Chronic Chagas’ heart disease 55 Applied Cardiopulmonary Pathophysiology 16: 55-81, 2012 Chronic Chagas’ heart disease – From pathogenesis to treatment regimes1 Silvia Gilka Munoz-Saravia, Annekathrin Haberland, Gerd Wallukat, Ingolf Schimke Charité - Universitätsmedizin Berlin, Berlin, Germany Abstract Chagas’ disease, caused by Trypanosoma cruziinfection, was discovered nearly 100 years ago (1909) by the Brazilian physician Carlos Chagas. Chronic Chagas’ disease is still ranked as the most serious parasitic disease in Latin America. Infected patients remain lifelong parasite carri- ers. With a latency of 10 to 30 years, nearly one third of parasite carriers develop life-threaten- ing complications: the majority develop Chagas’ heart disease (90%). Gastrointestinal disor- ders (megaesophagus, megacolon) and neuronal afflictions mainly affecting the parasympa- thetic nerve system were found in the others. Chagas’ heart disease presenting with sudden death, heart failure, malign cardiac arrhythmia, and thromboembolism is currently the major cause of morbidity and mortality in Latin America, enormously burdening economic resources and dramatically affecting patients’ social and employment situations. Chagas’ disease is start- ing to become a worldwide problem due to migration, international tourism and parasite trans- fer by blood contact, intrauterine transfer and organ transplantation. In this review, we reflect on the epidemiology and etiopathology of Chagas’ heart disease. We summarize the mecha- nisms that have been suggested to drive Chagas’ heart disease, mainly those based on autoim- munity phenomena. In this context, we focus on autoantibodies directed to G-protein coupled receptors. Following the autoimmunity story in chronic Chagas’ heart disease – and in addi- tion to antiparasitic therapy, the treatment of heart failure, arrhythmia and thromboembolism and under study strategies such as heart transplantation and cell therapy – we describe regimes that use peptides and aptamers for autoantibody removal or neutralization. At present, such regimes are mostly proposed for beta-1-receptor autoantibodies in patients with dilated car- diomyopathy but, in principle, they can be adapted for patients with chronic Chagas’ heart dis- ease who are positive for comparable autoantibodies. Key words: autoantibodies, Chagas’ heart disease, epidemiology, G-protein coupled receptors, pathogenesis, treatment, Trypanosoma cruzi 1The paper contains excerpts from "Chronic Chagas' heart disease: a disease on its way to becoming a world- wide health problem: epidemiology, etiopathology, treatment, pathogenesis and laboratory medicine.” Munoz- Saravia SG, Haberland A, Wallukat G, Schimke I. Heart Fail Rev. 2010 Dec 17 [Epub ahead of print]; with per- mission of Springer-Verlag, Berlin-Heidelberg-New York; License Number: 2701860576037. 56 S. G. Munoz-Saravia, A. Haberland, G. Wallukat, I. Schimke 1. Introduction 4, which is based on some excellent reviews [2-6]. Despite lifelong parasite persistence, Chagas’ disease (American: trypanosomiasis) two thirds of patients remain asymptomatic. is an endemic parasitic disease that mainly Of the remaining third, and sometimes only occurs in Latin American countries and is after decades, 90% can develop heart dis- caused by the flagellate protozoan Try- ease, which causes enormous socio-econom- panosoma cruzi (T. cruzi). The disease was ic problems in Latin American countries. The named in honor of the Brazilian physician other 10% are affected by gastrointestinal Carlos Chagas (born in 1879 in Oliveira, died diseases and neuronal afflictions. in 1934 in Rio de Janeiro) who, in 1909, dis- Consequently, initiatives and control pro- covered a new trypanosome species in the grams were started, which include 1) initia- intestine of the triatomine bug, which he tives for interrupting the domestic and named T. cruzi in honor of his mentor Oswal- peridomestic transmission cycles by chemi- do Cruz. A biographical sketch of Carlos cal control of the vectors, animal reservoirs, Chagas was recently published in memory of and infected humans, 2) initiatives for im- the discovery of T. cruzi one hundred years proving housing conditions and health edu- ago [1]. cation, and 3) screening for infected blood Trypanosoma cruzi (Fig. 1) is commonly donors, who form one of the main non-vec- transmitted to humans and other mammals tor routes of transmission. by the blood-sucking triatomine bug (Reduvi- For subjects who are already infected, dae), also colloquially referred to as the kiss- strategies for an earlier diagnosis, improved ing bug (Fig. 2), which can transmit T. cruzi monitoring of the progression of the disease, throughout its lifetime (up to 2 years). As car- and optimal treatment guidance are essential tooned in Figure 3, besides infected humans, elements