Amiodarone or implantable cardioverter-defibrillator in chagas cardiomyopathy: the CHAGASICS randomized clinical trial

IMPORTANCE: Over 10 000 people with Chagas disease experience sudden cardiac death (SCD) annually, mostly caused by ventricular fibrillation. Amiodarone hydrochloride and the implantable cardioverter-defibrillator (ICD) have been empirically used to prevent SCD in patients with chronic Chagas cardiomyopathy. OBJECTIVE: To test the hypothesis that ICD is more effective than amiodarone therapy for primary prevention of all-cause mortality in patients with chronic Chagas cardiomyopathy and moderate to high mortality risk, assessed by the Rassi score. DESIGN, SETTING, AND PARTICIPANTS: CHAGASICS is an open-label, randomized clinical trial. The study enrolled patients from 13 centers in Brazil from May 30, 2014, to August 13, 2021, with the last follow-up November 8, 2021. Patients with serological findings positive for Chagas disease, a Rassi risk score of at least 10 points (intermediate to high risk), and at least 1 episode of nonsustained ventricular tachycardia were eligible to participate. Data were analyzed from May 3, 2022, to June 16, 2023. INTERVENTIONS: Patients were randomized 1:1 to receive ICD or amiodarone (with a loading dose of 600 mg after randomization). MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause mortality, and secondary outcomes included SCD, hospitalization for heart failure, and necessity of a pacemaker during the entire follow-up. RESULTS: The study was stopped prematurely for administrative reasons, with 323 patients randomized (166 in the amiodarone group and 157 in the ICD group), rather than the intended 1100 patients. Analysis was by intention to treat at a median follow-up of 3.6 (IQR, 1.8-4.4) years. Mean (SD) age was 57.4 (9.8) years, 185 patients (57.3%) were male, and the mean (SD) left ventricular ejection fraction was 37.0% (11.6%). There were 60 deaths (38.2%) in the ICD arm and 64 (38.6%) in the amiodarone group (hazard ratio [HR], 0.86 [95% CI, 0.60-1.22]; P = .40). The rates of SCD (6 [3.8%] vs 23 [13.9%]; HR, 0.25 [95% CI, 0.10-0.61]; P = .001), bradycardia requiring pacing (3 [1.9%] vs 27 [16.3%]; HR, 0.10 [95% CI, 0.03-0.34]; P < .001), and heart failure hospitalization (14 [8.9%] vs 28 [16.9%]; HR, 0.46 [95% CI, 0.24-0.87]; P = .01) were lower in the ICD group compared with the amiodarone arm. CONCLUSIONS AND RELEVANCE: In patients with chronic Chagas cardiomyopathy at moderate to high risk of mortality, ICD did not reduce the risk of all-cause mortality. However, ICD significantly reduced the risk of SCD, pacing need, and heart failure hospitalization compared with amiodarone therapy. Further studies are warranted to confirm the evidence generated by this trial.

INFO IST Setembro 2024 / INFO IST September 2024

Jornal na sua 9ª edição (setembro 2024) com a análise e elaboração de conteúdo pela gerência de IST/AIDS e gerência de Hepatites Virais - SES- RJ.

Synthesis and Anti-Trypanosoma cruzi Activity of New Pyrazole-Thiadiazole Scaffolds.

Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.

The effects of inflammation on connexin 43 in chronic Chagas disease cardiomyopathy.

