MARIANA MEIRA CLAVE
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Increased Expression of Platelet Membrane Glycoprotein IIb/IIIa (GPIIb/IIIa) is Associated With Pulmonary Vasoreactivity After Pediatric Cardiac Surgery.(2018) MAEDA, Nair Y.; CLAVE, Mariana M.; CARVALHO, Eloisa S.; GALAS, Filomena R.; BYDLOWSKI, Sergio P.; LOPES, Antonio A.- Relation of Cytokine Profile to Clinical and Hemodynamic Features in Young Patients With Congenital Heart Disease and Pulmonary Hypertension(2017) ZORZANELLI, Leina; MAEDA, Nair; CLAVE, Mariana; THOMAZ, Ana; GALAS, Filomena; RABINOVITCH, Marlene; LOPES, AntonioIn congenital heart disease, severity of pulmonary hypertension and operability is defined by noninvasive parameters (clinical history, physical examination, and echocardiography) and sometimes, cardiac catheterization. We investigated how circulating levels of inflammatory mediators correlate with such parameters in a young pediatric population (age, 2.0 months to 3.1 years) and the effects of preoperative pulmonary vasodilator therapy with sildenafil. Cytokines were analyzed in serum using chemiluminescence signals. In the whole patient group (n = 47), interleukin 17E, a Th2 immune response mediator increased with increasing age, considered as a parameter of disease severity (R-2 = 0.24, p <0.001), whereas the angiogenic chemokine growth-regulated oncogene alpha decreased (R-2 = 0.21, p = 0.001). Macrophage migration inhibitory factor chemokine was greater in subjects with elevated pulmonary vascular resistance (n = 16, p = 0.022), whereas regulated on activation, normal T cell expressed and secreted chemokine was greater in subjects with pulmonary congestion due to increased pulmonary blood flow (n = 31, p = 0.037). The observations were the same for the specific subpopulation of patients with Down syndrome (p = 0.009 and p = 0.012 for migration inhibitory factor and regulated on activation, normal T cell expressed and secreted in the respective subgroups). Sildenafil administration to patients with elevated pulmonary vascular resistance resulted in improvement of pulmonary blood flow (p = 0.012) and systemic oxygen saturation (p = 0.010), with a decrease in serum interleukin 6 (p = 0.027) and soluble ICAM-1 (p = 0.011). In conclusion, levels of circulating inflammatory molecules seem to correlate with disease severity in this population, with potential pathophysiological and therapeutic implications.
- Decreased circulating thrombomodulin is improved by tadalafil therapy in hypoxemic patients with advanced pulmonary arterial hypertension(2016) MAEDA, N. Y.; CLAVE, M. M.; BYDLOWSKI, S. P.; LOPES, A. A.Introduction: Advanced pulmonary arterial hypertension (PAH) in patients with congenital cardiac communications and right -to -left shunting (Eisenmenger syndrome - PAH-ES) is associated with hypoxemia and decreased circulating levels o{thrombomodulin (TM), probably reflecting decreased endothelial TM production. The combination of these two factors has been shown to induce fibrin deposition, with increased risk of thrombosis, a well known complication in this syndrome. Patients and methods: We tested the hypothesis that vasodilator therapy with the phosphocliesterase-5 inhibitor taclalafil, an approved drug for management of PAH could improve endothelial dysfunction markers, in particular plasma TM, in addition to improving the physical capacity (expected effect of pulmonary vasodilatation) in PAHES patients. This was a prospective observational study of treatment naive patients subjected to specific PAH therapy. Fifteen patients aged 12 to 51 years (median 30 years) were treated for 6 months with a single daily dose of 40 mg oral tadalafil. The physical capacity (distance walked during the 6 -min walk test - 6MWD), systemic oxygen saturation and laboratory parameters were measured at baseline, and 90 days and 180 days of treatment. Results: Plasma TM, which was decreased at baseline compared to controls (p < 0.001) increased at 90 and 180 days (p = 0.003), and this was directly related (r = 0.57, p = 0.026) to improvement of oxygen saturation (p = 0.008). Heightened baseline tissue -type plasminogen activator decreased during treatment (p = 0.010), while heightened von Willebrancl factor antigen remained unchanged. The 6MWD improved significantly (p < 0.001). Conclusion: Tadalafil therapy improved circulating TM and tissue -type plasminogen activator, in addition to improving the physical capacity and oxygen saturation in PAM ES patients. (C) 2016 Published by Elsevier Ltd.
