A systematic review of the Trypanosoma cruzi genetic heterogeneity, host immune response and genetic factors as plausible drivers of chronic chagasic cardiomyopathy.

Chagas disease is a complex tropical pathology caused by the kinetoplastid Trypanosoma cruzi. This parasite displays massive genetic diversity and has been classified by international consensus in at least six Discrete Typing Units (DTUs) that are broadly distributed in the American continent. The main clinical manifestation of the disease is the chronic chagasic cardiomyopathy (CCC) that is lethal in the infected individuals. However, one intriguing feature is that only 30-40% of the infected individuals will develop CCC. Some authors have suggested that the immune response, host genetic factors, virulence factors and even the massive genetic heterogeneity of T. cruzi are responsible of this clinical pattern. To date, no conclusive data support the reason why a few percentages of the infected individuals will develop CCC. Therefore, we decided to conduct a systematic review analysing the host genetic factors, immune response, cytokine production, virulence factors and the plausible association of the parasite DTUs and CCC. The epidemiological and clinical implications are herein discussed.

Inhibition of TGF-ß pathway reverts extracellular matrix remodeling in T. cruzi-infected cardiac spheroids.

Chagasic cardiomyopathy (CC) is the main manifestation of Chagas Disease (CD). CC is a progressive dysfunctional illness, in which transforming growth factor beta (TGF-ß) plays a central role in fibrogenesis and hypertrophy. In the present study, we tested in a three-dimensional (3D) model of cardiac cells culture (named cardiac spheroids), capable of mimicking the aspects of fibrosis and hypertrophy observed in CC, the role of TGF-ß pathway inhibition in restoring extracellular matrix (ECM) balance disrupted by T. cruzi infection. Treatment of T. cruzi-infected cardiac spheroids with SB 431542, a selective inhibitor of TGF-ß type I receptor, resulted in a reduction in the size of spheroids, which was accompanied by a decrease in parasite load and in fibronectin expression. The inhibition of TGF-ß pathway also promoted an increase in the activity of matrix metalloproteinase (MMP)-2 and a decrease in tissue inhibitor of matrix metalloproteinase (TIMP)-1 expression, which may be one of the mechanisms regulating extracellular matrix remodeling. Therefore, our study provides new insights into the molecular mechanisms by which inhibition of TGF-ß signaling reverts fibrosis and hypertrophy generated by T. cruzi during CC and also highlights the use of cardiac spheroids as a valuable tool for the study of fibrogenesis and anti-fibrotic compounds.

Host and parasite genetics shape a link between Trypanosoma cruzi infection dynamics and chronic cardiomyopathy.

Host and parasite diversity are suspected to be key factors in Chagas disease pathogenesis. Experimental investigation of underlying mechanisms is hampered by a lack of tools to detect scarce, pleiotropic infection foci. We developed sensitive imaging models to track Trypanosoma cruzi infection dynamics and quantify tissue-specific parasite loads, with minimal sampling bias. We used this technology to investigate cardiomyopathy caused by highly divergent parasite strains in BALB/c, C3H/HeN and C57BL/6 mice. The gastrointestinal tract was unexpectedly found to be the primary site of chronic infection in all models. Immunosuppression induced expansion of parasite loads in the gut and was followed by widespread dissemination. These data indicate that differential immune control of T. cruzi occurs between tissues and shows that the large intestine and stomach provide permissive niches for active infection. The end-point frequency of heart-specific infections ranged from 0% in TcVI-CLBR-infected C57BL/6 to 88% in TcI-JR-infected C3H/HeN mice. Nevertheless, infection led to fibrotic cardiac pathology in all models. Heart disease severity was associated with the model-dependent frequency of dissemination outside the gut and inferred cumulative heart-specific parasite loads. We propose a model of cardiac pathogenesis driven by periodic trafficking of parasites into the heart, occurring at a frequency determined by host and parasite genetics.

Primary cardiac hydatid cyst presenting as noncompaction cardiomyopathy.

