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
340 resultados
Resultados de Busca
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bookPart Regeneração tecidual no sistema cardiovascular e células-tronco(2016) GOWDAK, Luís Henrique Wolff; KRIEGER, José Eduardo- 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.
- Prevalence and laboratorial determinants of the clinical relevance of antibodies of undetermined specificity(2019) CONRADO, Marina Cavalcanti de Albuquerque da Veiga; CARDOSO, Regina A.; DEZAN, Marcia Regina; OLIVEIRA, Valeria Brito; NETO, Abel da Costa; ZIZA, Karen Chinoca; KRIEGER, Jose Eduardo; PEREIRA, Alexandre Costa; SABINO, Ester Cerdeira; ROCHA, Vanderson; MENDRONE-JUNIOR, Alfredo; DINARDO, Carla LuanaBackground and Objectives Antibodies of unknown specificity (AUS) are frequently identified in the pre-transfusion testing. These antibodies can be insignificant or potentially cause post-transfusion haemolysis. Information about the prevalence of clinically relevant AUS is still lacking. Our aim was to predict the potential clinical relevance of AUS using the monocyte monolayer assay (MMA) and to identify the clinical and laboratorial determinants of AUS' significance. Materials and Methods Antibodies of unknown specificity identified at a single institution from 2015-2017 were evaluated through MMA. A monocyte index (MI) of more than 5% was predictive of potential post-transfusion haemolysis. Results Thirty-two patients with AUS were included in the study. Of the studied AUS, 37 center dot 5% (12/32) presented with a monocyte index (MI) more than 5%. In the group of significant AUS, 41 center dot 7% of the patients presented with sickle cell disease (SCD) and the AUS were associated with Rh antibodies in 75% of the cases. In the group of insignificant AUS, only 10% of the patients had SCD and the association with Rh antibodies was detected in 20% of the cases. The presence of Rh antibodies was independently associated with the AUS clinical relevance (P = 0 center dot 012). Conclusion More than one-third of the AUS are potentially clinically relevant, and the association with Rh antibodies is predictive of AUS relevance. Services must honour AUS in the pre-transfusion process in order to ensure transfusion safety.
- A prospective study of patients with refractory angina: outcomes and the role of high-sensitivity troponin T(2017) POPPI, Nilson T.; GOWDAK, Luis H. W.; DOURADO, Luciana O. C.; ADAM, Eduardo L.; LEITE, Thiago N. P.; MIOTO, Bruno M.; KRIEGER, Jose E.; CESAR, Luiz A. M.; PEREIRA, Alexandre C.BackgroundThe predictors of cardiovascular events in patients with chronic refractory angina are limited. High-sensitivity cardiac troponin T (hs-cTnT) assays are biomarkers that may be used to determine the prognosis of patients with stable coronary artery disease. HypothesisHs-cTnT is a predictor of death and nonfatal myocardial infarction (MI) in patients with refractory angina. MethodsWe prospectively enrolled 117 consecutive patients in this study. A heart team ruled out myocardial revascularization feasibility after assessing recent coronary angiograms; evidence of myocardial ischemia served as an inclusion criterion. Optimal medical therapy was encouraged via outpatient visits every 6 months; plasma hs-cTnT levels were determined at baseline. The primary endpoint was the composite incidence of death and nonfatal MI. ResultsDuring a median follow-up period of 28.0 months (interquartile range, 18.0-47.5 months), an estimated 28.0-month cumulative event rate of 13.4% was determined via the Kaplan-Meier method. Univariate predictors of the composite endpoint were hs-cTnT levels and LV dysfunction. Following a multivariate analysis, only hs-cTnT was independently associated with the events in question, either as a continuous variable (hazard ratio per unit increase in the natural logarithm: 2.83, 95% confidence interval: 1.62-4.92, P < 0.001) or as a categorical variable (hazard ratio for concentrations above the 99th percentile: 5.14, 95% confidence interval: 2.05-12.91, P < 0.001). ConclusionsIn patients with chronic refractory angina, plasma concentration of hs-cTnT is the strongest predictor of death and nonfatal MI. Notably, none of the outcomes in question occurred in patients with baseline plasma levels <5.0 ng/L.
