JOSE EDUARDO KRIEGER
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cardio-Pneumologia, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
30 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 30
- Different Transcriptomic Response to T. cruzi Infection in hiPSC-Derived Cardiomyocytes From Chagas Disease Patients With and Without Chronic Cardiomyopathy(2022) OLIVEIRA, Theo G. M.; VENTURINI, Gabriela; ALVIM, Juliana M.; FEIJO, Larissa L.; DINARDO, Carla L.; SABINO, Ester C.; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.; KRIEGER, Jose E.; PEREIRA, Alexandre C.Chagas disease is a tropical zoonosis caused by Trypanosoma cruzi. After infection, the host present an acute phase, usually asymptomatic, in which an extensive parasite proliferation and intense innate immune activity occurs, followed by a chronic phase, characterized by low parasitemia and development of specific immunity. Most individuals in the chronic phase remain without symptoms or organ damage, a state called indeterminate IND form. However, 20 to 40% of individuals develop cardiac or gastrointestinal complications at any time in life. Cardiomyocytes have an important role in the development of Chronic Chagas Cardiomyopathy (CCC) due to transcriptional and metabolic alterations that are crucial for the parasite survival and replication. However, it still not clear why some infected individuals progress to a cardiomyopathy phase, while others remain asymptomatic. In this work, we used hiPSCs-derived cardiomyocytes (hiPSC-CM) to investigate patterns of infection, proliferation and transcriptional response in IND and CCC patients. Our data show that T. cruzi infection and proliferation efficiency do not differ significantly in PBMCs and hiPSC-CM from both groups. However, RNA-seq analysis in hiPSC-CM infected for 24 hours showed a significantly different transcriptional response to the parasite in cells from IND or CCC patients. Cardiomyocytes from IND showed significant differences in the expression of genes related to antigen processing and presentation, as well as, immune co-stimulatory molecules. Furthermore, the downregulation of collagen production genes and extracellular matrix components was significantly different in these cells. Cardiomyocytes from CCC, in turn, showed increased expression of mTORC1 pathway and unfolded protein response genes, both associated to increased intracellular ROS production. These data point to a differential pattern of response, determined by baseline genetic differences between groups, which may have an impact on the development of a chronic outcome with or without the presentation of cardiac symptoms.
- Time-regulated transcripts with the potential to modulate human pluripotent stem cell-derived cardiomyocyte differentiation(2022) MUNOZ, Juan J. A. M.; DARIOLLI, Rafael; SILVA, Caio Mateus da; NERI, Elida A.; VALADAO, Iuri C.; TURACA, Lauro Thiago; LIMA, Vanessa M.; CARVALHO, Mariana Lombardi Peres de; VELHO, Mariliza R.; SOBIE, Eric A.; KRIEGER, Jose E.Background Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising disease model, even though hiPSC-CMs cultured for extended periods display an undifferentiated transcriptional landscape. MiRNA-target gene interactions contribute to fine-tuning the genetic program governing cardiac maturation and may uncover critical pathways to be targeted. Methods We analyzed a hiPSC-CM public dataset to identify time-regulated miRNA-target gene interactions based on three logical steps of filtering. We validated this process in silico using 14 human and mouse public datasets, and further confirmed the findings by sampling seven time points over a 30-day protocol with a hiPSC-CM clone developed in our laboratory. We then added miRNA mimics from the top eight miRNAs candidates in three cell clones in two different moments of cardiac specification and maturation to assess their impact on differentiation characteristics including proliferation, sarcomere structure, contractility, and calcium handling. Results We uncovered 324 interactions among 29 differentially expressed genes and 51 miRNAs from 20,543 transcripts through 120 days of hiPSC-CM differentiation and selected 16 genes and 25 miRNAs based on the inverse pattern of expression (Pearson R-values < - 0.5) and consistency in different datasets. We validated 16 inverse interactions among eight genes and 12 miRNAs (Person R-values < - 0.5) during hiPSC-CMs differentiation and used miRNAs mimics to verify proliferation, structural and functional features related to maturation. We also demonstrated that miR-124 affects Ca2+ handling altering features associated with hiPSC-CMs maturation. Conclusion We uncovered time-regulated transcripts influencing pathways affecting cardiac differentiation/maturation axis and showed that the top-scoring miRNAs indeed affect primarily structural features highlighting their role in the hiPSC-CM maturation.
