Infectious diseases are the main cause of acquired dilated cardiomyopathy. This group of disorders shares in common inflammatory cell infiltrate and myocardial remodeling. As part of its pathophysiology, there is coronary microvascular dysfunction, distinct from that observed in coronary artery disease. Chagas cardiomyopathy presents several vascular characteristics that are similar to those presented in other acquired cardiomyopathies. There is convincing evidence of the microvascular involvement and the inflammatory processes that lead to endothelial activation and ischemic damage. Current therapy for the Chagas disease is limited, and it is proposed to combine it with other pharmacological strategies that modify critical physiopathological aspects beneficial for the clinical course of the Chagas cardiomyopathy.
Cardiomyopathy is a myocardial disorder occurring in the absence of coronary artery disease, and it is associated with mechanical and electrical dysfunction that usually exhibit ventricular hypertrophy or dilatation . It is due to genetic and acquired etiologies . Infectious diseases are the leading cause of acquired dilated cardiomyopathy (ADCM). Viruses (Coxsackie, adenovirus, parvovirus, HIV and hepatitis C virus) and parasites (Trypanosoma cruzi) are pathogens of particular importance . Indeed, Chronic Chagas cardiomyopathy (CCC), produced by the protozoan T. cruzi, is the leading cause of ADCM and chronic systolic heart failure (HF) in endemic areas .
Clinically, Chagas' disease evolves from an acute to a chronic phase. Frequently, the acute phase goes unnoticed, but a small group of patients may present a wide range of signs and symptoms, from fever and muscle pain to HF due to myocardial inflammation (myocarditis) . The chronic phase may be asymptomatic (indeterminate), lasts 10–30 years and is characterized by positive serology and some degree of cardiac involvement evidenced by minimal, but persistent, inflammation. However, in ∼30% of patients, it progresses to the symptomatic forms of the disease, involving esophagus, colon or heart . Symptoms and physical signs of CCC arise from HF, cardiac arrhythmias and arterial or venous thromboembolism . The most frequent and severe manifestation of Chagas' disease, associated with poor prognosis and high mortality rates, is biventricular HF with reduced left ventricular ejection fraction. Rhythm disturbances, such as ventricular arrhythmias, atrioventricular block, supraventricular tachycardia or atrial fibrillation, are observed . Sudden death from arrhythmia occasionally complicates patients with severe underlying cardiac involvement, including ventricular aneurysms, which is a characteristic finding in CCC . However, these manifestations are nonspecific, and the diagnosis relies on clinical and electrocardiographic findings and serological or PCR tests [8,9]. Parasite persistence is a critical factor in causing inflammation and in initiating and progressing chronic myocarditis . The infection of the myocardium with the parasite produces an acute myocarditis that goes unnoticed in the vast majority of cases. The inflammatory process that mounts the host is crucial in the future evolution of the infection and, apparently, determines if the patient develops or not symptomatic cardiomyopathy . Thus, to achieve improved care and outcomes in patients, a broadened understanding of the causes of these disorders is needed.
ADCM is the resultant of a progressive inflammatory cell infiltrate that leads to interstitial edema, focal cardiomyocyte necrosis and ultimately, fibrosis. In consequence, complex ventricular remodeling ensues with atrophied and hypertrophied cardiomyocytes. All these changes create an electrically unstable substrate, potentially predisposing to the development of tachyarrhythmias and even sudden death . In ADCM, the myocardial blood flow abnormalities and the consequent coronary microvascular dysfunction are different from those encountered patients with arteriosclerotic coronary artery disease (CAD) . Moreover, ADCM occurs in the absence or concomitantly with CAD . Remodeling of the intramural coronary arterioles and perivascular fibrosis alters the coronary flow reserve (the ratio of blood flow during near-maximal coronary vasodilatation to basal blood flow). Also, there is endothelial dysfunction. Moreover, it has been postulated that microvascular dysfunction may have an independent role in the progression of the ADCM . Consequently, vascular remodeling and abnormal endothelial function contribute to microvascular ischemia in ADCM .
Thus, chronic cardiomyopathy has an important vascular component, including remodeling and endothelial dysfunction, that explains alterations in the myocardial blood flow and its ischemic nature generates progressive inflammation leading to myocyte necrosis and fibrosis.
Diverse evidence supports four primary pathogenic mechanisms to explain CCC: (i) parasite-dependent myocardial damage; (ii) immune-mediated myocardial injury; (iii) cardiac dysautonomia and (iv) microvascular abnormalities and ischemia .