of disease control. In our view, im- more than 100 mammals, including dogs, provements in the understanding of the cats, rats, sloths, armadillos, and bats, are pathogenesis of chronic Chagas’ disease in known to be parasite reservoirs. Due to tri- general and specifically of Chagas’ heart dis- atomine bug cannibalism, T. cruzi can also be ease are the most important conditions for spread throughout triatomine populations. guaranteeing this. Birds and reptiles do not carry T. cruzi. Once infected with T. cruzi, subjects become life- long parasite carriers and pass through sever- al stages of the disease, as illustrated in Figure Figure 1: Electron micrograph image of Trypanosoma cruzi (Reproduced with permission of Rubem F. S. Menna-Bar- reto, Instituto Oswaldo Cruz – FIO- CRUZ, Rio de Janeiro) Chronic Chagas’ heart disease 57 Figure 2: Triatomine bug (Reduvidae) (Reproduced from [25] with permission of F. Torrico and M. Castro; Universidad Mayor de San Simon, Cochabamba, Bo- livia and E. van der Enden; ITGPRESS, Antwerpen, Bergium) Figure 3: Sylvatic and domestic net- work of infection with Trypanosoma cruzi including the pathogen (Trypano- soma cruzi), vector (Reduvidae) and hosts (more than 100 wild and do- mestic animals). Beside in humans, pathology of Cha- gas’ cardiomyopathy was seen in dogs. Figure 4: Time course from Trypa- nosoma cruzi in- fection to chronic Chagas’ disease 58 S. G. Munoz-Saravia, A. Haberland, G. Wallukat, I. Schimke 2. Epidemiology The geographic distribution of the triatomine vector and consequently the area of infection risk extend from the southern USA down to southern Argentina. The main endemic area of Chagas’ disease covers more than 20 countries from Mexico down to northern Ar- gentina (Fig. 5). As indicated in Table 1 (adapted from Dias et al. [7] and Salvatella [8]), there were 30 million cases of infection in the 1980s, with an annual rate of 700,000 newly-infected subjects and more than 45,000 fatalities. Following successful multi- national initiatives for interrupting Chagas’ Figure 5: Endemic area of Chagas’ disease (Re- disease transmission, in 2006 it was estimat- produced from Wikipedia public domain) ed that there were 28 million people at risk, 15 million infected cases, and an annual inci- dence and mortality of 41,200 and 12,500, systems. For the USA, it was estimated that respectively. The number of endemic areas there are more than 300,000 infected peo- decreased from 21 countries in the 1980s to ple, based on the immigrant population of 23 18 countries at present. million Latin Americans and the known Chagas’ disease, which historically was a prevalence of T. cruziin their countries of ori- disease of poor, rural areas, proliferated due gin [11]. Figure 6 shows that “Europe is not to continuous rural-urban migration, which spared” from Chagas’ disease [12]. In Spain, was widespread throughout urban centers with nearly 1,700,000 immigrants, 87,000 in- such as Sao Paulo, with about 300,000 in- dividuals could be infected. For the remain- fected individuals, and Rio de Janeiro and der of Europe, with a total of 500,000 immi- Buenos Aires, with more than 200,000 infect- grants, nearly 3,000 people were estimated ed individuals [9]. to be infected. For Australia and Canada with For the United States, only a very small 85,000 and 157,000 immigrants, 3000 and number of autochthonous vector-borne cas- 5000 infected subjects were calculated, re- es of infection have been reported, located in spectively [13]. Since unknown T. cruzi carri- the south [10]. ers can serve as blood donors, about 100 Due to the international migration of Lat- million people are at risk of becoming infect- in Americans, Chagas’ disease is increasingly ed via contaminated blood [14,15]. Other becoming a worldwide problem for health groups at risk of T. cruziinfection via contact Table 1: Changes in some epidemiological parameters following the interruption of Chagas’ disease transmission, 1999-2006; adapted from [7] and [8] 1990 2000 2006 Annual death (thousand) > 45 21 12,5 Cases of infection (million) 30 18 15 Annual incidence (thousand) 700 200 41, 2 Population at risk (million) 100 40 28 Distribution (countries) 21 19 18 Chronic Chagas’ heart disease 59 Figure 6: Estimated number of Chagas’ disease (in- fected) patients in Europe. (Color code denotes ex- pected frequency). (Repro- duced from [12] with permis- sion of Oxford University Press, License Number: 2692410596257) with the blood of infected subjects are occu- it has been reported that diaplacental and/or pational groups such as social and healthcare perinatal transfer from the mother to her fe- employees. Consequently, blood donor tus can contribute to T. cruzi transmission screening began in 2007 in the USA [16]. [20]. Outside Latin America, one case of the Since 2005 [17], Spanish