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
25 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 25
- Cysteine and glycine-rich protein 3 (Crp3) as a critical regulator of elastolysis, inflammation, and smooth muscle cell apoptosis in abdominal aortic aneurysm development(2023) MATTOS, Ana Barbosa Marcondes de; RIBEIRO-SILVA, Joao Carlos; FONSECA-ALANIZ, Miriam Helena; VALADAO, Iuri Cordeiro; SILVA, Erasmo Simao da; KRIEGER, Jose Eduardo; MIYAKAWA, Ayumi AureaAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease for which surgical or endovascular repair are the only currently available therapeutic strategies. The development of AAA involves the breakdown of elastic fibers (elastolysis), infiltration of inflammatory cells, and apoptosis of smooth muscle cells (SMCs). However, the specific regulators governing these responses remain unknown. We previously demonstrated that Cysteine and glycine-rich protein 3 (Crp3) sensitizes SMCs to apoptosis induced by stretching. Building upon this finding, we aimed to investigate the influence of Crp3 on elastolysis and apoptosis during AAA development. Using the elastase-CaCl2 rat model, we observed an increase in Crp3 expression, aortic diameter, and a reduction in wall thickness in wild type rats. In contrast, Crp3-/- rats exhibited a decreased incidence of AAA, with minimal or no changes in aortic diameter and thickness. Histopathological analysis revealed the absence of SMC apoptosis and degradation of elastic fibers in Crp3-/- rats, accompanied by reduced inflammation and diminished proteolytic capacity in Crp3-/- SMCs and bone marrow-derived macrophages. Collectively, our findings provide evidence that Crp3 plays a crucial role in AAA development by modulating elastolysis, inflammation, and SMC apoptosis. These results underscore the potential significance of Crp3 in the context of AAA progression and offer new insights into therapeutic targets for this disease.
- Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation(2023) VENTURINI, Gabriela; ALVIM, Juliana M.; PADILHA, Kallyandra; TOEPFER, Christopher N.; GORHAM, Joshua M.; WASSON, Lauren K.; BIAGI, Diogo; SCHENKMAN, Sergio; CARVALHO, Valdemir M.; SALGUEIRO, Jessica S.; CARDOZO, Karina H. M.; KRIEGER, Jose E.; PEREIRA, Alexandre C.; SEIDMAN, Jonathan G.; SEIDMAN, Christine E.IntroductionChagas cardiomyopathy, a disease caused by Trypanosoma cruzi (T. cruzi) infection, is a major contributor to heart failure in Latin America. There are significant gaps in our understanding of the mechanism for infection of human cardiomyocytes, the pathways activated during the acute phase of the disease, and the molecular changes that lead to the progression of cardiomyopathy. MethodsTo investigate the effects of T. cruzi on human cardiomyocytes during infection, we infected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with the parasite and analyzed cellular, molecular, and metabolic responses at 3 hours, 24 hours, and 48 hours post infection (hpi) using transcriptomics (RNAseq), proteomics (LC-MS), and metabolomics (GC-MS and Seahorse) analyses. ResultsAnalyses of multiomic data revealed that cardiomyocyte infection caused a rapid increase in genes and proteins related to activation innate and adaptive immune systems and pathways, including alpha and gamma interferons, HIF-1 alpha signaling, and glycolysis. These responses resemble prototypic responses observed in pathogen-activated immune cells. Infection also caused an activation of glycolysis that was dependent on HIF-1 alpha signaling. Using gene editing and pharmacological inhibitors, we found that T. cruzi uptake was mediated in part by the glucose-facilitated transporter GLUT4 and that the attenuation of glycolysis, HIF-1 alpha activation, or GLUT4 expression decreased T. cruzi infection. In contrast, pre-activation of pro-inflammatory immune responses with LPS resulted in increased infection rates. ConclusionThese findings suggest that T. cruzi exploits a HIF-1 alpha-dependent, cardiomyocyte-intrinsic stress-response activation of glycolysis to promote intracellular infection and replication. These chronic immuno-metabolic responses by cardiomyocytes promote dysfunction, cell death, and the emergence of cardiomyopathy.
