CINTHIA ELIM JANNES LEPSKI
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/13 - Laboratório de Genética e Cardiologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Coronary Artery Calcium Score and Risk of Cardiovascular Events in Heterozygous Familial Hypercholesterolemia Patients Undergoing Standard Lipid Lowering Therapy(2018) MINAME, Marcio; BITTENCOURT, Marcio S.; MORAES, Sergio R.; I, Romulo Alves; SILVA, Pamela R.; JANNES, Cinthia E.; PEREIRA, Alexandre C.; NASIR, Khurram; SANTOS, Raul D.- Health related quality of life in individuals at high risk for familial hypercholesterolemia undergoing genetic cascade screening in Brazil(2018) SOUTO, Ana Cristina; MINAME, Marcio H.; FUKUSHIMA, Julia; JANNES, Cinthia E.; KRIEGER, Jose E.; HAGGER, Martin; PEREIRA, Alexandre C.; SANTOS, Raul D.Background and aims: Familial hypercholesterolemia (FH) is a genetic disorder associated with high risk of early major cardiovascular events (MACE) that can impact the health related quality of life (HRQoL), however, this association is unclear. This study evaluated HRQoL in index cases (IC) and first-degree relatives (FDR) of individuals at high risk of FH undergoing genetic cascade screening. Methods: Data collection was performed before awareness of molecular diagnosis results. Individuals were divided into four groups according to the molecular diagnosis: IC with (ICthorn) and without (IC-) identified mutations (n = 93 and n = 175, respectively), and affected (FDRthorn, n = 231) and non-affected (FDR-, n = 159) FDR of ICthorn. HRQoL measurements, mental (MCS) and physical component (PCS) scores were carried out with SF-12 questionnaire. Associations were tested by generalized linear models. Results: The mean age was 49 +/- 15 years, 42.2% were men, MACE had occurred in 30.7%. Overall, both PCS and MCS did not differ between FH and non-FH individuals, however, IC trended to have lower PCS independent of FH presence (p = 0.003). Lower PCS were associated with female sex (p = 0.018), lower education (p < 0.001), professional inactivity (p = 0.028), previous MACE occurrence (p < 0.001), hypertension (p = 0.016), depression (p < 0.001) and obesity (p < 0.001). Lower MCS were associated with female sex (p = 0.009), previous MACE occurrence (p = 0.034), depression (p < 0.001) and smoking (p = 0.009). Neither the presence of FH causing mutations nor pharmacological lipid lowering treatment was associated with HRQoL. Conclusions: HRQoL is not reduced in both IC and FDR FH individuals in comparison with their nonaffected counterparts. Previous MACE and co-morbidities are associated with reduced HRQoL.
- Presence and type of low density lipoprotein receptor (LDLR) mutation influences the lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia(2014) SANTOS, Paulo Caleb Junior Lima; MORGAN, Aline Cruz; JANNES, Cintia Elin; TUROLLA, Luciana; KRIEGER, Jose Eduardo; SANTOS, Raul D.; PEREIRA, Alexandre CostaObjectives: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Methods: For 14 +/- 3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class. Results: The frequencies of the types of LDLR mutations were: null-mutation (n = 40, 25.6%), defective-mutation (n = 59, 37.8%), and without an identified mutation (n = 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9 +/- 1.9 mmol/L, 7.9 +/- 1.7 mmol/L), compared to those with a defective (8.9 +/- 2.2 mmol/L, 7.0 +/- 2.0 mmol/L), or no mutation (7.9 +/- 1.9 mmol/L, 5.8 +/- 1.9 mmol/L) (p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective (27.1%), and without mutations (47.4%) (p = 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41-58.16, p = 0.02). Conclusions: Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation. (C) 2014 Published by Elsevier Ireland Ltd.
