1. Introduction
1.1. Myocarditis
In 1995, the last World Health Organization (WHO)/International Society and Federation of Cardiology (ISFC) Task Force on the definition and classification of cardiomyopathies defined myocarditis (also named “inflammatory cardiomyopathy”) as an “inflammatory disease of the myocardium associated with cardiac dysfunction” [1]. In myocarditis, the inflammatory infiltrate of the myocardium is associated with necrosis and/or degeneration of adjacent myocytes, which is not typical of – nor consistent with – myocardial ischemic damage seen with coronary artery disease [1, 2]. The clinical presentation of myocarditis is dependent upon the magnitude of myocardial inflammation, thus it may be quite variable. Clinical signs and symptoms may range from subclinical disease (which may initially be unrecognized) to new-onset acute heart failure or sudden death due to ventricular arrhythmias [3]. Moreover, the clinical course of myocarditis may be as variable as its clinical presentations: some individuals may develop acute myocarditis that resolves spontaneously within a few weeks, while others may develop symptoms of chronic heart failure due to dilated cardiomyopathy (DCM) [3]. Although many patients with hemodynamically stable heart failure may respond well to optimal medical therapy, a significant percentage of patients with DCM become medically refractory and progress to irreversible end-stage heart failure for which heart transplantation becomes the only hope of survival. Indeed, it is estimated that acute myocarditis resolves completely in approximately 50% of cases, with an additional 25% of patients having incomplete recovery (i.e.; partial normalization of cardiac function), while the remainder 25% will inexorably progress to end-stage heart failure and death [1, 4-6].
Despite its seemingly over simplistic definition, myocarditis is a disease with multiple heterogeneous etiologies, which in turn lead to a highly variable and very complex pathology. The etiologies of myocarditis can be divided into three groups: infective, immune-mediated and toxic. Infective myocarditis may be bacterial (including gram-positive cocci, gram-negative rods, gram-negative cocci, mycobacterium, mycoplasma); spirochetal (Borrelia, Leptospira); fungal (including Aspergillus, Candida, Histoplasma and Cryptococcus, among others); protozoal (including
This extraordinary multitude of ethiopathogenetic agents underscores the fact that proper and accurate diagnosis of myocarditis at the tissue and molecular level is of utmost importance because it may impact therapeutic choices as well as short- and long-term prognosis. Although management of myocarditis should ideally consist of very specific and targeted therapeutic strategies that go beyond symptomatic control of heart failure and temporary reversal of cardiac dysfunction, such therapies are not clinically available for patients with most types of myocarditis.
Myocarditis should be suspected on the basis of clinical presentation and imaging data, and objective diagnosis should be made by endomyocardial biopsy (EMBx) using established histological, immunological and immunohistochemical criteria combined with molecular biological techniques, particularly polymerase chain reaction (PCR) and nested-PCR [1, 2, 7]. Histopathological analysis is essential to reach a classification of myocarditis based on histological criteria (i.e., lymphocytic, giant cell, granulomatous, etc), while semi-quantitative assessments of the specimens with regards to myocyte necrotic damage/inflammatory activity (“grading”) and to measure the extension of fibrosis and architectural changes (“staging”) have also been proposed [2]. Large panels of antibodies should be performed to characterize the inflammatory cell population and the activated immunological processes. Immunohistochemistry increases the sensitivity of EMBx, while amplification methods such as PCR are capable of detecting few copy viral genomes even from an extremely small amount of tissue such as an EMBx specimen [2]. A combination of these techniques will most likely reveal the pathological nature of myocarditis and help predict which patients may respond to immunomodulatory therapies or not [8].