- CYP2C9 and VKORC1 Polymorphisms Are Differently Distributed in the Brazilian Population According to Self-Declared Ethnicity or Genetic Ancestry(2012) SOARES, Renata Alonso Gadi; SANTOS, Paulo Caleb Junior Lima; MACHADO-COELHO, George Luiz Lins; NASCIMENTO, Raimundo Marques do; MILL, Jose Geraldo; KRIEGER, Jose Eduardo; PEREIRA, Alexandre CostaBackground: Warfarin-dosing pharmacogenetic algorithms have presented different performances across ethnicities, and the impact in admixed populations is not fully known. Aims: To evaluate the CYP2C9 and VKORC1 polymorphisms and warfarin-predicted metabolic phenotypes according to both self-declared ethnicity and genetic ancestry in a Brazilian general population plus Amerindian groups. Methods: Two hundred twenty-two Amerindians (Tupinikin and Guarani) were enrolled and 1038 individuals from the Brazilian general population who were self-declared as White, Intermediate (Brown, Pardo in Portuguese), or Black. Samples of 274 Brazilian subjects from Sao Paulo were analyzed for genetic ancestry using an Affymetrix 6.0 (R) genotyping platform. The CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), and VKORC1 g.-1639G>A (rs9923231) polymorphisms were genotyped in all studied individuals. Results: The allelic frequency for the VKORC1 polymorphism was differently distributed according to self-declared ethnicity: White (50.5%), Intermediate (46.0%), Black (39.3%), Tupinikin (40.1%), and Guarani (37.3%) (p < 0.001), respectively. The frequency of intermediate plus poor metabolizers (IM + PM) was higher in White (28.3%) than in Intermediate (22.7%), Black (20.5%), Tupinikin (12.9%), and Guarani (5.3%), (p < 0.001). For the samples with determined ancestry, subjects carrying the GG genotype for the VKORC1 had higher African ancestry and lower European ancestry (0.14 +/- 0.02 and 0.62 +/- 0.02) than in subjects carrying AA (0.05 +/- 0.01 and 0.73 +/- 0.03) (p = 0.009 and 0.03, respectively). Subjects classified as IM + PM had lower African ancestry (0.08 +/- 0.01) than extensive metabolizers (0.12 +/- 0.01) (p = 0.02). Conclusions: The CYP2C9 and VKORC1 polymorphisms are differently distributed according to self-declared ethnicity or genetic ancestry in the Brazilian general population plus Amerindians. This information is an initial step toward clinical pharmacogenetic implementation, and it could be very useful in strategic planning aiming at an individual therapeutic approach and an adverse drug effect profile prediction in an admixed population.
- Role of Trimetazidine in Ischemic Preconditioning in Patients With Symptomatic Coronary Artery Disease(2015) COSTA, Leandro M. A.; REZENDE, Paulo C.; GARCIA, Rosa M. R.; UCHIDA, Augusto H.; SEGURO, Luis Fernando B. C.; SCUDELER, Thiago L.; BOCCHI, Edimar A.; KRIEGER, Jose E.; HUEB, Whady; RAMIRES, Jose Antonio F.; KALIL FILHO, RobertoIschemic preconditioning (IP) is a powerful cardioprotective cellular mechanism that has been related to the warm-up phenomenon or walk-through angina, and has been documented through the use of sequential exercise tests (ETs). It is known that several drugs, for example, cromokalim, pinacidil, adenosine, and nicorandil, can interfere with the cellular pathways of IP. The purpose of this article is to report the effect of the anti-ischemic agent trimetazidine (TMZ) on IP in symptomatic coronary artery disease (CAD) patients.We conducted a prospective study evaluating IP by the analysis of ischemic parameters in 2 sequential ETs. In phase I, without TMZ, patients underwent ET1 and ET2 with a 30-minute interval between them. In phase II, after 1 week of TMZ 35mg twice daily, all patients underwent 2 consecutive ETs (ET3 and ET4). IP was considered present when the time to 1.0-mm segment ST on electrocardiogram deviation (T-1.0mm) and rate pressure product (RPP) were greater in the second of 2 tests. The improvement in T-1.0mm and RPP were compared in the 2 phases: without TMZ and after 1-week TMZ to assess the action of such drug in myocardial protective mechanisms. ETs were analyzed by 2 independent cardiologists.From 135 CAD patients screened, 96 met inclusion criteria and 62 completed the study protocol. Forty patients manifested IP by demonstrating an improvement in T-1.0mm in ET2 compared with ET1, without the use of any drugs (phase I). In phase II, after 1-week TMZ, 26 patients (65%) did not show any incremental result in ischemic parameters in ET4 compared with ET3. Furthermore, of these patients, 8 (20%) had IP blockage.In this study, TMZ did not add any benefit to IP in patients with stable symptomatic CAD.