We report a case of cyst was initially labeled as left ventricular noncompaction cardiomyopathy. An accurate diagnosis is essential to establish the most effective treatment strategy. In particular, echocardiographic examination assists in identifying the correct diagnosis. In this case, two-dimensional and three-dimensional echocardiography and computed tomography were used for definitive diagnosis of cardiac hydatid cyst.

A case of intracardiac echinococcosis.

We describe a case of multisystemic cystic echinococcosis exhibiting intracardiac involvement. A lesion inside the lateral wall of the left ventricle induced negative T waves on leads V5 and V6.

Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses.

BACKGROUND: Chronic Chagas disease presents different clinical manifestations ranging from asymptomatic (namely indeterminate) to severe cardiac and/or digestive. Previous results have shown that the immune response plays an important role, although no all mechanisms are understood. Immunoregulatory mechanisms such as apoptosis are important for the control of Chagas disease, possibly affecting the morbidity in chronic clinical forms. Apoptosis has been suggested to be an important mechanism of cellular response during T. cruzi infection. We aimed to further understand the putative role of apoptosis in Chagas disease and its relation to the clinical forms of the disease. METHODS: Apoptosis of lymphocytes, under antigenic stimuli (soluble T. cruzi antigens - TcAg) where compared to that of non-stimulated cells. Apoptosis was evaluated using the expression of annexin and caspase 3(+) by T cells and the percentage of cells positive evaluated by flow cytometry. In addition activation and T cell markers were used for the identification of TCD4(+) and TCD8(+) subpopulations. The presence of intracellular and plasma cytokines were also evaluated. Analysis of the activation status of the peripheral blood cells showed that patients with Chagas disease presented higher levels of activation determined by the expression of activation markers, after TcAg stimulation. PCR array were used to evaluate the contribution of this mechanism in specific cell populations from patients with different clinical forms of human Chagas disease. RESULTS: Our results showed a reduced proliferative response associated a high expression of T CD4(+)CD62L(-) cells in CARD patients when compared with IND group and NI individuals. We also observed that both groups of patients presented a significant increase of CD4(+) and CD8(+) T cell subsets in undergoing apoptosis after in vitro stimulation with T. cruzi antigens. In CARD patients, both CD4(+) and CD8(+) T cells expressing TNF-α were highly susceptible to undergo apoptosis after in vitro stimulation. Interestingly, the in vitro TcAg stimulation increased considerably the expression of cell death TNF/TNFR superfamily and Caspase family receptors genes in CARD patients. CONCLUSIONS: Taken together, our results suggest that apoptosis may be an important mechanism for the control of morbidity in T. cruzi infection by modulating the expression of apoptosis genes, the cytokine environment and/or killing of effector cells.

[Cardiac hydatidosis: Report of one case]. / Hidatidosis cardiaca: caso clínico.

Hydatidosis is an endemic zoonosis in Chile. We report a 48-year-old former slaughterman, with a previous history of pulmonary hydatidosis, who presented a stroke without associated cardiovascular symptoms. An echocardiogram revealed a tumor mass with cystic features in the left ventricle. The patient was operated and the cyst was successfully excised. During the follow up, the patient remains asymptomatic.

Reduced cardiac output in imported Plasmodium falciparum malaria.

