon, reported in the early 1960s, occurs mainly in patients who are under cellular suppression, either by whole-body irradiation, hematological malignancies, chemotherapy and immunologically compromised, such as those coinfected with the Human Immunodeficiency Virus (HIV) [24]. The most frequent clinical manifestations in Chagas disease reactivation are usually meningitis, encephalitis [24], myocarditis, inflammatory panniculitis, skin nodules and even fever, signs and symptoms that lead to allograft dysfunction and probably to a rapid onset of heart failure [25]. Reported rates of reactivation in heart transplant recipients with chronic Chagas disease in Latin America vary widely from 20–90%, and the time from transplantation until reactivation of Chagas disease ranges from 11 to 23 weeks [25,26].

According to the most conservative estimations, in Mexico, there are 1.1 million people infected by T. cruzi, both in the acute and chronic phases. Since 2017, the Mexican government has registered both acute and chronic cases in SINAVE Epidemiological Bulletin [12]. However, these reported cases are below the predicted estimates. On the other hand, there is no correlation of heart diseases associated with Chagas disease in its acute and chronic forms, so the estimates indicate that a high percentage of these heart diseases have an origin associated with Chagas disease (Figure 2), and although there are no official data in Mexico, presumptively, some authors have predicted the percentage of cardiac affectations due to Chagas disease, with an approximate of <1% of cardiomyopathies derived from infection in the acute phase [21] and 25% ± 5% in the chronic phase [19]. It is important to consider that the asymptomatic chronic phase contributes with more cases that are not identified or recorded, and therefore, it is possible that the total data of T. cruzi infections are underestimated.

The figure represents the total reported T. cruzi infections in both acute and chronic phases; these data are based on the epidemiological bulletins published by the Ministry of Health in Mexico [12], as well as estimated cardiopathies related to Chagas disease that were predicted according to that described by Rassi et al. 2010 [19] and Bonney et al. 2019 [21], who propose that the prevalence of cardiopathies associated with Chagas disease corresponds to 25% in the chronic phase and less than 1% in the acute phase of the total of reported cases, respectively. The estimated cases of cardiopathies in the chronic phase are represented by double asterisks and with an asterisk the estimated cases of cardiopathies in the acute phase of Chagas disease.