Background: Cardiac arrhythmias are the main cause of sudden death due to Chronic Chagasic Cardiomyopathy (CCC). Here we investigated alterations in connexin 43 (Cx43) expression and phosphorylation in cardiomyocytes as well as associations with cardiac arrhythmias in CCC. Methods: C57Bl/6 mice infected with Trypanosoma cruzi underwent cardiac evaluations at 6 and 12 months after infection via treadmill testing and EKG. Histopathology, cytokine gene expression, and distribution of total Cx43 and its phosphorylated forms Cx43S368 and Cx43S325/328/330 were investigated. Human heart samples obtained from subjects with CCC were submitted to immunofluorescence analysis. In vitro simulation of a pro-inflammatory microenvironment (IL-1ß, TNF, and IFN-γ) was performed in H9c2 cells and iPSC-derived cardiomyocytes to evaluate Cx43 distribution, action potential duration, and Lucifer Yellow dye transfer. Results: Mice chronically infected with T. cruzi exhibited impaired cardiac function associated with increased inflammation, fibrosis and upregulated IL-1ß, TNF, and IFN-γ gene expression. Confocal microscopy revealed altered total Cx43, Cx43S368 and Cx43S325/328/330 localization and phosphorylation patterns in CCC, with dispersed staining outside the intercalated disc areas, i.e., in lateral membranes and the cytoplasm. Reduced co-localization of total Cx43 and N-cadherin was observed in the intercalated discs of CCC mouse hearts compared to controls. Similar results were obtained in human CCC heart samples, which showed Cx43 distribution outside the intercalated discs. Stimulation of human iPSC-derived cardiomyocytes or H9c2 cells with IL-1ß, TNF, and IFN-γ induced alterations in Cx43 localization, reduced action potential duration and dye transfer between adjacent cells. Conclusion: Heart inflammation in CCC affects the distribution and phosphorylation pattern of Cx43, which may contribute to the generation of conduction disturbances in Chagas disease.

Organic solvent-free benznidazole nanosuspension as an approach to a novel pediatric formulation for Chagas disease.

Aim: Benznidazole (BNZ), a class-II drug, is the primary treatment for Chagas disease, but its low aqueous solubility presents challenges in formulation and efficacy. Nanosuspensions (NS) could potentially address these issues.Methods: BNZ-NS were prepared using a simple, organic solvents-free nano-milling approach. Physicochemical characterizations were conducted on both NS and lyophilized solid-state BNZ-nanocrystals (NC).Results: BNZ-NS exhibited particle size <500 nm, an acceptable polydispersity index (0.23), high Z-potential, and physical stability for at least 90 days. BNZ-NC showed tenfold higher solubility than pure BNZ. Dissolution assays revealed rapid BNZ-NS dissolution. BNZ-NC demonstrated biocompatibility on an eukaryotic cell and enhanced BNZ efficacy against trypomastigotes of Trypanosoma cruzi.Conclusion: BNZ-NS offers a promising alternative, overcoming limitations associated with BNZ for optimized pharmacotherapy.

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Sometimes, the size matters: Wing geometric morphometrics as a tool to assess domiciliation by Triatoma sordida (Stäl 1859).

BACKGROUND: Domiciliation by Triatoma sordida is a public health concern in South America. This study aimed to evaluate the morphometric changes in the domestic and peridomestic populations of T. sordida. METHODS: Specimen hemelytra were mounted, digitized, and processed for geometric morphometric analyses. RESULTS: The specimens captured in houses were smaller than those captured in peridomiciles. A large size reduction effect was observed in female peridomicile populations compared with female house populations. CONCLUSIONS: T. sordida house populations were smaller than peridomestic populations. Wing geometric morphometry can be used as a tool to indicate T. sordida domiciliation.

New insights into the pro-oxidant mechanism of dehydroleucodine on Trypanosoma cruzi.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is one of the most important neglected diseases in Latin America. The limited use of the current nitro-derivative-based chemotherapy highlights the need for alternative drugs and the identification of their molecular targets. In this study, we investigated the trypanocidal effect of the sesquiterpene lactone dehydroleucodine (DhL) and its derivatives, focusing on the antioxidative defense of the parasites. DhL and two derivatives, at lesser extent, displayed antiproliferative effect on the parasites. This effect was blocked by the reducing agent glutathione (GSH). Treated parasites exhibited increased intracellular ROS concentration and trypanothione synthetase activity, accompanied by mitochondrial swelling. Although molecular dynamics studies predicted that GSH would not interact with DhL, 1H-NMR analysis confirmed that GSH could protect parasites by interacting with the lactone. When parasites overexpressing mitochondrial tryparedoxin peroxidase were incubated with DhL, its effect was attenuated. Overexpression of cytosolic tryparedoxin peroxidase also provided some protection against DhL. These findings suggest that DhL induces oxidative imbalance in T. cruzi, offering new insights into potential drug targets against this parasite.