conferenceObject Circulating Levels of RANTES Chemokine Correlate With Pulmonary Hemodynamic Patterns in Pediatric Patients With Congenital Cardiac Communications(2018) SOUZA, Maria F.; MAEDA, Nair Y.; CASTRO, Claudia R.; ZORZANELLI, Leina; CLAVE, Mariana M.; LOPES, Antonio A.bookPart Alterações endoteliais na hipertensão pulmonar(2016) CLAVé, Mariana Meira; LOPES, Antonio Augusto- Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease(2019) CLAVE, Mariana M.; MAEDA, Nair Y.; THOMAZ, Ana M.; BYDLOWSKI, Sergio P.; LOPES, Antonio A.Background Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity. Methods We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days. Results Compared to controls, patients had elevated baseline beta-thromboglobulin (beta-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of beta-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05). Conclusion In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.
- Serum Cytokines in Young Pediatric Patients with Congenital Cardiac Shunts and Altered Pulmonary Hemodynamics(2016) ZORZANELLI, Leina; MAEDA, Nair Yukie; CLAVE, Mariana Meira; AIELLO, Vera Demarchi; RABINOVITCH, Marlene; LOPES, Antonio AugustoBackground and Objective. Inflammation is central in the pathogenesis of pulmonary hypertension. We investigated how serum cytokines correlate with clinical features, hemodynamics, and lung histology in young patients with pulmonary hypertension associated with congenital cardiac shunts. Design. Prospective, observational study. Methods and Results. Patients (n = 44) were aged 2.6 to 37.6 months. Group I patients (n = 31) were characterized by pulmonary congestion and higher pulmonary blood flow compared to group II (p = 0.022), with no need for preoperative cardiac catheterization. Group II patients (n = 13) had no congestive features. At catheterization, they had elevated pulmonary vascular resistance (5.7 [4.4-7.4] Wood units.m(2), geometric mean with 95% CI). Cytokines were measured by chemiluminescence. Macrophage migration inhibitory factor (MIF) was found to be inversely related to pulmonary blood flow(r = -0.33,p = 0.026) and was higher in group II (high pulmonary vascular resistance) compared to group I (high pulmonary blood flow) (p = 0.017). In contrast, RANTES chemokine (regulated on activation, normal T cell expressed and secreted) was characteristically elevated in Group I (p = 0.022). Interleukin 16 was also negatively related to pulmonary blood flow (r(s) = -0.33, p = 0.029) and was higher in patients with obstructive vasculopathy at intraoperative lung biopsy (p = 0.021). Conclusion. Cytokines seem to be important and differentially regulated in subpopulations of young patients with cardiac shunts.
- Factors influencing outcomes in patients with Eisenmenger syndrome: a nine-year follow-up study(2017) CLAVE, Mariana M.; MAEDA, Nair Y.; CASTRO, Claudia R. P.; BYDLOWSKI, Sergio P.; LOPES, Antonio A.In patients with Eisenmenger syndrome, life expectancy is usually longer than in patients with other forms of pulmonary arterial hypertension (PAH). We conducted a cohort study in which patients were followed over a long period of time in an attempt to identify potential predictors of clinical outcomes. Sixty-seven treatment-naive patients were enrolled (age range = 12-60 years; median age = 33 years). Baseline demographic, diagnostic, and functional parameters, plasma levels of endothelial dysfunction markers, and treatment-related data were tested for possible correlations with event-free survival. Patients were started on oral PAH drugs at the beginning of follow-up (n = 23), during follow-up (n = 33), or remained untreated (n = 11). The duration of follow-up was 0.54-9.89 years (median = 7.13 years), with an overall survival rate of 82% and an event-free survival rate of 70%. The estimated mean for event-free survival time was 7.71 years (95% confidence interval [CI] = 6.86-8.55 years). Of the 16 variables that were analyzed, the duration of exposure to PAH drugs was identified as an independent protective factor (hazard ratio [HR] = 0.25 for quartiles, 95% CI = 0.14-0.47, P < 0.001). The initial functional class (HR = 3.07; 95% CI = 1.01-9.34; P = 0.048), the severity of right ventricular dysfunction (HR = 2.51 [mild, moderate or severe dysfunction]; 95% CI = 1.22-5.19; P = 0.013) and plasma von Willebrand factor concentration (HR = 1.74 for quartiles; 95% CI = 1.07-2.83; P = 0.026) were identified as risk factors. The length of exposure to oral PAH therapies influences survival favorably in Eisenmenger patients. This may be of interest for communities where access to medications is restricted.