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- BDKRB2+9/-9 Polymorphism Is Associated with Higher Risk for Diabetes Mellitus in the Brazilian General Population(2012) ALVIM, Rafael de Oliveira; SANTOS, Paulo C. J. L.; NASCIMENTO, Raimundo M.; COELHO, George L. L. M.; MILL, Jose G.; KRIEGER, Jose E.; PEREIRA, Alexandre C.Some mechanisms have been proposed to explain the role of bradykinin on glucose homeostasis and some studies reported that the BDKRB2 +9/-9 polymorphism was associated to the transcriptional activity of the receptor. In this scenario, the main aim of this study was to evaluate the association of the BDKRB2 +9/-9 polymorphism with diabetes mellitus risk in the Brazilian general population. This study included 1,032 subjects of the general urban population. Anthropometrical, blood pressure, biochemical, and genotype analyses for the BDKRB2 +9/-9 bp insertion/deletion polymorphism were performed. Individuals carrying +9/+9 or +9/-9 genotypes had higher glucose values (84.5 mg/dL versus 80.6 mg/dL, resp.) and higher frequency of diabetes mellitus (7.6% versus 3.6%, resp.) compared to individuals carrying -9/-9, adjusting for age and gender. In addition, higher diabetes mellitus risk was associated to presence of the +9/+9 or +9/-9 genotypes (OR = 1.91; 95% CI = 1.09-4.19; P = 0.03). Our data suggest that the BDKRB2 +9/-9 polymorphism may act as a genetic modulator of glucose homeostasis. It was previously associated to insulin sensitivity, glucose uptake, and insulin secretion, and, in this study, data suggest that the polymorphism may increase susceptibility to chronic metabolic conditions such as diabetes in the Brazilian population.
- Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart Failure(2013) SANTOS, Leonardo dos; SALLES, Thiago A.; ARRUDA-JUNIOR, Daniel F.; CAMPOS, Luciene C. G.; PEREIRA, Alexandre C.; BARRETO, Ana Luiza T.; ANTONIO, Ednei L.; MANSUR, Alfredo J.; TUCCI, Paulo J. F.; KRIEGER, Jose E.; GIRARDI, Adriana C. C.Background The present study addresses the hypothesis that the activity of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates peptides that possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). The therapeutic potential of DPPIV inhibition in preventing cardiac dysfunction is also investigated. Methods and Results Measurements of DPPIV activity in blood samples obtained from 190 patients with HF and 42 controls demonstrated that patients with HF exhibited an increase of approximate to 130% in circulating DPPIV activity compared with healthy subjects. Furthermore, an inverse correlation was observed between serum DPPIV activity and left ventricular (LV) ejection fraction in patients with HF. Similarly, radiofrequency LV ablation-induced HF rats displayed higher DPPIV activity in the plasma (approximate to 50%) and heart tissue (approximate to 3.5-fold) compared with sham-operated rats. Moreover, positive correlations were observed between the plasma DPPIV activity and LV end-diastolic pressure and lung congestion. Two days after surgery, 1 group of LV ablation-induced HF rats was treated with the DPPIV inhibitor sitagliptin (40 mg/kg BID) for 6 weeks, whereas the remaining rats were administered water. Hemodynamic measurements demonstrated that radiofrequency LV-ablated rats treated with sitagliptin exhibited a significant attenuation of HF-related cardiac dysfunction, including LV end-diastolic pressure, systolic performance, and chamber stiffness. Sitagliptin treatment also attenuated cardiac remodeling and cardiomyocyte apoptosis and minimized pulmonary congestion. Conclusions Collectively, the results presented herein associate circulating DPPIV activity with poorer cardiovascular outcomes in human and experimental HF. Moreover, the results demonstrate that long-term DPPIV inhibition mitigates the development and progression of HF in rats.
- 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.