A standardized clinical database for research in Chagas disease: The NHEPACHA network.

The NHEPACHA Iberoamerican Network, founded on the initiative of a group of researchers from Latin American countries and Spain, aims to establish a research framework for Chagas disease that encompasses diagnosis and treatment. For this purpose, the network has created a questionnaire to gather relevant data on epidemiological, clinical, diagnostic, and therapeutic aspects of the disease. This questionnaire was developed based on a consensus of expert members of the network, with the intention of collecting high-quality standardized data, which can be used interchangeably by the different research centers that make up the NHEPACHA network. Furthermore, the network intends to offer a clinical protocol that can be embraced by other researchers, facilitating comparability among published studies, as well as the development of therapeutic response and progression markers.

Sublingual microcirculatory alterations in Chagas disease: an observational study in an endemic rural population.

BACKGROUND: Chagas disease is a systemic illness with widespread microvascular involvement. Experimental and clinical studies suggest that functional and structural microcirculatory abnormalities might be relevant to the disease progression. OBJECTIVES: To show the presence of sublingual microcirculatory alterations in patients with chronic Chagas disease. METHODS: This was a cross-sectional study including adult patients with serologic diagnosis of Chagas disease (n = 41) and control volunteers with negative serology (n = 38), from an endemic rural population. Study participants underwent clinical, electrocardiographic, echocardiographic, and sublingual videomicroscopic assessment. Videos were acquired by a sidestream-dark-field (SDF) imaging device and evaluated by a software-assisted analysis (AVA 3.2 software). FINDINGS: Most of Chagas disease patients were in the indeterminate phase (n = 34) and had lower heart rate and more echocardiographic abnormalities than control group (50 vs. 26%, p = 0.03). They also exhibited higher small microvessels total and perfused vascular density (20.12 ± 2.33 vs. 19.05 ± 2.25 and 20.03 ± 2.28 vs. 19.01 ± 2.25 mm/mm2, p < 0.05 for both). Other microvascular variables did not differ between groups. MAIN CONCLUSIONS: Patients with chronic Chagas disease exhibited increases in sublingual total and perfused microvascular density. Angiogenesis might be the underlying mechanism. The videomicroscopic assessment of mucosal sublingual microcirculation might be an additional tool in the monitoring of Chagas disease.

Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial.

Chronic Chagas cardiomyopathy (CCC) has unique pathogenic and clinical features with worse prognosis than other causes of heart failure (HF), despite the fact that patients with CCC are often younger and have fewer comorbidities. Patients with CCC were not adequately represented in any of the landmark HF studies that support current treatment guidelines. PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate the effect of sacubitril/valsartan 200 mg twice daily vs enalapril 10 mg twice daily added to standard of care treatment for HF. The study aims to enroll approximately 900 patients with CCC and reduced ejection fraction at around 100 sites in Latin America. The primary outcome is a hierarchical composite of time from randomization to cardiovascular death, first HF hospitalization, or relative change from baseline to week 12 in NT-proBNP levels. PARACHUTE-HF will provide new data on the treatment of this high-risk population. (Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC [PARACHUTE-HF]; NCT04023227).

The Rpfor gene modulates the locomotory activity and host-seeking behaviour of Rhodnius prolixus.

The molecular bases of animal behaviour are intricate due to the pleiotropic nature of behaviour-modulating genes, which are often expressed across multiple tissues. The foraging gene (for) encodes a cGMP-dependent protein kinase (PKG), pivotal in regulating downstream target proteins through phosphorylation. In insects, for has been implicated in various behavioural contexts and physiological processes regarding searching for food. Rhodnius prolixus, a hematophagous bug that transmits Trypanosoma cruzi, the causative agent of Chagas disease, exhibits specific activity patterns associated with its hematophagous behaviour. Our previous work demonstrated a correlation between locomotor activity profiles and the expression of Rpfor, suggesting its involvement in modulating triatomine locomotion. In this study, we investigated the impact of Rpfor knockdown on locomotory activity, host-seeking behaviour, feeding performance and lipid metabolism in R. prolixus nymphs. Using RNA interference, we achieved a significant reduction of Rpfor expression in both the brain and fat body of R. prolixus nymphs. Knocked-down nymphs exhibited diminished non-oriented locomotory activity compared with controls, without altering the characteristic bimodal pattern of activity. Additionally, they displayed an increased tendency to approach a host, suggesting a role for Rpfor in modulating host-seeking behaviour. Feeding performance and lipid metabolism remained unaffected by Rpfor knockdown. Our findings underscore the multifaceted role of Rpfor in modulating locomotor activity and host-seeking behaviour in R. prolixus nymphs, shedding light on the molecular mechanisms underlying their hematophagous behaviour and potential implications for disease transmission. Further research is necessary to elucidate the intricate interplay between Rpfor expression, behaviour and physiological processes in triatomine bugs.