2. Pathophysiology and ciinical presentation of Trypanosoma cruzi -induced myocarditis
In the particular case of myocarditis induced by
In this review we will focus on the importance of the acquired immune response to the control of
3. Trypanosoma cruzi infection
In 1909, Brazilian physician Carlos Chagas, M.D., identified a hemoflagellate parasite in a child’s blood, leading to the discovery of the American Trypanosomiasis, or Chagas disease (named in his honor). Dr. Chagas accomplished a unique feat in the history of medicine: not only did he identify a new disease, but he also discovered the invertebrate vector and its biological characteristics; isolated the causative agent –
The disease can be transmitted by transplacental infection or during childbirth, organ transplantation, laboratory accidents with contaminated sharp objects, blood transfusion, or ingestion of food or drink contaminated with infected vectors or their feces. During the process of natural infection in endemic areas,
The infection is followed by a typically benign acute-phase that lasts up to two months. In this period, high numbers of circulating parasites are observed in blood. Symptoms, when present, may include fever, headache, enlarged lymph nodes, pallor, muscle pain, difficulty in breathing, swelling and abdominal or chest pain. All patients will then enter a chronic phase, which starts with a so-called “indeterminate” asymptomatic period. Most chronic patients will remain asymptomatic throughout their lives. However, about 10% will develop digestive tract (enlargement of the esophagus and/or colon, known as “megaesophagus” and “megacolon”), neurological or mixed symptoms; and about 30% will develop Chagasic myocarditis, the most common cause of death in infected patients [13].
Twenty years ago, the number of infected people was estimated at 16-18 million, with about 100 million people at risk of contracting the disease [14]. This dire epidemiological situation has improved thanks mostly to a combined effort by many Latin American countries to control the burden of transmission through insecticide spraying and serologic screening in blood banks. Contemporary estimates indicate that approximately 10 million people are infected with
An important aspect of the infection in the current globalized world is the broader geographic distribution of infected patients. In the last decades, many cases of Chagas disease were reported in the USA, Canada, Europe and some Western Pacific countries. Most of those cases were considered “imported” because they originated from infected Latin American immigrants [16]. This changing geographical distribution highlights the increasing necessity to heighten efforts to combat the spread of the disease and to develop new strategies to treat
4. Pathogenesis of Trypanosoma cruzi -induced myocarditis
In the acute phase, many cardiomyocytes are parasitized [17]. This process typically occurs in close proximity to extensive and diffuse inflammatory foci, which consists mostly of mononuclear cells. However, opposite to what is observed in the acute-phase of the disease, parasites are much less frequently found in the heart of symptomatic chronic patients, despite the persistence of extensive mononuclear inflammatory foci. Contrary to what was previously hypothesized, chronic heart involvement in Chagas disease most likely does not rely on autoimmune mechanisms, but on parasites persistence [18]. However, the reason why most patients will not develop chronic myocarditis and heart failure is unknown to this date. It is postulated that the final outcome of the infection results from a complex and random combination of pathological characteristics, including microcirculatory derangements; micro ischemia; significant impairment of the autonomic nervous system due to ganglia cells death; deregulation of the immune system balance; progressive cardiomyocytolysis induced by parasite nests; individual genetic background; malnutrition; and comorbidities.
Experiments using murine infection and
With regards to acquired immunity, a number of published reports support the role and importance of both CD4 and CD8 T cells in the control of the infection. Experimental approaches can be used to deplete sub populations of lymphocytes, including the use of thymectomized mice; injection of neutralizing antibodies; or the infection of
5. Treatment of T. cruzi infected patients
During the 1960s, two new drugs proved to be effective
The side-effects of nifurtimox include anorexia, weight loss, insomnia, nausea, vomiting, and others. Benznidazole-associated side-effects are classified in three types: (i) hypersensitivity manifestations, such as dermatitis with cutaneous eruptions, periorbital or generalized edema, fever, lymphadenopathy, and muscular and articular pain; (ii) depression of the bone marrow, among which neutropenia, granulomatosis, and thrombocytopenic purpura: (iii) peripheral polyneuropathy, in the form of paresthesia and polyneuritis.
More recently, new progenitor cell-based therapies have been developed with good and promising results. In this therapy, total bone marrow cells are collected from individual patients and a mononuclear cell-enriched preparation is slowly injected into the left and right coronary systems. No adverse effects have been described with this procedure [27] and a few months after treatment some patients had improved cardiac function. However, it is still necessary to characterize the phenotype of the transferred cells and the mechanisms underlying such improvement in cardiac function.