regulatory law re- congenital transmission of T. cruzi has been quires that all at-risk donors (people born in documented in Spain [21]. an endemic area, people whose mothers Europe is colonized by different subfami- were native to an endemic area, people who lies of the triatomine bug. However, there is have undergone blood transfusions in an en- no indication of T. cruzi transmission by tri- demic area) are screened for Chagas’ disease atomine bugs in Europe. As previously report- or otherwise be excluded from donation. ed [22], fleas, flies, bedbugs, mosquitos and Chagas’ disease is also being increasingly rec- lice have been suggested as possible candi- ognized as an emerging public health prob- dates for T. cruzi transmission in Europe. lem in other European countries [18,19]. Some subspecies of ticks (Ixodida) are poten- However up to now, strategies for detecting tial T. cruzi carriers; some of these live in Eu- T. cruzi-infected blood such as established in rope. However, at present, there is no indica- Spain did not exist for other European coun- tion that insects transfer T. cruzito humans in tries. Europe. International tourism is increasingly be- coming another route for the worldwide spread of Chagas’ disease. In endemic areas, 60 S. G. Munoz-Saravia, A. Haberland, G. Wallukat, I. Schimke 3. Etiopathology with infected feces has been reported. However, genetic variations in the para- 3.1 The vicious cycle of site and its hosts could be responsible for the Trypanosoma cruzi infection regional differences found in the incidence of The life cycle of T. cruziinvolves stages in the this disease [23,24]. digestive tract of the triatomine bug (sec- ondary host), which is the vector, and stages in the blood and tissues of mammals (host, 3.2 Acute Chagas’ disease reservoir). Parasites freely circulating in the host’s blood are unable to replicate, but after The acute stage of Chagas’ disease can be they colonize phagocytic and non-phagocyt- symptomless or it can present with only mild ic cells of host tissues, large quantities of T. clinical symptoms and therefore remain undi- cruzi are produced via replication and are agnosed. A typical sign that is often ignored subsequently released into the blood. After due to its non-specificity is chagoma, a local infection, the parasites exhibit clear tropism infection characterized by swelling around for heart, skeletal, and smooth muscle cells, the bug’s bite. If the route of parasite entry is as well as neuronal cells, which can act as through the conjunctiva of the eye, patients reservoirs for the parasites. Trypanosoma present after 4 to 12 days with a more typi- cruzi parasites are taken up by triatomine cal symptom called Romaña’s sign [25], bugs when they suck human blood or blood which comprises conjunctivitis, unilateral from any other contaminated mammal; they palpebral edema and pre-auricular lym- then multiply in the gut of the bugs. After a phadenopathy (Fig. 7). However, other symp- bug has fed on blood, it excretes the parasite toms are less common and only 5-10% of pa- in its feces onto the skin of the host, from tients present with fever, malaise and lym- where it can enter and continue the vicious phadenopathy. cycle of T. cruzi infection. A bug’s infectious In a small number of patients, especially feces pass via the bug’s bite or other small children, hepatosplenomegaly, myocarditis, wounds into human blood, but the parasite and meningoencephalitis are occasionally can also pass from the feces through intact seen. The mortality rate due to acute Chagas’ mucous membranes, especially those in the disease is 2-6%, which is mainly caused by mouth and eyes. The feces remain infectious myocarditis and meningoencephalitis for a long time, most likely even when they [3,4,5,26,27]. are outside of the bug. Consequently, infec- tion via the ingestion of food contaminated Figure 7: Child with Romana's sign (also named chagoma); uni- lateral painless periorbital swel- ling associated with the acute stage of Chagas' disease. (Re- produced from [25] with permis- sion of F. Torrico and M. Castro; Universidad Mayor de San Si- mon, Cochabamba, Bolivia and E. van der Enden; ITGPRESS, Antwerpen, Bergium) Chronic Chagas’ heart disease 61 3.3 Mechanisms of parasite control tion for surgery. The heart and the gastroin- testinal tract have no distinct pathological Both humoral and cellular immune responses findings on ECG, sonography, or radiology. participate in parasite control, but their high- However, small focal inflammatory lesions ly complex interactions are far from being have been detected in tissue samples of the clarified [28]. The humoral immune response heart, skeletal muscle and the gastrointestinal comprises CD8+ T cells and macrophages, as tract from asymptomatic patients [41-43]. well as IFN-γsecretion, which