- Artificial Intelligence-Driven Screening System for Rapid Image-Based Classification of 12-Lead ECG Exams: A Promising Solution for Emergency Room Prioritization(2023) DIAS, Felipe Meneguitti; RIBEIRO, Estela; MORENO, Ramon Alfredo; RIBEIRO, Adele Helena; SAMESIMA, Nelson; PASTORE, Carlos Alberto; KRIEGER, Jose Eduardo; GUTIERREZ, Marco AntonioThe electrocardiogram (ECG) serves as a valuable diagnostic tool, providing crucial information about life-threatening cardiac conditions such as atrial fibrillation and myocardial infarction. A prompt and efficient assessment of ECG exams in environments such as Emergency Rooms (ERs) can significantly enhance the chances of survival for high-risk patients. Despite the presence of numerous works on ECG classification, most of these studies have concentrated on one-dimensional ECG signals, which are commonly found in publicly available ECG datasets. Nevertheless, the practical relevance of such methods is limited in hospital settings, where ECG exams are usually stored as images. In this study, we have developed an artificial intelligence-driven screening system specifically designed to analyze 12-lead ECG images. Our proposed method has been trained on an extensive dataset comprising 99,746 12-lead ECG exams collected from the ambulatory section of a tertiary hospital. The primary goal was to precisely classify the exams into three classes: Normal (N), Atrial Fibrillation (AFib), and Other (O). The evaluation of our approach yielded AUROC scores of 93.2%, 99.2%, and 93.1% for N, AFib, and O, respectively. To further validate our approach, we conducted evaluations using the 2018 China Physiological Signal Challenge (CPSC) database. In this evaluation, we achieved AUROC scores of 91.8%, 97.5%, and 70.4% for the classes N, AFib, and O, respectively. Additionally, we assessed our method using 1,074 exams acquired in the ER and obtained AUROC values of 98.3%, 98.0%, and 97.7% for the classes N, AFib, and O, respectively. Furthermore, we developed and deployed a system with a trained model within the ER of a tertiary hospital for research purposes. This system automatically retrieves newly captured ECG chart images from the Picture Archiving and Communication System (PACS) within the ER. These images undergo necessary preprocessing steps and serve as input for our proposed classification method. This comprehensive approach established an efficient and versatile end-to-end framework for ECG classification. The results of our study highlight the potential of leveraging artificial intelligence in the screening of ECG exams, offering a promising solution for the rapid assessment and prioritization of patients in the ER.
- Cardiovascular disease onset in old people with severe hypercholesterolemia(2023) COUTINHO, Elaine R.; MINAME, Marcio H.; ROCHA, Viviane Z.; BITTENCOURT, Marcio S.; JANNES, Cinthia E.; KRIEGER, Jose E.; PEREIRA, Alexandre C.; SANTOS, Raul D.Background and aims: Familial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT.Methods: Hypercholesterolemic individuals >= 60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 x 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75).Results: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497-6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants.Conclusions: In old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not.
- Challenges and Applications of Genetic Testing in Dilated Cardiomyopathy: Genotype, Phenotype and Clinical Implications(2023) FURQUIM, Silas Ramos; LINNENKAMP, Bianca; SANGIORGI, Natalia Quintella; GIUGNI, Fernando Rabioglio; LIPARI, Layara Fernanda Vicente Pereira; ANDRADE, Fernanda Almeida; KRIEGER, Jose EduardoGenetic tests for dilated cardiomyopathy (DCM) have a diagnostic yield of up to 40%, but there is significant genetic heterogeneity and other challenges, such as variable expressivity and incomplete penetrance. Pedigree analysis is essential for distinguishing between sporadic and familial DCM cases by assessing family history. Familial DCM yields higher results in genetic testing, but sporadic DCM does not rule out the possibility of a genetic cause. Some genes have specific phenotypes, with the Lamin gene (LMNA) being associated with a phenotype of malignant arrhythmias and advanced heart failure (HF). The presence of a causal genetic variant can also aid in prognostic evaluation, identifying more severe cases with lower rates of reverse remodeling (RR) compared to individuals with a negative genotype. Current guidelines recommend genetic evaluation and counseling for individuals with DCM, along with cascade screening in first-degree relatives in cases where one or more variants are identified, offering an opportunity for early diagnosis and treatment. Relatives with a positive genotype and negative phenotype are candidates for serial evaluation, with frequency varying by age. Genotype also assists in individualized recommendations for implantable cardioverter-defibrillator (ICD) placement and advice regarding physical activity and family planning. Ongoing studies are progressively elucidating the details of genotype/ phenotype relationships for a large number of variants, making molecular genetics increasingly integrated into clinical practice.