- Phenotypical, Clinical, and Molecular Aspects of Adults and Children With Homozygous Familial Hypercholesterolemia in Iberoamerica(2020) ALVES, Ana Catarina; ALONSO, Rodrigo; DIAZ-DIAZ, Jose Luis; MEDEIROS, Ana Margarida; JANNES, Cinthia E.; MERCHAN, Alonso; VASQUES-CARDENAS, Norma A.; CUEVAS, Ada; CHACRA, Ana Paula; KRIEGER, Jose E.; ARROYO, Raquel; ARRIETA, Francisco; SCHREIER, Laura; CORRAL, Pablo; BANARES, Virginia G.; ARAUJO, Maria B.; BUSTOS, Paula; ASENJO, Sylvia; STOLL, Mario; DELL'OCA, Nicolas; REYES, Maria; RESSIA, Andres; CAMPO, Rafael; MAGANA-TORRES, Maria T.; METHA, Roopa; AGUILAR-SALINAS, Carlos A.; CEBALLOS-MACIAS, Jose J.; MORALES, Alvaro J. Ruiz; MATA, Pedro; BOURBON, Mafalda; SANTOS, Raul D.Objective: Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3 +/- 15.8 years, 38.0% males), and 63 children (age 8.8 +/- 4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in theLDLR. True HoFH due toLDLRvariants had higher total (P=0.015) and LDL (low-density lipoprotein)-cholesterol (P=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (P=0.051) and had a greater frequency of xanthomas (P=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults withLDLRvariants. Children who are true HoFH had higher frequency of major cardiovascular events (P=0.02), coronary heart (P=0.013), and aortic/supra-aortic valve diseases (P=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type ofLDLRvariant. From 118 subjects withLDLRvariants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2LDLRvariants, those with at least one null allele were younger (P=0.003) and had a greater frequency of major cardiovascular events (P=0.038) occurring at an earlier age (P=0.001). Conclusions: There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.
- Delayed functional maturation of human neuronal progenitor cells in vitro(2011) LEPSKI, G.; MACIACZYK, J.; JANNES, C. E.; MACIACZYK, D.; BISCHOFBERGER, J.; NIKKHAH, G.Introduction: Differentiation of neuronal progenitor cells (NPCs) in vitro into functional neurons is dependent on a complex cascade of molecular signaling pathways, many of which remain unknown. More specifically, in human NPCs the relationship between the expression of typical neuronal marker proteins and functional properties, such as firing action potential and synaptic transmission, is not well understood. In the present report, the immunocytochemical, morphological and electrophysiological changes that human NPCs undergo during neuronal differentiation in vitro were investigated. Methods: Human NPCs were differentiated toward a neuronal phenotype. The time course of the expression of neuronal markers and morphological cell changes was mapped and passive and active electrophysiological membrane properties assessed, throughout the neuronal maturation process. Results: The acquisition of neuronal markers preceded functional physiological maturation by several weeks. Cell input resistance decreased in the first 2 weeks as cells became less sensitive to input current, while cell capacitance progressively increased with continued neuronal process growth. Functional maturation was observed only by the fifth/sixth week, preceded by a marked increase in Na+ and K+ currents. In contrast, electrophysiological maturation of rodent precursor cells was observed at the end of the first week in vitro. Functionally, human neuronal cells became capable of firing action potentials and forming active synaptic contacts. Many features of the firing pattern however remained immature. Conclusions: The results showed that human NPCs develop remarkably slowly and retain immature neuronal features for a prolonged period. The importance of Na-dependent activity for proper neuronal maturation is emphasized.