seem to be es- The asymptomatic stage might be interrupted sential players. Perforin/granzyme-dependent by episodes showing non-specific character- killing of infected cells and FAS-mediated istics of acute infection. In particular, patients apoptosis, as well as the macrophage pro- with immunosuppressive disorders, such as duction of IL-12, for induction of T. cruzi re- HIV-positive patients, show such episodes sistance, must be considered [29,30]. Other [3,4,44]. important players in parasite defense via reg- ulation of the immune response and due to their cytotoxic properties are cytokines such 3.4.2 Symptomatic chronic Chagas’ as e.g. IFN-γ and TNF-α and NO [31-37]. In disease (symptomatic stage) contrast, there is evidence to show that CD8+ T cells can lose their activity and that Genetic variability has been discussed as be- immune suppression elements come directly ing responsible [23,24,45] for whether pa- from T. cruzi, causing ineffective parasite tients are asymptomatic or develop heart dis- control by the immune system, which could ease, gastrointestinal disease or neuronal dis- be a reason for the incomplete parasite erad- orders, but this debate has not yet been con- ication and consequent life-long parasite per- cluded [46]. With respect to the relationship sistence that result in chronically infected pa- between the HLA polymorphism and the tients [38]. manifestation of chronic Chagas’ disease, as- sociations were observed between distinct HLA alleles and an increased risk of develop- 3.4 Chronic Chagas’ disease ing chronic Chagas’ disease in some studies [47,48], but others denied finding any such Typical signs of chronic Chagas’ disease are relationships [49]. positivity for anti-T. cruzi antibodies and – by using modern analytical equipment such PCR techniques – the detection of parasites 3.4.2.1 Chagas’ heart disease in patient tissue samples [39,40]. Despite this permanent parasitic load in all patients, only Chagas’ heart disease becomes manifest in one third of patients progress from the men and women with a comparable frequen- asymptomatic phase to the symptomatic cy, and it mainly begins between the ages of stage of chronic Chagas’ disease (Fig. 4). 30 and 50 years old. In line with the diagnos- tic options available in endemic areas, car- diac arrhythmia, found by Holter ECG exam- 3.4.1 Asymptomatic chronic Chagas’ ination, is often the first clinical indication of disease (latency stage, the development of Chagas’ cardiomyopathy indeterminate stage) [50,51]. With increasing severity, right bun- dle branch block, left anterior hemiblock, Asymptomatic patients are only diagnosed ventricular extrasystoles, sinus bradycardia, by chance or by screening for T. cruzi anti- auricular fibrillation and complete atrioven- bodies, for example in the case of enrolment tricular block were found to be the most fre- into the blood donor system or in prepara- quent symptoms [3,5,25]. Consequently, for 62 S. G. Munoz-Saravia, A. Haberland, G. Wallukat, I. Schimke newly diagnosed chronic Chagas’ patients out any characteristic signs of advanced Cha- based on T. cruzi antibody positivity, it was gas’ heart disease. recommended that patients should undergo Chagas’ cardiomyopathy is characterized a medical history interview, a physical exam- by progressive heart enlargement resulting ination, and a resting 12-lead ECG with a 30- from chamber dilatation. Figures 8A (photo- second lead rhythm strip [52]. In the case of graph of explanted chagasic hearts) and 8B normality, examinations should be repeated (thorax radiography) show typically enlarged annually. Where Chagas’ heart disease is di- chagasic hearts. Whereas microscopic para- agnosed, a comprehensive cardiac evalua- site detection was found to be successful in tion is recommended, which should include only 10-20% of cardiomyopathic hearts, Holter ECG examination and echocardiogra- DNA amplification tests showed the appear- phy, which is clearly more sensitive than ECG ance of parasites in almost all patients with [53,54]. Cardiac MRI can successfully com- Chagas’ heart disease [57,58]. plete the diagnosis and aid planning of the However, the severity of cardiomyopathy management of chronic Chagas’ disease did not correlate with the occurrence of par- [55,56]. From a clinical point of view, my- asite DNA. Therefore, direct heart damage in ocarditis, thromboembolic events, sudden relation to parasite load and inflammation cardiac death and congestive heart failure does not seem to be the only mechanism re- are typical of advanced Chagas’ heart dis- sponsible for heart damage. The histopatho- ease. However, about 30% of Chagas’ heart logical pattern of the chagasic heart shows patients die from sudden cardiac death with- nests of focal inflammation with T cells and Figure 8: A)Explanted hearts of patients with chronic Chagas disease demonstrating increasing car- diomegaly. (reproduced with permission of E. van der Enden, Institut voor Tropische Geneeskunde Antwerpen, Belgium). B)Cardiomegaly of a chronic Chagas’ patient with implanted pacemaker, de- monstrated by thorax radiography (Reproduced with permission of R. Araujo, Santa Barbara Hospi- tal, Sucre, Bolivia) Chronic Chagas’ heart disease 63 varying numbers of B cells and macrophages, used for early diagnosis; however, a simple diffuse interstitial fibrosis, and a disturbed radiological investigation is often sufficient. morphology of the myocytes. The conduc- tion system in the heart also shows alter- ations [59-61]. 