Vascular and ischemic involvement in CCC
There is both experimental and clinical evidence of coronary microvascular disturbances leading to ischemic myocardial damage in animals infected with T. cruzi and in patients with CCC . Some authors consider this fact as ancillary ; however, it has been postulated that transient microvascular ischemic disturbances of low intensity and short duration are the cause of the ischemic myocardial damage leading to the development of cardiomyopathy . This affirmation is supported by findings on magnetic resonance imaging, which are similar to those observed in CAD patients . Furthermore, this observation agrees with a recent report describing alterations in the coronary flow reserve during the chronic, asymptomatic phase of Chagas' disease . Also, there are perfusion changes in patients with advanced cardiomyopathy .
At the microscopic level, the coalescence of several zones with microinfarcts may contribute to the generation of apical aneurysms, typical of the Chagas disease. Several investigators described alterations in cardiac microcirculation associated with occlusive platelet thrombi capable of triggering ischemia . Moreover, focal areas of vascular constriction and endothelial microvascular proliferation are present , suggesting vascular remodeling and angiogenesis. Also, occlusive platelet thrombosis and microcirculatory spams are a consequence of direct endothelial damage produced by T. cruzi and the interaction with immune effector cells . Consequently, the vascular involvement in the etiology of the Chagas heart disease is evident, and endothelial dysfunction might be a key factor in the physiopathology of chagasic cardiomyopathy.
T. cruzi increases the production of the vasoconstrictor endothelin-1 [23,24], which could explain the focal spasm observed. T. cruzi also increases thromboxane A2 levels, inducing platelet aggregation and thrombosis and aggravating myocardial ischemia . These abnormal findings may be increased by endothelial cell (EC) activation. EC activation occurs early in inflammatory processes, leading to vascular dysfunction and injury. These are crucial events associated with acute and chronic inflammation, including sepsis, atherosclerosis  and, as shown by us, Chagas disease . Inflammatory signaling cascades enhance expression of cellular adhesion molecules and activation of neutrophils and cytotoxic T cells , amplifying the initial inflammatory input. Thus, dysregulation of apoptosis, secondary necrosis and overt vascular injury lesions occurs.
EC activation in T. cruzi-infected adipocytes conveys the expression of several proinflammatory molecules, such as proinflammatory cytokines and chemokines, including interleukin (IL)-1β, interferon-γ, tumor necrosis factor-α, CCL2, CCL5 and CXCL10, is increased . The expression of Toll-like receptor-2 and -9 and activation of the Notch pathway are also increased . Therefore, it is reasonable to postulate that this profile would be similar in cardiac endothelial cells. Indeed, cytokines from inflammatory cells contribute to EC activation and amplify the process. Consequently, myocardial perfusion disorders, due to EC damage and microcirculatory alterations, contribute to the progress of the segmental LV dysfunction observed in the chronic phase of Chagas heart disease . Similarly, changes causing hibernating myocardium in long-standing CAD have a similar origin . Any therapeutic approach improving left ventricle function by preventing these vascular derangements could be beneficial to patients with the Chagas disease. Thus, considering the role of endothelium in the initiation and propagation of vascular wall injury in Chagas disease, there is a need for the discovery of molecular targets to serve as inhibitors of EC activation, dysfunction and vascular injury.
Pharmacological modulation of the vascular endothelial dysfunction and research projections
Chagas disease is treated with benznidazole (Bz), a nitroheterocycle drug that is effective in children and during the acute phase of the disease. In the chronic forms of the disease, the evidence available is rather disappointing [31,32]. There is a high rate of drug failure, adverse events are frequent [33,34] and the mortality for cardiac causes still is high. Other pharmacological approaches, such as azole drugs usage, have also been unfavorable [32,35]. However, some objections have been raised concerning the design of these studies, by an eventual under-exposure to Bz  or posaconazole , derived from inadequate dosing regimens or formulations. Probably, if these issues are corrected in future studies, the final results will be much more promising. The treatment of HF in Chagas' cardiomyopathy is the same for that produced by other causes though the outcome is poorer in Chagas [38,39].
Interestingly, there is evidence suggesting that Bz can modulate proinflammatory molecules, even in the absence of infection with T. cruzi . This modulator effect could be mediated by blocking the IκB kinase (IKK) p38 MAPK complexes . Both signal transduction pathways can be activated by TNF-α and regulate the expression of intracelular adhesion molecule 1 (ICAM1) and vascular celular adhesion molecule 1 (VCAM-1)  and can be modulated pharmacologically. As a consequence, Bz treatment could participate not only in eradicating the parasite but also in promoting a protective endothelial environment in CCC. This effect is increased with aspirin [26,43–45] or statins [46,47].