BACKGROUND: Volume substitution remains subject of controversy in the light of effusions and oedema potentially complicating this highly febrile disease. Understanding the role of myocardial and circulatory function appears to be essential for clinical management. In the present study, cardiac function and cardiac proteins have been assessed and correlated with parasitological and immunologic parameters in patients with imported Plasmodium falciparum malaria. METHODS: In a prospective case-control study, 28 patients with uncomplicated and complicated P. falciparum malaria were included and findings were compared with 26 healthy controls. Cardiac function parameters were assessed by an innovative non-invasive method based on the re-breathing technique. In addition, cardiac enzymes and pro- and anti-inflammatory cytokines were measured and assessed with respect to clinical symptoms and conditions of malaria. RESULTS: Cardiac index (CI) as a measurement of cardiac output (CO) was 21% lower in malaria patients than in healthy controls (2.7 l/min/m2 versus 3.4 l/min/m2; P < 0.001). In contrast, systemic vascular resistance index (SVRI) was increased by 29% (32.6 mmHg⋅m2/(l/min) versus 23.2 mmHg⋅m2/(l/min); P < 0.001). This correlated with increased cardiac proteins in patients versus controls: pro-BNP 139.3 pg/ml versus 60.4 pg/ml (P = 0.03), myoglobin 43.6 µg/l versus 27.8 µg/l (P = < 0.001). All measured cytokines were significantly increased in patients with malaria. CI, SVRI as well as cytokine levels did not correlate with blood parasite density. CONCLUSIONS: The results support previous reports suggesting impaired cardiac function contributing to clinical manifestations in P. falciparum malaria. Findings may be relevant for fluid management and should be further explored in endemic regions.

Surgical management of hydatid cyst of the interventricular septum.

Cardiac hydatidosis constitutes about 0.5-2% of all hydatid diseases. The interventricular septum is involved in 4% of cardiac hydatidosis cases. We demonstrate the surgical management of a large (76 x 66 mm) septal hydatid cyst in a 20-year-old man. The hydatid cyst was approached through a right ventriculotomy under cardiopulmonary bypass. The germinative membrane was removed in toto. The cavity was then obliterated to prevent recurrence of the cyst. The patient had an uneventful postoperative recovery. Histopathological examination confirmed the diagnosis of hydatid cyst. The patient remains asymptomatic with echocardiographic and magnetic resonance imaging evidence of freedom from disease at the 3-month follow-up.

Risk of Chronic Cardiomyopathy Among Patients With the Acute Phase or Indeterminate Form of Chagas Disease: A Systematic Review and Meta-analysis.

Importance: Chagas cardiomyopathy is associated with substantial morbidity and mortality. Precise estimates of the risk of developing cardiomyopathy among patients with the acute or indeterminate chronic forms of Chagas disease are lacking. Objective: To estimate the risk of developing chronic cardiomyopathy in patients with acute and indeterminate chronic forms of Chagas disease. Data Sources: A systematic search in the Cochrane Library, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), Medline, and Web of Science Core Collection databases was conducted from October 8 to October 24, 2018. Studies published between January 1, 1946, and October 24, 2018, that were written in the English, Spanish, and Portuguese languages were included. Search terms included Chagas disease; development of cardiomyopathy; latency duration; and determinants of the Chagas latency period. Study Selection: Longitudinal observational studies of participants diagnosed with the acute phase of Chagas infection or the indeterminate chronic form of Chagas disease who were followed up until the development of cardiomyopathy were included. Studies were excluded if they did not provide sufficient outcome data. Of 10 761 records initially screened, 32 studies met the criteria for analysis. Data Extraction and Synthesis: Critical appraisals of studies were performed using checklists from the Joanna Briggs Institute Reviewer's Manual, and data were collected from published studies. A random-effects meta-analysis was used to obtain pooled estimated annual rates. Data were analyzed from September 11 to December 4, 2019. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for the registration of the protocol, data collection and integrity, assessment of bias, and sensitivity analyses. Main Outcomes and Measures: Main outcomes were defined as the composite of the development of any new arrhythmias or changes in electrocardiogram results, dilated cardiomyopathy and segmental wall motion abnormalities in echocardiogram results, and mortality associated with Chagas disease. Results: A total of 5005 records were screened for eligibility. Of those, 298 full-text articles were reviewed, and 178 of those articles were considered for inclusion in the quantitative synthesis. After exclusions, 32 studies that included longitudinal observational outcomes were selected for the analysis; 23 of those studies comprised patients with the indeterminate chronic form of Chagas disease, and 9 of those studies comprised patients in the acute phase of Chagas infection. The analysis indicated that the pooled estimated annual rate of cardiomyopathy development was 1.9% (95% CI, 1.3%-3.0%; I2 = 98.0%; τ2 [ln scale] = 0.9992) in patients with indeterminate chronic Chagas disease and 4.6% (95% CI, 2.7%-7.9%; I2 = 86.6%; τ2 [ln scale] = 0.4946) in patients with acute Chagas infection. Conclusions and Relevance: Patients with the indeterminate chronic form of Chagas disease had a significant annual risk of developing cardiomyopathy. The annual risk was more than double among patients in the acute phase of Chagas infection.