3.4.2.3 The nerve system in chronic The often apically aneurysmatic Chagas’ Chagas’ disease heart is thought to be the cause of thrombus formation, which may lead to thromboem- Damage to the parasympathetic nervous sys- bolic events in the brain and lungs, and tem could be the main driver of alterations in which are thought to be responsible for the the vegetative nervous system in chronic high rate of sudden death in Chagas’ heart Chagas’ disease [62]. Damage to the disease. However, the main life-threatening parasympathetic nervous system starts in the complication of chronic Chagas’ disease is acute phase and proceeds into the chronic the continuous progress towards severe heart phase. The central nervous system, however, failure. Nearly 60% of patients die due to car- is mostly affected during the acute phase of diomyopathy. the disease. Rare cases of changes in the psy- che of chronically infected Chagas’ patients are also a sign of nerve damage during the 3.4.2.2 Chagas’ gastrointestinal chronic phase of the disease [3]. disease (megaesophagus and megacolon) 4. Pathogenesis of chronic Malnutrition caused by swallowing problems Chagas’ heart disease and regurgitation leading to weight loss, as well as obstipation with abdominal pain, Several hypotheses – extensively summa- mark the progress of chronic Chagas’ disease rized by Gironés et al. [28] and Engman and into megacolon (Fig. 9) and megaesophagus Leon [63] – have been formulated: conditions. Radiological investigations em- A: Primary damage of the neuronal system ploying barium as the contrast agent can be with denervation of the autonomous Figure 9: Photograph of the megacolon of a patient with chronic Chagas disease. (Re- produced with per- mission G. Valda, Santa Barbara Hospi- tal Succre, Bolivia) 64 S. G. Munoz-Saravia, A. Haberland, G. Wallukat, I. Schimke parasympathetic system in the heart. This D: Polyclonal B cell activation following the neuronal damage starts in the acute phase disruption of normal immune regulation of the disease and accelerates in the and leading to immunosuppression and chronic stage, resulting in lesions. autoimmune processes could support B: Cardiomyocyte toxicity due to T. cruzi pathogenetic events. and/or T. cruzi-derived productsresulting E: Persistent T. cruzi antigensmight trigger T in host myocytolysis in the acute stage, is cell-mediated responses of the delayed- thought to start the progress toward Cha- type hypersensitivity cells or cytotoxic gas’ heart disease. Due to the finding of cells, leading to damage of the host’s in- myocardial parasite persistence, chronic fected and/or bystander cells. myocytolysis could aggravate Chagas’ F: Autoimmunity induced by T. cruzi-specif- heart disease. However, with the excep- ic antigens or by host antigens might re- tion of immunosuppressed subjects and sult from T. cruzi antigen-associated molec- the minority of Chagas’ patients with a ular mimicry, as well as from bystander ac- high parasite titer, the generally low para- tivation. site titer in the chronic stage should mean that parasite cytotoxicity and/or the cyto- Although none of these hypotheses claim toxicity of parasite-derived products exclusivity, autoimmunity is being increasing- should only be of limited relevance. ly accepted as a pathogenetic driver of Cha- C: Parasite-induced microvascular alter- gas’ heart disease. The potential cooperation ationis based on the assumption that par- between molecular mimicry and bystander asites interact with essential metabolic re- activation for T. cruzi-induced “autoimmune” actions in microvascular cells, causing hy- Chagas’ heart disease is demonstrated in Fig- poperfusion, subsequent hypoxic/is- ure 10, which is based on [28]. chemic damage of the cardiomyocytes Bystander activation means that parasites, and inflammatory conditions in the heart. especially in the case of strong intracellular All together could drive Chagas’ heart dis- parasite replication, cause pro-inflammatory ease. conditions (release of cytokines, NO/peroxy - Figure 10: Sug- gested mecha- nisms of T. cru- zi pathogenicity by molecular mimicry and by- stander activati- on adapted from [28]