In this regard, the statins, a cholesterol-lowering drug class, have several ‘pleiotropic’ effects including decreasing endothelial activation and platelet aggregation both in vitro and in vivo models of the T. cruzi infection. Notably, simvastatin reduces inflammation in chronically infected hearts . Furthermore, this activity is accomplished through a ciclooxygenase 1 (COX-2) switch prompted by a nitrosylation from endothelial nitric oxide synthase (eNOS) induced by statin activity. This effect is probably the result of the reduction in the synthesis of several lipid intermediates in cholesterol synthesis, such as the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), prompting against lipid modification of key proteins in several signal transduction pathways . This switch enables COX-2 to produce 15(R)-hydroxyeicosatetraenoic acid (15(R)-HETE), a substrate of 5-lipoxygenase, that further produces 15-epi-lipoxin A4 (15-epi-LXA4), an anti-inflammatory lipid. Moreover, 15-epi-LXA4 reduces endothelial activation and heart parasite load, probably by decreased inflammatory input and immunologic clearance of tissue parasites [45,47]. Undoubtedly, chagasic cardiomyopathy is an inflammatory disease. However, it can also be seen as a non-arteriosclerotic ischemic heart disease due to the microvascular alterations. In this context, it is worth asking if it is possible to focus part of the treatment toward the prevention of the pro-fibrotic derangements resulting from the ischemic disorders generated by the infection?. Thus, it has been seen in ischemia models how bone marrow stem cells are recruited after an infarct. This recruitment is mediated by the activation of the Notch pathway , which functions in direct cell-to-cell interactions during cardiac morphogenesis in embryonic life. On the other hand, it has been seen in other tissues, such as the brain, that simvastatin activates Notch in hypoxic models, generating a protective environment . Therefore, it is proposed that, as part of its pleiotropic effects, simvastatin may participate in the activation of the Notch pathway in the chagasic heart. However, the Notch pathway is also involved in inflammatory processes, regulating innate immunity throughout cross-talk between inflammatory and Notch signaling pathways. Indeed, inhibition of Notch decreases vascular inflammation. But Notch is a complex pathway, which has the peculiarity of working contextually, depending on the ligand (there are five ligands: jagged 1 and 2, and Delta-like ligands 1, 3 and 4) and the type of receptor (Notch1–4) that is activated, as well as the cell types involved in the process . Thus, it is possible that the Notch pathway, pharmacologically modulated by statins, may contribute to the generation of a protective environment in chagasic hearts and thus allows decreasing the remodeling forces that damage the hearts irreversibly.
In summary, chronic cardiomyopathy has an important vascular component, including remodeling and endothelial dysfunction that explains alterations in the myocardial blood flow and its ischemic nature that generate progressive inflammation leading to myocyte necrosis and fibrosis. Additionally, there is a relationship between endothelial activation, cardiomyocyte infection with T. cruzi and the Notch pathway activation, and finally, modulating Notch with the widely used statins may contribute to produce a protective milieu in chagasic hearts by decreasing the remodeling forces that damage the hearts irreversibly. Thus, endothelial activation, inflammation and subsequently parasite load and cardiac damage can be prevented by simvastatin that is a commonly used drug in cardiovascular diseases.
Although Chagas cardiomyopathy therapy follows the standard recommendations for the treatment of HF, the efficacy and safety of medication for HF in people with Chagas disease are uncertain [53,54]. A clinical trial with rosuvastatin did not provide conclusive information relating its utility in the management of CCC . However, efforts are being made to link standard therapies for HF to potential benefits in CCC. Thus, there is a report indicating that enalapril might enhance aspects of inflammation in CCC in a murine model of Chagas disease . On the other hand, specific antiparasitic therapy with azole antifungals is very promising . Further advances in CCC therapy include stem cell treatment such as bone marrow mononuclear cells (BMMCs), which contains hematopoietic progenitors and also mesenchymal stem cells (MSCs), nanotechnology for drug delivery, and antioxidants such as curcumin . Most of these strategies are in preclinical stages or the preliminary results are not as promising as expected. Thus, we are encouraged to find drugs capable of altering the natural course of this neglected tropical disease, improving the activity of current antichagasic drugs or decreasing aspects of pathophysiology, which may increase patients survival and quality of life [58,59]. It is necessary to emphasize that, at this time, there is no curative treatment for chronic Chagas' heart disease.
Cardiomyopathy in chronic Chagas disease has a vascular component that contributes to the development of a chronic ischemic condition.
Myocardial inflammation can be modulated by drugs that are currently in use, for example aspirin or the cholesterol-lowering statins.
Pharmacological modulation of key aspects of inflammation as well as the activation of cardioprotective pathways is an attractive strategy that deserves further study.
The Authors declare that there are no competing interests associated with the manuscript.