As bases moleculares do comportamento animal são complexas devido à natureza pleiotrópica dos genes envolvidos na sua modulação, normalmente expressos em múltiplos tecidos. O gene foraging (for) codifica para uma proteína quinase dependente de cGMP, fundamental para a regulação de proteínas alvo via fosforilação. Em insetos, o gene for tem sido associado a vários contextos comportamentais e processos fisiológicos relacionados com forrageamento. Rhodnius prolixus, um inseto hematófago que transmite Trypanosoma cruzi, o agente causativo da doença de Chagas, exibe padrões de atividade específicos associados com o seu comportamento hematófago. Em um estudo anterior, demonstramos uma correlação entre os perfis de atividade locomotora e a expressão de Rpfor, sugerindo o seu envolvimento na modulação da locomoção de triatomíneos. No presente estudo, investigamos o impacto do silenciamento de Rpfor na atividade locomotora, no comportamento de busca por hospedeiro, na performance alimentar, e no metabolismo de lipídeos em ninfas de R. prolixus. Através da técnica de RNA de interferência, obtivemos uma redução significativa da expressão do gene Rpfor no cérebro e no corpo gorduroso de R. prolixus. Insetos silenciados exibiram uma redução da atividade locomotora não orientada em comparação com controles, sem alterações no padrão bimodal da atividade. Adicionalmente, os insetos apresentaram um aumento no comportamento de busca por hospedeiro, sugerindo um papel para o Rpfor na sua modulação. A performance alimentar e o metabolismo de lipídeos não foram alterados pelo silenciamento do gene. Nossas descobertas ressaltam o papel multifuncional do gene Rpfor na modulação da atividade locomotora e no comportamento de busca por hospedeiro em R. prolixus, ampliando o conhecimento sobre os mecanismos moleculares relacionados ao seu comportamento hematófago e potenciais implicações para a transmissão de doenças. Estudos adicionais são necessários para elucidar a intrincada interação entre expressão, comportamento e processos fisiológicos de Rpfor em insetos triatomíneos.

Potential of extracellular vesicles in the pathogenesis, diagnosis and therapy for parasitic diseases.

Parasitic diseases have a significant impact on human and animal health, representing a major hazard to the public and causing economic and health damage worldwide. Extracellular vesicles (EVs) have long been recognized as diagnostic and therapeutic tools but are now also known to be implicated in the natural history of parasitic diseases and host immune response modulation. Studies have shown that EVs play a role in parasitic disease development by interacting with parasites and communicating with other types of cells. This review highlights the most recent research on EVs and their role in several aspects of parasite-host interactions in five key parasitic diseases: Chagas disease, malaria, toxoplasmosis, leishmaniasis and helminthiases. We also discuss the potential use of EVs as diagnostic tools or treatment options for these infectious diseases.

Humans seropositive for Trypanosoma cruzi co-infected with intestinal helminths have higher infectiousness, parasitaemia and Th2-type response in the Argentine Chaco.

