Staff member

Dolores Blanco Almazán

PhD Student
Biomedical Signal Processing and Interpretation
+34 934 020 559
Staff member publications

Uriarte, J. J., Meirelles, T., Del Blanco, D. G., Nonaka, P. N., Campillo, N., Sarri, E., Navajas, D., Egea, G., Farré, R., (2016). Early impairment of lung mechanics in a murine model of marfan syndrome PLoS ONE 11, (3), e0152124

Early morbidity and mortality in patients with Marfan syndrome (MFS) -a connective tissue disease caused by mutations in fibrillin-1 gene- are mainly caused by aorta aneurysm and rupture. However, the increase in the life expectancy of MFS patients recently achieved by reparatory surgery promotes clinical manifestations in other organs. Although some studies have reported respiratory alterations in MFS, our knowledge of how this connective tissue disease modifies lung mechanics is scarce. Hence, we assessed whether the stiffness of the whole lung and of its extracellular matrix (ECM) is affected in a well-characterized MFS mouse model (FBN1C1039G/+). The stiffness of the whole lung and of its ECM were measured by conventional mechanical ventilation and atomic force microscopy, respectively. We studied 5-week and 9-month old mice, whose ages are representative of early and late stages of the disease. At both ages, the lungs of MFS mice were significantly more compliant than in wild type (WT) mice. By contrast, no significant differences were found in local lung ECM stiffness. Moreover, histopathological lung evaluation showed a clear emphysematous- like pattern in MFS mice since alveolar space enlargement was significantly increased compared with WT mice. These data suggest that the mechanism explaining the increased lung compliance in MFS is not a direct consequence of reduced ECM stiffness, but an emphysema-like alteration in the 3D structural organization of the lung. Since lung alterations in MFS are almost fully manifested at an early age, it is suggested that respiratory monitoring could provide early biomarkers for diagnosis and/or follow-up of patients with the Marfan syndrome.

Castillo, Y., Blanco, D., Cámara, M.A., Jané, R., (2016). Study of time-frequency characteristics of single snores: extracting new information for sleep apnea diagnosis CASEIB Proceedings XXXIV Congreso Anual de la Sociedad Española de Ingeniería Biomédica (CASEIB 2016) , Sociedad Española de Ingeniería Biomédica (Valencia, Spain) , 105-108

Obstructive sleep apnea (OSA) is a highly prevalent chronic disease, especially in elderly and obese population. Despite constituting a huge health and economic problem, most patients remain undiagnosed due to limitations in current strategies. Therefore, it is essential to find cost-effective diagnostic alternatives. One of these novel approaches is the analysis of acoustic snoring signals. Snoring is an early symptom of OSA which carries pathophysiological information of high diagnostic value. For this reason, the main objective of this work is to study the characteristics of single snores of different types, from healthy and OSA subjects. To do that, we analyzed snoring signals from previous databases and developed an experimental protocol to record simulated OSA-related sounds and characterize the response of two commercial tracheal microphones. Automatic programs for filtering, downsampling, event detection and time-frequency analysis were built in MATLAB. We found that time-frequency maps and spectral parameters (central, mean and peak frequency and energy in the 100-500 Hz band) allow distinguishing regular snores of healthy subjects from non-regular snores and snores of OSA subjects. Regarding the two commercial microphones, we found that one of them was a suitable snoring sensor, while the other had a too restricted frequency response. Future work shall include a higher number of episodes and subjects, but our study has contributed to show how important the differences between regular and non-regular snores can be for OSA diagnosis, and how much clinically relevant information can be extracted from time-frequency maps and spectral parameters of single snores.

Crosas-Molist, E., Meirelles, T., López-Luque, J., Serra-Peinado, C., Selva, J., Caja, L., Gorbenko Del Blanco, D., Uriarte, J. J., Bertran, E., Mendizábal, Y., Hernández, V., García-Calero, C., Busnadiego, O., Condom, E., Toral, D., Castellà, M., Forteza, A., Navajas, D., Sarri, E., Rodríguez-Pascual, F., Dietz, H. C., Fabregat, I., Egea, G., (2015). Vascular smooth muscle cell phenotypic changes in patients with marfan syndrome Arteriosclerosis, Thrombosis, and Vascular Biology 35, (4), 960-972

Objective - Marfan's syndrome is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix microfibrils and chronic tissue growth factor (TGF)-β signaling. TGF-β is a potent regulator of the vascular smooth muscle cell (VSMC) phenotype. We hypothesized that as a result of the chronic TGF-β signaling, VSMC would alter their basal differentiation phenotype, which could facilitate the formation of aneurysms. This study explores whether Marfan's syndrome entails phenotypic alterations of VSMC and possible mechanisms at the subcellular level. Approach and Results - Immunohistochemical and Western blotting analyses of dilated aortas from Marfan patients showed overexpression of contractile protein markers (α-smooth muscle actin, smoothelin, smooth muscle protein 22 alpha, and calponin-1) and collagen I in comparison with healthy aortas. VSMC explanted from Marfan aortic aneurysms showed increased in vitro expression of these phenotypic markers and also of myocardin, a transcription factor essential for VSMC-specific differentiation. These alterations were generally reduced after pharmacological inhibition of the TGF-β pathway. Marfan VSMC in culture showed more robust actin stress fibers and enhanced RhoA-GTP levels, which was accompanied by increased focal adhesion components and higher nuclear localization of myosin-related transcription factor A. Marfan VSMC and extracellular matrix measured by atomic force microscopy were both stiffer than their respective controls. Conclusions - In Marfan VSMC, both in tissue and in culture, there are variable TGF-β-dependent phenotypic changes affecting contractile proteins and collagen I, leading to greater cellular and extracellular matrix stiffness. Altogether, these alterations may contribute to the known aortic rigidity that precedes or accompanies Marfan's syndrome aneurysm formation.

Keywords: Actin, Aortic aneurysms, Aortic stiffness, Extracellular matrix, Focal adhesion, Myocardin, RhoA, TGF-β

da Palma, R. K., Farré, R., Montserrat, J. M., Gorbenko Del Blanco, D., Egea, G., de Oliveira, L. V. F., Navajas, D., Almendros, I., (2015). Increased upper airway collapsibility in a mouse model of Marfan syndrome Respiratory Physiology & Neurobiology 207, 58-60

Marfan syndrome (MFS) is a genetic disorder caused by mutations in the FBN1 gene that codifies for fibrilin-1. MFS affects elastic fiber formation and the resulting connective tissue shows abnormal tissue laxity and organization. Although an increased prevalence of obstructive sleep apnea among patients with MFS has been described, the potential effects of this genetic disease on the collapsible properties of the upper airway are unknown. The aim of this study was to assess the collapsible properties of the upper airway in a mouse model of MFS Fbn1(C1039G/+) that is representative of most of the clinical manifestations observed in human patients. The upper airway in wild-type and Marfan mice was cannulated and its critical pressure (Pcrit) was measured in vivo by increasing the negative pressure through a controlled pressure source. Pcrit values from MFS mice were higher (less negative) compared to wild-type mice (-3.1±0.9cmH2O vs. -7.8±2.0cm H2O) suggesting that MFS increases the upper airway collapsibility, which could in turn explain the higher prevalence of OSA in MFS patients.

Keywords: Marfan syndrome, Obstructive sleep apnea, Upper airway collapsibility

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