- CORONARY ARTERY CALCIFICATION IS SUPERIOR TO CLASSICAL RISK FACTORS AS PREDICTOR OF CARDIOVASCULAR DISEASE IN FAMILIAL HYPERCHOLESTEROLEMIA(2018) MINAME, Marcio; ALVES, Romulo; MORAES, Sergio; SILVA, Pamela; BITTENCOURT, Marcio; JANNES, Cinthia; PEREIRA, Alexandre; SANTOS, Raul
- Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries(2017) SANTOS, Raul D.; BOURBON, Mafalda; ALONSO, Rodrigo; CUEVAS, Ada; VASQUES-CARDENAS, Norma Alexandra; PEREIRA, Alexandre C.; VILLAMIZAR, Alonso M.; ALVES, Ana Catarina; MEDEIROS, Ana Margarida; JANNES, Cinthia E.; KRIEGER, Jose E.; SCHREIER, Laura; ISLA, Leopoldo Perez de; MAGANA-TORRES, Maria Teresa; STOLL, Mario; MATA, Nelva; OCA, Nicolas Dell; CORRAL, Pablo; ASENJO, Sylvia; BANARES, Virginia G.; REYES, Ximena; MATA, PedroBACKGROUND: There is little information about familial hypercholesterolemia (FH) epidemiology and care in Ibero-American countries. The Ibero-American FH network aims at reducing the gap on diagnosis and treatment of this disease in the region. OBJECTIVE: To describe clinical, molecular, and organizational characteristics of FH diagnosis in Argentina, Brazil, Chile, Colombia, Mexico, Portugal, Spain, and Uruguay. METHODS: Descriptive analysis of country data related to FH cascade screening, molecular diagnosis, clinical practice guidelines, and patient organization presence in Ibero-America. RESULTS: From a conservative estimation of an FH prevalence of 1 of 500 individuals, there should be 1.2 million heterozygous FH individuals in Ibero-America and roughly 27,400 were diagnosed so far. Only Spain, Brazil, Portugal, and Uruguay have active cascade screening programs. The prevalence of cardiovascular disease ranged from 10% to 42% in member countries, and the highest molecular identification rates are seen in Spain, 8.3%, followed by Portugal, 3.8%, and Uruguay with 2.5%. In the 3 countries with more FH patients identified (Spain, Portugal, and Brazil) between 10 and 15 mutations are responsible for 30% to 47% of all FH cases. Spain and Portugal share 5 of the 10 most common mutations (4 in low density lipoprotein receptor [LDLR] and the APOB3527). Spain and Spanishspeaking Latin American countries share 6 of the most common LDLR mutations and the APOB3527. LDL apheresis is available only in Spain and Portugal and not all countries have specific FH diagnostic and treatment guidelines as well as patient organizations. CONCLUSIONS: Ibero-American countries share similar mutations and gaps in FH care.
- 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.
- Equivalent Neurogenic Potential of Wild-Type and GFP-Labeled Fetal-Derived Neural Progenitor Cells Before and After Transplantation Into the Rodent Hippocampus(2011) LEPSKI, Guilherme; JANNES, Cinthia E.; WESSOLLECK, Johanna; KOBAYASHI, Eiji; NIKKHAH, GuidoIntroduction. The hippocampal formation is a specific structure in the brain where neurogenesis occurs throughout adulthood and in which the neuronal cell loss causes various demential states. The main goal of this study was to verify whether fetal neural progenitor cells (NPCs) from transgenic rats expressing green fluorescent protein (GFP) retain the ability to differentiate into neuronal cells and to integrate into the hippocampal circuitry after transplantation. Methods. NPCs were isolated from E14 (gestational age: 14 days postconception) transgenic-Lewis and wild-type Sprague-Dawley rat embryos. Wild-type and transgenic cells were expanded and induced to differentiate into a neuronal lineage in vitro. Immunocytochemical and electrophysiological analysis were performed in both groups. GFP-expressing cells were implanted into the hippocampus and recorded electrophysiologically 3 months thereafter. Immunohistochemical analysis confirmed neuronal differentiation, and the yield of neuronal cells was determined stereologically. Results. NPCs derived from wild-type and transgenic animals are similar regarding their ability to generate neuronal cells in vitro. Neuronal maturity was confirmed by immunocytochemistry and electrophysiology, with demonstration of voltage-gated ionic currents, firing activity, and spontaneous synaptic currents. GFP-NPCs were also able to differentiate into mature neurons after implantation into the hippocampus, where they formed functional synaptic contacts. Conclusions. GFP-transgenic cells represent an important tool in transplantation studies. Herein, we demonstrate their ability to generate functional neurons both in vitro and in vivo conditions. Neurons derived from fetal NPCs were able to integrate into the normal hippocampal circuitry. The high yield of mature neurons generated render these cells important candidates for restorative approaches based on cell therapy.
conferenceObject GENETIC ANALYSIS OF FAMILIAL HYPERCHOLESTEROLAEMIA IN IBEROAMERICAN COUNTRIES(2016) CHORA, J.; MATA, P.; SANTOS, R.; VAZQUEZ, A. Cardenas; STOLL, M.; SCHREIER, L.; CUEVAS, A.; ALVES, A. C.; MEDEIROS, A. M.; ISLA, L. Perez; JANNES, C.; PEREIRA, A.; DELL'OCA, N.; REYES, X.; CORRAL, P.; BANARES, V.; MAGANA-TORRES, T.; AGUILAR-SALINAS, C.; ALONSO, R.; BOURBON, M.