BACKGROUND: The Gran Chaco ecoregion is a well-known hotspot of several neglected tropical diseases (NTDs) including Chagas disease, soil-transmitted helminthiasis and multiparasitic infections. Interspecific interactions between parasite species can modify host susceptibility, pathogenesis and transmissibility through immunomodulation. Our objective was to test the association between human co-infection with intestinal parasites and host parasitaemia, infectiousness to the vector and immunological profiles in Trypanosoma cruzi-seropositive individuals residing in an endemic region of the Argentine Chaco. METHODS: We conducted a cross-sectional serological survey for T. cruzi infection along with an intestinal parasite survey in two adjacent rural villages. Each participant was tested for T. cruzi and Strongyloides stercoralis infection by serodiagnosis, and by coprological tests for intestinal parasite detection. Trypanosoma cruzi bloodstream parasite load was determined by quantitative PCR (qPCR), host infectiousness by artificial xenodiagnosis and serum human cytokine levels by flow cytometry. RESULTS: The seroprevalence for T. cruzi was 16.1% and for S. stercoralis 11.5% (n = 87). We found 25.3% of patients with Enterobius vermicularis. The most frequent protozoan parasites were Blastocystis spp. (39.1%), Giardia lamblia (6.9%) and Cryptosporidium spp. (3.4%). Multiparasitism occurred in 36.8% of the examined patients. Co-infection ranged from 6.9% to 8.1% for T. cruzi-seropositive humans simultaneously infected with at least one protozoan or helminth species, respectively. The relative odds of being positive by qPCR or xenodiagnosis (i.e. infectious) of 28 T. cruzi-seropositive patients was eight times higher in people co-infected with at least one helminth species than in patients with no such co-infection. Trypanosoma cruzi parasite load and host infectiousness were positively associated with helminth co-infection in a multiple regression analysis. Interferon-gamma (IFN-γ) response, measured in relation to interleukin (IL)-4 among humans infected with T. cruzi only, was 1.5-fold higher than for T. cruzi-seropositive patients co-infected with helminths. The median concentration of IL-4 was significantly higher in T. cruzi-seropositive patients with a positive qPCR test than in qPCR-negative patients. CONCLUSIONS: Our results show a high level of multiparasitism and suggest that co-infection with intestinal helminths increased T. cruzi parasitaemia and upregulated the Th2-type response in the study patients.

Recombinant proteins as promising antigens applied to the immunodiagnosis of Chagas disease: a scoping review.

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is an important public health problem, occurring mainly in Latin America. The disease has a major social and economical effect, negatively impacting the life of the infected individuals, and bringing great costs to public health. An early and accurate diagnosis is essential for administration of early treatment. In addition, prognostic tests may aid disease management, decreasing hospitalization costs. However, the serological diagnostic scenario for CD still faces several challenges, making the development of new diagnostic kits a pressing matter. Facing this scenario, several researchers have expanded efforts in developing and testing new antigens, such as recombinant proteins and recombinant multiepitope proteins, with promising results. These recombinant antigens offer several advantages, such as improved sensitivity and specificity, in addition to facilitated scaling. Also, it has been possible to observe a rising number of studies using ELISA and point-of-care platforms, employing these antigens in the past few years. Among them, recombinant proteins were the most applied antigens, demonstrating great capacity to discriminate between positive and negative samples. Although fewer in number, recombinant multiepitope proteins also demonstrated an improved diagnostic performance. Indeed, a great number of studies employing these antigens showed sensitivity and specificity values above 90%, greatly impacting diagnostic accuracy. Nevertheless, despite the good results found, it is still possible to observe some bottlenecks in the development of new antigens, such as the scarcity of tests with sera from the acute phase and the variability of results in different geographic areas. In this sense, aiming to contribute to control and health programs, the continuous search for a more accurate serological diagnosis is essential, both for the acute and chronic phases of the disease.

Range size positively correlates with temperature and precipitation niche breadths but not with dietary niche breadth in triatomine insects, vectors of Chagas disease.