- Trypanosoma cruzi cardiomyocyte infection promotes innate immune response and metabolic rewiring(2022) VENTURINI, Gabriela; ALVIM, Juliana; PADILHA, Kallyandra; TOEPFER, Christopher; GORHAM, Joshua; BIAGI, Diogo; SCHENKMAN, Sergio; CARVALHO, Valdemir; SALGUEIRO, Jessica; CARDOZO, Karina; KRIEGER, Jose; PEREIRA, Alexandre; SEIDMAN, Jonathan; SEIDMAN, Christine
- Screening of ABCG5 and ABCG8 Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program(2022) TADA, Mauricio Teruo; ROCHA, Viviane Zorzanelli; LIMA, Isabella Ramos; OLIVEIRA, Theo Gremen Mimary; CHACRA, Ana Paula; MINAME, Marcio Hiroshi; NUNES, Valeria Sutti; NAKANDAKARE, Edna Regina; CASTELO, Maria Helane Costa Gurgel; JANNES, Cinthia Elim; SANTOS, Raul D.; KRIEGER, Jose Eduardo; PEREIRA, Alexandre CostaBackground: Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in ABCG5/ABCG8. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program. Methods: From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the ABCG5/8 genes. Clinical and laboratory characteristics of affected individuals were determined. Results: Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2 +/- 19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean beta-Sitosterol and campesterol, respectively, 160.3 +/- 107.1 and 32.0 +/- 19.6 mu g/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0 +/- 120.0 mg/dL (range: 122-521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities. Conclusions: Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.
- IoT Medical Device Architecture to Estimate Non-invasive Arterial Blood Pressure(2022) MORENO, Ramon; DIAS, Felipe; ARRUDA, Marcelo; OLIVEIRA, Filipe; BULHOES, Thiago; KRIEGER, Jose; GUTIERREZ, MarcoHigh blood pressure (BP) is the leading cause of death worldwide. Besides being a treatable condition, alongside medication and a healthy diet, it requires regular BP measurements to assess whether a patient is properly responding to treatment. There have been many attempts to use the photoplethysmography (PPG) signal to estimate BP continuously, but there has yet to be an effective solution. This work presents our efforts to develop a new method for estimating BP from PPG and infrastructure to collect, process, and store this information. PPG signal is measured from a smartband; our App reads the data from the smartband to a smartphone, processes them using a machine learning method, and estimates BP, which is sent to a server that stores and displays the data
- Uncovering emergent phenotypes in endothelial cells by clustering of surrogates of cardiovascular risk factors(2022) PINHEIRO-DE-SOUSA, Iguaracy; FONSECA-ALANIZ, Miriam H.; TEIXEIRA, Samantha K.; V, Mariliza Rodrigues; KRIEGER, Jose E.Endothelial dysfunction (ED) is a hallmark of atherosclerosis and is influenced by well-defined risk factors, including hypoxia, dyslipidemia, inflammation, and oscillatory flow. However, the individual and combined contributions to the molecular underpinnings of ED remain elusive. We used global gene expression in human coronary artery endothelial cells to identify gene pathways and cellular processes in response to chemical hypoxia, oxidized lipids, IL-1 beta induced inflammation, oscillatory flow, and these combined stimuli. We found that clustering of the surrogate risk factors differed from the sum of the individual insults that gave rise to emergent phenotypes such as cell proliferation. We validated these observations in samples of human coronary artery atherosclerotic plaques analyzed using single-cell RNA sequencing. Our findings suggest a hierarchical interaction between surrogates of CV risk factors and the advent of emergent phenotypes in response to combined stimulation in endothelial cells that may influence ED.