Myocardial fluid balance in dogs with naturally acquired heartworm infection.

OBJECTIVE: To determine the effect of naturally acquired heartworm (Dirofilaria immitis) infection on myocardial fluid balance as indicated by myocardial water content and the dynamics of transepicardial fluid flow. ANIMALS: 7 dogs infected with adult heartworms and 8 dogs free of heartworm infection. PROCEDURES: Infected dogs had heartworms in the right ventricle, pulmonary artery, or both but no evidence of cardiovascular disease on physical examination. A hemispheric capsule was attached to the epicardial surface of all dogs for determination of transepicardial fluid dynamics and permeability of the epicardium to water and protein. Myocardial water content and hydroxyproline content were assessed at necropsy. RESULTS: Myocardial water content was significantly lower in heartworm-infected dogs. No differences in myocardial hydroxyproline content, transepicardial fluid flow, or epicardial water or protein permeability were detected. CONCLUSIONS AND CLINICAL RELEVANCE: Heartworm infection significantly altered myocardial fluid balance in dogs, possibly because of a change in the myocardial interstitial pressure-volume relationship. These changes may be associated with increased vulnerability to cardiovascular stressors in heartworm-infected dogs.

[Cardiac Hydatid Cyst in a Child: A Case Report]. / Quiste hidatídico intracardíaco en una niña: Reporte de caso.

Echinococcosis is a parasitic infection caused by Echinococcus granulosus, which, in its cystic state, forms the socalled hydatid cyst. It presents important morbidity, with possible sequelae related to the location, and high costs due to surgical and prolonged pharmacological treatment. The liver and the lung are the most common anatomical locations, and much rarer are the kidney, spleen, brain, and heart, where the latter represents 0.5 to 2% of total cases. Peru is an endemic country of this anthropozoonosis and mainly records cases in the central highlands (95%). This paper presents the case of a 10-year-old girl, diagnosed with this disease, CE1 ultrasound classification, clinical group 1 (confirmed by pathological anatomy) with specific surgical and pharmacological treatment (albendazole) afterward. The patient recovered satisfactorily from the surgery and was discharged at 16 days, without complications.

La equinococosis es una infección parasitaria provocada por Echinococcus granulosus, que, en su estado quístico, forma al denominado quiste hidatídico. Presenta morbilidad importante, con posibles secuelas relacionadas con la ubicación, y altos costos debido al tratamiento quirúrgico y farmacológico prolongado. El hígado y el pulmón son las ubicaciones anatómicas más usuales, mucho más raras son el riñón, bazo, cerebro y corazón, este último representa el 0,5 % a 2 % del total de casos. El Perú es un país endémico de esta antropozoonosis y principalmente registra casos procedentes de la sierra central (95 %). Se presenta el caso de una niña de diez años, con diagnóstico de esta entidad, clasificación ecográfica CE 1, grupo clínico 1 (confirmado por anatomía patológica) con posterior tratamiento quirúrgico y farmacológico específico (albendazol). La paciente se recuperó satisfactoriamente de la cirugía practicada, y fue dada de alta a los 16 días, sin complicaciones.

Cardiac manifestations of parasitic infections part 1: overview and immunopathogenesis.

Parasitic infections produce a wide spectrum of cardiac manifestations. They may involve various anatomic structures of the heart and are manifested clinically as myocarditis, cardiomyopathies, pericarditis, or pulmonary hypertension in many resource-constrained settings. However, many parasitic infections involving the heart may also be currently diagnosed in developed countries due to growing worldwide travel, blood transfusions, and increasing numbers of immunosuppression states such as organ transplantation, use of immunosuppressive agents, or HIV/AIDS. Clinicians anywhere in the globe need to be aware of the potential cardiac manifestations of parasitic diseases. This is part one of a three-part series discussing parasites of the heart. In this section, we provide a general overview and immunopathogenesis of parasitic infections of the heart.