Ecological theory predicts that species that can utilise a greater diversity of resources and, therefore, have wider niche breadths should also occupy larger geographic areas (the 'niche breadth-range size hypothesis'). Here, we tested this hypothesis for a blood-sucking group of insects of medical significance: the Triatominae (aka 'kissing bugs') (Hemiptera: Reduviidae). Given that niches can be viewed from different perspectives, we tested this hypothesis based on both dietary and climatic niches. We assembled the most complete dataset of triatomine feeding patterns to date by reviewing 143 studies from the literature up to 2021 and tested whether the niche breadth-range size hypothesis held for this group for both dietary and climatic components of the niche. Temperature and precipitation niche breadths were estimated from macro-environmental variables, while diet breadth was calculated based on literature data that used PCR and/or ELISA to identify different types of hosts as blood sources per triatomine species. Our results showed that temperature and precipitation niche breadths, but not dietary breadth, were positively correlated with range sizes, independent of evolutionary history among species. These findings support the predictions from the range size-niche breadth hypothesis concerning climate but not diet, in Triatominae. It also shows that support for the niche breadth-range size hypothesis is dependent upon the niche axis under consideration, which can explain the mixed support for this hypothesis in the ecological literature.

SuFEx-Functionalized Quinones via Ruthenium-Catalyzed C-H Alkenylation: A Potential Building Block for Bioactivity Valorization.

Herein, we describe the Ru-catalyzed C-H alkenylation of 1,4-naphthoquinones (1,4-NQs), resulting in 1,4-naphthoquinoidal/SuFEx hybrids with moderate to good yields. This method provides a novel route for direct access to ethenesulfonyl-fluorinated quinone structures. We conducted mechanistic studies to gain an in-depth understanding of the elementary steps of the reaction. Additionally, we evaluated the prototypes against trypomastigote forms of T. cruzi, leading to the identification of compounds with potent trypanocidal activity.

Design, Synthesis, and In Vitro and In Silico Evaluation of 1,3,4-Oxadiazoles as Anti-Trypanosoma cruzi and Anti-Leishmania mexicana Agents.

A series of novel 4-acetyl-1,3,4-oxadiazole derivatives was designed and synthesized for their biological evaluation in vitro against Trypanosoma cruzi and Leishmania mexicana. Additionally, compounds were evaluated by molecular docking on the cruzain of T. cruzi (TcCz) and the cysteine protease B (CPB) of L. mexicana (LmCPB) to know their potential mechanism of binding. Compound OX-12 had better trypanocidal activity against NINOA (IC50= 10.5 µM) and A1 (IC50= 21.7 µM) T. cruzi strains that reference drug benznidazole (IC50= 30.3 µM and 39.8 µM, respectively). Compound OX-2 had the best biological activity against L. mexicana in M379 (IC50= 11.9 µM) and FCQEPS (IC50= 34.0 µM) strains that the reference drug glucantime (IC50 ˃120 µM). All the compounds showed important interactions with residues on the active site of TcCz (Gly66, Trp26, Leu67, and Ala138) and LmCPB (Gly67, Asn62, Leu68, and Ala140). Finally, the molecular dynamics simulations of the compound OX-12 shown moderate stability from 40 to 115 ns with an RMSD value of 6.5 Å. Meanwhile, compound OX-2 showed a minor stability in complex with CPB from 25 to 200 ns of simulation (RMSD <9 Å). These results encourage to develop more potent and efficient trypanocidal and leishmanicidal agents using the 1,3,4-oxadiazole scaffold.

Comparacão dos Parâmetros Ecocardiográficos Convencionais e com Speckle Tracking entre Indivíduos Saudáveis e Transplantados Cardíacos sem Rejeição / Comparative Analysis of Conventional and Speckle Tracking Echocardiographic Variables between Patients with Unrejected Heart Transplants and Healthy Individuals