- Bone Marrow Cells Improve Coronary Flow Reserve in Ischemic Nonrevascularized Myocardium(2022) ASSUNCAO-JR, Antonildes N.; ROCHITTE, Carlos Eduardo; KWONG, Raymond Y.; GOWDAK, Luis Henrique Wolff; KRIEGER, Jose Eduardo; JEROSCH-HEROLD, MichaelOBJECTIVES This study investigated whether intramyocardial bone marrow-derived hematopoietic progenitor cells (BMCs) increase coronary flow reserve (CFR) in ischemic myocardial regions where direct revascularization was unsuitable. BACKGROUND Patients with diffuse coronary artery disease frequently undergo incomplete myocardial revascularization, which increases their risk for future adverse cardiovascular outcomes. The residual regional ischemia related to both untreated epicardial lesions and small vessel disease usually contributes to the disease burden. METHODS The MiHeart/IHD study randomized patients with diffuse coronary artery disease undergoing incomplete coronary artery bypass grafting to receive BMCs or placebo in ischemic myocardial regions. After the procedure, 78 patients underwent cardiovascular magnetic resonance (CMR) at 1, 6, and 12 months and were included in this cardiac magnetic resonance substudy with perfusion quantification. Segments were classified as target (injected), adjacent (surrounding the injection site), and remote from injection site. RESULTS Of 1,248 segments, 269 were target (22%), 397 (32%) adjacent, and 582 (46%) remote. The target had significantly lower CFR at baseline (1.40 +/- 0.79 vs 1.64 +/- 0.89 in adjacent and 1.79 +/- 0.79 in remote; both P < 0.05). BMCs significantly increased CFR in target and adjacent segments at 6 and 12 months compared with placebo. In target regions, there was a progressive treatment effect (27.1% at 6 months, P = 0.037, 42.2% at 12 months, P = 0.001). In the adjacent segments, CFR increased by 21.8% (P = 0.023) at 6 months, which persisted until 12 months (22.6%; P = 0.022). Remote segments in both the BMC and placebo groups experienced similar improvements in CFR (not significant at 12 months compared with baseline). CONCLUSIONS BMCs, injected in severely ischemic regions unsuitable for direct revascularization, led to the largest CFR improvements, which progressed up to 12 months, compared with smaller but persistent CFR changes in adjacent and no improvement in remote segments. (J Am Coll Cardiol Img 2022;15:812-824) (c) 2022 The Authors.
- The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells(2022) SANTOS-MIRANDA, Artur; JOVIANO-SANTOS, V. Julliane; CRUZ-NASCIMENTO, Taynara; NERI, Elida Adalgisa; SOUZA, Diego Santos; MARQUES, Leisiane Pereira; KRIEGER, Jose E.; ROMAN-CAMPOS, DaniloTebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is widely used in agriculture and its use has experienced a tremendous increase in the last decade. The long-term exposure of humans to this pesticide is a real threat because it is stable in water and soil. The association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity is evident, however, acute toxicological studies to reveal the toxicity of TEB are limited. This research paper addressed the acute exposure of TEB in murine hearts, cardiomyocytes, and human cardiomyocytes derived from an induced pluripotent stem cell (hiPSC-CMs), spelling out TEB's impact on electromechanical properties of the cardiac tissue. In ex vivo experiments, TEB dose dependently, caused significant electrocardiogram (ECG) remodeling with prolonged PR and QTc interval duration. The TEB was also able to change the action potential waveform in murine cardiomyocytes and hiPSC-CMs. These effects were associated with the ability of the compound to block the L-type calcium current (IC50 = 33.2 +/- 7.4 mu mol.l(-1)) and total outward potassium current (IC50 = 5.7 +/- 1.5 mu mol.l(-1)). TEB also increased the sodium/calcium exchanger current in its forward and reverse modes. Additionally, sarcomere shortening and calcium transient in isolated cardiomyocytes were enhanced when cells were exposed to TEB at 30 mu mol.l(-1). Combined, our results demonstrated that acute TEB exposure affects the cardiomyocyte's electrocontractile properties and triggers the appearance of ECG abnormalities.