The lack of effective treatments for most chronic symptomatic patients reinforces the need for new drugs and strategies for treating
6. Molecular therapies
Advances in basic research that focus on interconnected molecular pathways in the immune system led to the design of more specific therapeutic strategies. Many autoimmune and inflammatory diseases can be treated using humanized or fully human-derived antibodies; fusion proteins targeting co-stimulatory molecules; or injection of competitive ligands. Neutralization of molecules involved in endothelial transmigration (CD11a/CD18, for example), T lymphocyte activation (CD80/CD86 and CD28; CD25) or function (CD2, lymphocyte function-associated antigen 3 (LFA-3) and cytotoxic T-lymphocyte antigen 4 CTLA-4) are now being used with very good results [8]. However, in the case of
7. T lymphocyte-based possible targets for treating T. cruzi -induced myocarditis
7.1. T lymphocytes senescence
Immunological senescence of memory T lymphocytes is a very interesting aspect of the immune response against pathogen-based and sterile inflammation in general, not only in
It was first shown that chronic patients with cardiac enlargement and clinical or radiological evidence of heart failure have a higher frequency (%) of late activated memory CD8+ T cells (CD27-/CD28-) in blood, when compared with patients that present mild cardiac alterations [32]. Accordingly, the frequency of early activated CD27+/CD28+/CD8+ T cells in the total memory CD8+ T cell population decreases, as disease becomes more severe. The authors hypothesize that there is a gradual clonal exhaustion of this sub-population of early activated memory CD8+ T cells, perhaps as a result of continuous antigenic stimulation by persistent parasites
It is still not known if there is indeed a causative relation between the increase of CD8+/CD27-/CD28- memory cells in chronic
Although this immunological characteristic of memory T lymphocytes senescence would probably be hard to be used as a target for treatment, these peripheral blood mononuclear cells (PBMC) markers could be used as a predictive tool for the severity of potentially developing myocarditis in chronic patients in the undetermined stage.
7.2. Chemokines and T lymphocyte migration to infected myocardium
One very important aspect of the myocarditis induced by
Chemokines are small (8-14 kDa) constitutive or inducible inflammatory cytokines, comprising four protein subfamilies (CXC or α, CC or β, C or γ, and CX3C or δ) that act through trans-membrane spanning G protein-coupled receptors expressed on the surface of several leukocyte and other cells. Chemokines are mostly known by their chemotactic capacity, but they also play a role in angiogenesis; dendritic cell maturation; tumor growth and metastasis; and others. These functions are mostly mediated by the activation of many protein kinases, increased cytoplasmic Ca++ and mainly activation of transcription factors [38].
In the case of non-experimental infection with
The idea that some CC chemokines, and particularly CCR5 receptor, could be involved in the pathogenesis of
7.3. Th17 immune response
When a naïve CD4+ T lymphocyte encounters an antigen presenting cell (APC), it has the potential to differentiate into a T (helper) h1; Th2; Th3 (secreting mostly TGF-β and IL-10 and usually found in mucosa); inducible regulatory T lymphocyte (iTReg - cited in a following item); or Th17 lymphocyte. This commitment is mostly based on the cytokines secreted by the APC, which will interact with cognate cytokine receptors on the lymphocyte’s surface and lead to the activation of the JAK/STAT (Janus kinases/Signal Transducers and Activator of Transcription proteins) pathway. The differentiation of cellular subtypes induced by the cytokines is mostly based on different combinations of JAK proteins and STAT transcription factors. In mammals, there are four members of the JAK family (JAK1, JAK2, JAK 3 and Tyk2) and seven members of the STAT family (STAT1-4; 5A; 5B; 6). These signaling molecules will ultimately induce the expression, or repression, of many genes that will orchestrate the final cellular differentiation, including the panel of cytokines that will be secreted by the final lineage committed CD4+ T lymphocyte [44]. Th1 cells are mainly induced by IL-12 and produce mostly IFN-γ, TNF-α, IL-2 and IL-12; while Th2 cells are mainly induced by IL-4 and produce IL4, IL5, IL-6, IL-10, and IL-13. In humans, the cytokines that instruct Th17 cell lineage development likely include IL-6; IL-21; IL-23; and IL-1β, with TGF-β playing a role in the suppression of Th1 cell lineage commitment. Then, STAT3 is necessary for gene clusters transcription, ultimately leading to the expression of their lineage-defining transcription factors, which are some retinoid orphan receptors (ROR). Th17 cells secrete mainly IL-17A, IL-17F, IL-21, IL-22, IFN-γ, IL-4, IL-10, IL-9, and IL-26 [45] and were initially described as destructive cells that induced autoimmunity and inflammatory diseases. However, more recently it became clear that they also play a role as protective cells, at least in the case of pathogenic infection with