Resumo Fundamento A ecocardiografia é essencial para avaliação do coração transplantado. No entanto, os valores de normalidade no transplante cardíaco (TC) não estão claramente definidos. Objetivos: Comparar parâmetros ecocardiográficos convencionais e pela técnica de Speckle Tracking entre pacientes transplantados cardíacos sem rejeição e uma população de indivíduos saudáveis. Métodos Foram estudados prospectivamente pacientes adultos, com menos de 1 ano de TC, que realizaram biópsia endomiocárdica de vigilância seguido de ecocardiograma transtorácico (ETT). Medidas convencionais de ETT acrescidas da avaliação de mecânica cardíaca por meio do Strain pelo Speckle Tracking foram realizadas e comparadas com um grupo de voluntários saudáveis. A significância estatística adotada para o estudo foi de 5%. Resultados Avaliou-se 36 pacientes transplantados sem rejeição, os quais foram comparados com 30 indivíduos saudáveis. Observou-se redução nos valores de Strain Global Longitudinal de Ventrículo Esquerdo em valor absoluto (11,99% transplantados, 20,60% controle, p<0,0001), Strain de parede livre de Ventrículo Direito (transplantados 16,67%, controle 25,50%, p<0,0001) e dos índices de trabalho miocárdico (p<0,0001), maior tamanho do átrio esquerdo (38,17 ml/m2 transplantados, controle 18,98 ml/m2, p<0,0001), maior índice de massa e espessura relativa das paredes (p<0,0001) e a presença da Doença de Chagas como principal etiologia para o transplante. Conclusão Os transplantados cardíacos estáveis e sem rejeição apresentaram diferenças com relação aos parâmetros ecocardiográficos comparados com indivíduos saudáveis. Estes achados indicam que medidas ecocardiográficas convencionais e de mecânica cardíaca são alteradas em transplantados mesmo na ausência de rejeição e podem ser relevantes para o contexto clínico e acompanhamento dos pacientes.

Abstract Background Echocardiography is essential for the assessment of patients with heart transplants. However, normal values in such individuals are not clearly defined. Objectives To compare conventional echocardiographic and speckle tracking variables between patients with unrejected heart transplants and healthy individuals. Methods : A prospective study was conducted with adult patients having undergone heart transplantation at least one year earlier and submitted to endomyocardial biopsy followed by transthoracic echocardiogram (TTE). Conventional TTE measures and mechanical heart strain assessments using speckle tracking were performed and the results were compared to those of a group of healthy volunteers. Statistical significance was set at 5% (p < 0.05). Results Thirty-six transplant patients without rejection were analyzed and compared to 30 healthy individuals. Chagas disease was the main reason for transplantation. Lower left ventricular global longitudinal strain expressed in absolute values was found (11.99% in transplant patients vs. 20.60% in controls; p <0.0001), right ventricular free wall longitudinal strain (16.67% in transplant patients vs. 25.50% in controls; p <0.0001) and myocardial work indices (p < 0.0001) as well as a larger size of the left atrium (38.17 ml/m2 in transplant patients vs. 18.98 ml/m2 in controls; p <0.0001) and greater mass and relative wall thickness (p <0.0001). Conclusion Stable patients having undergone heart transplants without rejection have differences concerning echocardiographic variables compared to healthy individuals. These findings indicate that conventional echocardiographic measures and heart mechanics are altered in transplant patients even in the absence of rejection. Such findings are relevant to the clinical context and follow-up of the patient.

Lipid Metabolism in Insect Vectors of Diseases.

According to the World Health Organization vector-borne diseases account for more than 17% of all infectious diseases, causing more than 700,000 deaths annually. Vectors are organisms that are able to transmit infectious pathogens between humans, or from animals to humans. Many of these vectors are hematophagous insects, which ingest the pathogen from an infected host during a blood meal, and later transmit it into a new host. Malaria, dengue, African trypanosomiasis, yellow fever, leishmaniasis, Chagas disease, and many others are examples of diseases transmitted by insects.Both the diet and the infection with pathogens trigger changes in many metabolic pathways, including lipid metabolism, compared to other insects. Blood contains mostly proteins and is very poor in lipids and carbohydrates. Thus, hematophagous insects attempt to efficiently digest and absorb diet lipids and also rely on a large de novo lipid biosynthesis based on utilization of proteins and carbohydrates as carbon source. Blood meal triggers essential physiological processes as molting, excretion, and oogenesis; therefore, lipid metabolism and utilization of lipid storage should be finely synchronized and regulated regarding that, in order to provide the necessary energy source for these events. Also, pathogens have evolved mechanisms to hijack essential lipids from the insect host by interfering in the biosynthesis, catabolism, and transport of lipids, which pose challenges to reproduction, survival, fitness, and other insect traits.In this chapter, we have tried to collect and highlight the current knowledge and recent discoveries on the metabolism of lipids in insect vectors of diseases related to the hematophagous diet and pathogen infection.