Intracavitary left ventricular hydatid cysts ruptured during cardiopulmonary resuscitation in a patient with acute myocardial infarction.

Cardiac hydatid cyst is a rare complication of parasitic infection caused by Echinococcus granulosus. Cardiac involvement occurs in only 0.2-2% of hydatidosis cases. Rupture of hydatid cysts into cardiac chambers is very rare. In this report, we present a case of intracavitary left ventricular hydatid cysts ruptured during cardiopulmonary resuscitation in a patient with acute myocardial infarction.

Sudden death due to an unrecognized cardiac hydatid cyst: three medicolegal autopsy cases.

Echinococcosis is a human infection caused by the larval stage of Echinococcocus granulosus. The most common sites of infection are the liver and the lungs. Cardiac hydatid cysts are very rare, even in regions where hydatic cysts are endemic (the Mediterranean, South America, Africa, and Australia). It has been reported that cardiac involvement is seen in about 0.5-3% of human echinococcosis cases. Three cases of cardiac hydatid disease that caused sudden death and which were histopathologically diagnosed are reported. Cardiac echinococcosis is rare, but due to its insidious presentation and affinity to cause sudden death, it is important that it be identified in the histopathological examination.

Evaluation of VDR gene polymorphisms in Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy.

Vitamin D is an important modulator of the immune response. It acts over several immune cell types where the Vitamin D receptor (VDR) is expressed. Due to the high relevance of this signaling pathway, several studies have investigated the possible influence of genes involved in the metabolism of Vitamin D and its receptor in different human diseases. Here, we analyzed whether four single-nucleotide polymorphisms of the VDR gene (rs731236, rs7975232, rs1544410 and rs2228570) are involved in the susceptibility to infection by Trypanosoma cruzi and/or to chronic Chagas cardiomyopathy (CCC) in a Colombian endemic population for this parasite. Our results showed that the rs2228570*A allele is associated with CCC development (P = 4.46E-03, OR = 1.51). In summary, the data presented in this report suggest that variation within the VDR gene may affect the immune response against T. cruzi, increasing the probability of cardiac complications in infected individuals.

Natriuretic peptides as prognostic and diagnostic markers in Chagas' disease.

Atrial natriuretic factor (ANF) is a hormone secreted predominantly from atrial myocardium in response to changes in wall tension. Chagas' disease is caused by the parasite Trypanosom cruzi (T. cruzi), the heart being one of the most affected organs, resulting in myocarditis and chronic cardiomyopathy. The inflammatory response of the myocardium may be the result of factors such as ischemia, direct parasite invasion, and autoimmune mechanisms. In this review, we discuss the current knowledge about ANF in Chagas' disease and describe our findings in studying: (1) the development of chagasic cardiomyophathy in T. cruzi-infected rats and its relationship with plasma ANF levels; (2) the evolution of plasma ANF in chagasic patients in different stages (asymptomatic, with conduction defects and with chronic heart failure [CHF]); and (3) the possible usefulness of plasma ANF as a prognostic factor of development of myocardial compromise and survival. In rats, the elevated ANF levels found could mirror the inflammatory response of myocardial cells to acute T. cruzi infection and of progressive failure of cardiac function in the chronic infection. In patients, plasma ANF could be a sensitive marker capable of detecting gradual impairments in cardiac function and poor survival in CHF patients and of myocardiopathy development in the asymptomatic state.

Right ventricle hydatid cyst requiring tricuspid valve excision.

Hydatid cyst in the heart is uncommon, with cardiac involvement occurring in about 0.4-2% of all hydatid infestations. The right ventricle is only rarely involved accounting for 8% of cases. We report a case of a hydatid cyst located in the right ventricle involving the posterior papillary muscle requiring tricuspid valve excision.