- Comparing different metabolic indexes to predict type 2 diabetes mellitus in a five years follow-up cohort: The Baependi Heart Study(2022) OLIVEIRA, Camila Maciel de; PAVANI, Jessica Leticia; LIU, Chunyu; BALCELLS, Mercedes; CAPASSO, Robson; ALVIM, Rafael de Oliveira; MOURAO-JUNIOR, Carlos Alberto; KRIEGER, Jose Eduardo; PEREIRA, Alexandre CostaThis study evaluates the association of anthropometric indexes and the incidence of type 2 diabetes mellitus (T2DM) after a 5-year follow-up. This analysis included 1091 middle-aged participants (57% women, mean age 47 +/- 15 years) who were free of T2DM at baseline and attended two health examinations cycles [cycle 1 (2005-2006) and cycle 2 (2010-2013)]. As expected, the participants who developed T2DM after five years (3.8%) had the worst metabolic profile with higher hypertension, dyslipidemia, and obesity rates. Besides, using mixed-effects logistic regression and adjustment for sex, age, and glucose, we found that one unit increase in body adiposity index (BAI) was associated with an 8% increase in their risk of developing T2DM (odds ratio [OR] = 1.08 [95% CI, 1.02-1.14]) and visceral adiposity index (VAI) was associated with a risk increase of 11% (OR = 1.11 [95% CI, 1.00-1.22]). Moreover, a one-unit increase in the triglycerides-glucose index (TyG) was associated with more than four times the risk of developing T2DM (OR = 4.27 [95% CI, 1.01-17.97]). The interquartile range odds ratio for the continuous predictors showed that TyG had the best discriminating performance. However, when any of them were additionally adjusted for waist circumference (WC) or even body mass index (BMI), all adiposity indexes lost the effect in predicting T2DM. In conclusion, TyG had the most substantial predictive power among all three indexes. However, neither BAI, VAI, nor TyG were superior to WC or BMI for predicting the risk of developing T2DM in a middle-aged normoglycemic sample in this rural Brazilian population.
- A deep learning approach for COVID-19 screening and localization on Chest X-Ray images(2022) MARCOMINI, Karem Daiane; CARDENAS, Diego Armando Cardona; TRAINA, Agma Juci Machado; KRIEGER, Jose Eduardo; GUTIERREZ, Marco AntonioChest X-ray (CXR) images have a high potential in the monitoring and examination of various lung diseases, including COVID-19. However, the screening of a large number of patients with diagnostic hypothesis for COVID-19 poses a major challenge for physicians. In this paper, we propose a deep learning-based approach that can simultaneously suggest a diagnose and localize lung opacity areas in CXR images. We used a public dataset containing 5, 639 posteroanterior CXR images. Due to unbalanced classes (69.2% of the images are COVID-19 positive), data augmentation was applied only to images belonging to the normal category. We split the dataset into train and test sets with proportional rate at 90:10. To the classification task, we applied 5-fold cross-validation to the training set. The EfficientNetB4 architecture was used to perform this classification. We used a YOLOv5 pre-trained in COCO dataset to the detection task. Evaluations were based on accuracy and area under the ROC curve (AUROC) metrics to the classification task and mean average precision (mAP) to the detection task. The classification task achieved an average accuracy of 0.83 +/- 0.01 (95% CI [0.81, 0.84]) and AUC of 0.88 +/- 0.02 (95% CI [0.85, 0.89]) in 5-fold over the test dataset. The best result was reached in fold 3 (0.84 and 0.89 of accuracy and AUC, respectively). Positive results were evaluated by the opacity detector, which achieved a mAP of 59.51%. Thus, the good performance and rapid diagnostic prediction make the system a promising means to assist radiologists in decision making tasks.
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