Targeting IL-17 alone with Secukinumab (AIN457) or Ixekizumab, both fully human neutralizing antibodies against IL-17A, has been shown to lead to clinical improvement in patients with psoriasis, rheumatoid arthritis, and other auto-immune diseases. On the other hand, in the case of experimental
7.4. Cell membrane fas/fas-L interaction
Fas agonistic stimulus was formerly a synonym of apoptosis. However, Fas/Fas-L interaction can no longer be inextricably associated with cell death. Fas-linked downstream pathways can lead to cellular survival; proliferation and/or activation, cytokines and chemokines secretion; genes transcription; inflammatory regulation; etc [8]. The Fas molecule is a type I membrane protein that belongs to the tumor necrosis factor (TNF) family, and is normally distributed as monomers on cell surface. These monomers spontaneously and temporarily group into non signaling oligomers, but agonistic activation through trimers of Fas-L leads to conformational changes and trimerization/coupling of Fas to intracellular signaling pathways. With regards to apoptosis, it has been demonstrated that two adjacent trimeric Fas complexes are sufficient to induce a functional response [48]. Alternative splicing of Fas generates soluble molecules (sFas) that retain the ability of binding to Fas-L and inhibit Fas-L-dependent responses. Fas-L is a type II membrane protein belonging to the TNF receptor family and can also exist as a membrane (mFas-L) or a soluble molecule (sFas-L). SFas-L is generated by matrix metalloproteinase (MMP7) and sFas-L monomers have no proapoptotic activity, as long as they do not induce Fas trimerization. On the other hand, sFas-L shows proinflammatory functions, acting as a strong chemotactic factor for polymorphonuclear cells, although not involved in neutrophils activation [8].
Many groups have published that Fas activation in the heart of experimental models or human patients leads to enhanced inflammation, cardiac dysfunction, and hypertrophy. Accordingly, lack of Fas/Fas-L interaction results in less severe myocarditis and cardiac involvement. To date, it has been shown that murine myocarditis induced by coxsackievirus B3 was reduced in mice treated with anti-Fas-L, in Fas-deficient mice (
With regards to a possible molecular therapy for myocarditis that modulates Fas/Fas-L interaction, a likely alternative would involve the blockage of the pathway, which however is very complicated. The injection of competitive ligands or neutralizing Abs can mislead to general Fas inactivation and important side effects could be induced by indiscriminate lack of apoptosis, such as tumor growth and metastasis, and reduced normal turnover of cells. Moreover, the Fas/Fas-L pathway is coupled to many different cytoplasmic signaling molecules that lead to a number of different cellular responses in different populations. This makes very difficult to predict what kind of side effects could be observed [8].
In the case of myocarditis induced by
7.5. Regulatory T cells
Regulatory T cells (TReg) were first described by Sakagushi et al [53] and consist of a thymus-derived sub-population of T lymphocytes (natural TReg cells) that have suppressive activity over effector peripheral T cells, avoiding autoimmunity. However, TReg cells can be generated in the periphery, and these cells are known as induced TReg cells. TReg cells were phenotypically described as CD4+/CD25+ and use a molecular arsenal to silence peripheral effector T cells, such as membrane IL-10 and TGF-β; CTLA-4; and others [54].
In the particular case of
8. Conclusion
All molecular pathways cited here could potentially be used to silence pathogenic T lymphocyte sub-populations that lead to myocarditis, or as a predictive tool for patients that have the potential to develop myocarditis and cardiac dysfunction. Despite this targeted modulation of sub-compartments of the immune system, the capacity of controlling the infection should in general terms be preserved to ensure infection resistance.
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