conferenceObject PREDICTORS OF CORONARY ARTERY CALCIFICATION INCIDENCE IN SEVERE HYPERCHOLESTEROLEMIA(2023) MARTE, Ana; MINAME, Marcio Hiroshi; PARDI, Estevao Magalhaes; GANEM, Lucas; MIZUTA, Marjorie Hayashida; ROCHA, Viviane Zorzanelli; PEREIRA, Alexandre Costa; KRIEGER, Jose Eduardo; SANTOS, Raul- Before and after AlphaFold2: An overview of protein structure prediction(2023) BERTOLINE, Leticia M. F.; LIMA, Angelica N.; KRIEGER, Jose E.; TEIXEIRA, Samantha K.Three-dimensional protein structure is directly correlated with its function and its determination is critical to understanding biological processes and addressing human health and life science problems in general. Although new protein structures are experimentally obtained over time, there is still a large difference between the number of protein sequences placed in Uniprot and those with resolved tertiary structure. In this context, studies have emerged to predict protein structures by methods based on a template or free modeling. In the last years, different methods have been combined to overcome their individual limitations, until the emergence of AlphaFold2, which demonstrated that predicting protein structure with high accuracy at unprecedented scale is possible. Despite its current impact in the field, AlphaFold2 has limitations. Recently, new methods based on protein language models have promised to revolutionize the protein structural biology allowing the discovery of protein structure and function only from evolutionary patterns present on protein sequence. Even though these methods do not reach AlphaFold2 accuracy, they already covered some of its limitations, being able to predict with high accuracy more than 200 million proteins from metagenomic databases. In this mini-review, we provide an overview of the breakthroughs in protein structure prediction before and after AlphaFold2 emergence.
- Factors Associated With Dysglycemia and Type 2 Diabetes Mellitus Onset in Familial Hypercholesterolemia(2023) MAIA, Flavia C.; MINAME, Marcio H.; MAIA, Kleisson A.; CHACRA, Ana P.; ROCHA, Viviane Z.; MIZUTA, Marjorie; JANNES, Cinthia Elim; KRIEGER, Jose E.; PEREIRA, Alexandre; SANTOS, Raul D.
- Cardiovascular Disease and Cholesterol Lowering Therapy in Women and Men With Molecularly Proven Familial Hypercholesterolemia(2023) MAIA, Kleisson A.; MINAME, Marcio H.; MAIA, Flavia C.; ROCHA, Viviane Z.; CHACRA, Ana P.; MIZUTA, Marjorie; JANNES, Cinthia Elim; PEREIRA, Alexandre; KRIEGER, Jose E.; SANTOS, Raul D.
- CardioBERTpt: Transformer-based Models for Cardiology Language Representation in Portuguese(2023) SCHNEIDER, Elisa Terumi Rubel; GUMIEL, Yohan Bonescki; SOUZA, Joao Vitor Andrioli de; MUKAI, Lilian Mie; OLIVEIRA, Lucas Emanuel Silva e; REBELO, Marina de Sa; GUTIERREZ, Marco Antonio; KRIEGER, Jose Eduardo; TEODORO, Douglas; MORO, Claudia; PARAISO, Emerson CabreraContextual word embeddings and the Transformers architecture have reached state-of-the-art results in many natural language processing (NLP) tasks and improved the adaptation of models for multiple domains. Despite the improvement in the reuse and construction of models, few resources are still developed for the Portuguese language, especially in the health domain. Furthermore, the clinical models available for the language are not representative enough for all medical specialties. This work explores deep contextual embedding models for the Portuguese language to support clinical NLP tasks. We transferred learned information from electronic health records of a Brazilian tertiary hospital specialized in cardiology diseases and pre-trained multiple clinical BERT-based models. We evaluated the performance of these models in named entity recognition experiments, fine-tuning them in two annotated corpora containing clinical narratives. Our pre-trained models outperformed previous multilingual and Portuguese BERT-based models for cardiology and multi-specialty environments, reaching the state-of-the-art for analyzed corpora, with 5.5% F1 score improvement in TempClinBr (all entities) and 1.7% in SemClinBr (Disorder entity) corpora. Hence, we demonstrate that data representativeness and a high volume of training data can improve the results for clinical tasks, aligned with results for other languages.
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