Depósito Académico
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214 results
Results
- Fibrosis miocárdica: hacia una nueva aproximación(Elsevier España, S.L.U, 2019) Gallego-Muñoz, C. (Catalina); Saldarriaga, C.I. (Clara Inés); Diez-Martinez, J. (Javier)La fibrosis miocárdica, que se evidencia en aquellas enfermedades que se presentan con sobrecarga de presión, como la estenosis aórtica o la cardiopatía hipertensiva, constituye una forma difusa de fibrosis progresiva y de tipo reactivo, con gran impacto en la función cardíaca, manifestada como disfunción diastólica y/o sistólica, desarrollo de arritmias e isquemia miocárdica. Se considera que precede los demás cambios estructurales del ventrículo izquierdo en este tipo de enfermedades y se caracteriza por la presencia de una matriz extracelular rica en fibras de colágeno tipos I y III con alto grado de entrecruzamiento. Constituye un marcador pronóstico y existe una correlación directa entre el grado de fibrosis miocárdica y desenlaces como hospitalización por insuficiencia cardiaca y mortalidad. El abordaje diagnóstico de la fibrosis miocárdica en este grupo de pacientes puede realizarse a través de biomarcadores químicos o de imagen; los primeros aún son materia de estudio para conseguir mayor precisión en sus resultados y la resonancia nuclear cardíaca con técnica de mapeo de T1 es la técnica de imagen más atractiva. El tratamiento de la fibrosis miocárdica en las enfermedades por sobrecarga de presión, está dado por el manejo estándar de la insuficiencia cardíaca, en cuyo caso los antihipertensivos de la familia de los IECA/ARAII se han relacionado en mayor nivel con modificación en el grado de fibrosis miocárdica; sin embargo, se necesitan más estudios para definir el uso de nuevos blancos terapéuticos que complementen el tratamiento y mejoren los desenlaces en este grupo de pacientes.
- Characterization of biventricular alterations in myocardial (reverse) remodelling in aortic bandinginduced chronic pressure overload(Springer Science and Business Media LLC, 2019) Almeida-Coelho, J. (João); Falcão-Pires, I. (Ines); Diez-Martinez, J. (Javier); Moura, C. (Cláudia); Sousa-Mendes, C. (Cláudia); Miranda-Silva, D. (Daniela); Leite-Moreira, A. (Adelino); Gonzalez, A. (Arantxa); Conceição, G. (Glória); Gonçalves-Rodrigues, P. (Patrícia); Lima, T. (Tania); Hamdani, N. (Nazha); Linke, W.A. (Wolfgang A.)Aortic Stenosis (AS) is the most frequent valvulopathy in the western world. Traditionally aortic valve replacement (AVR) has been recommended immediately after the onset of heart failure (HF) symptoms. However, recent evidence suggests that AVR outcome can be improved if performed earlier. After AVR, the process of left ventricle (LV) reverse remodelling (RR) is variable and frequently incomplete. In this study, we aimed at detecting mechanism underlying the process of LV RR regarding myocardial structural, functional and molecular changes before the onset of HF symptoms. Wistar-Han rats were subjected to 7-weeks of ascending aortic-banding followed by a 2-week period of debanding to resemble AS-induced LV remodelling and the early events of AVR-induced RR, respectively. This resulted in 3 groups: Sham (n = 10), Banding (Ba, n = 15) and Debanding (Deb, n = 10). Concentric hypertrophy and diastolic dysfunction (DD) were patent in the Ba group. Aortic-debanding induced RR, which promoted LV functional recovery, while cardiac structure did not normalise. Cardiac parameters of RV dysfunction, assessed by echocardiography and at the cardiomyocyte level prevailed altered after debanding. After debanding, these alterations were accompanied by persistent changes in pathways associated to myocardial hypertrophy, fibrosis and LV inflammation. Aortic banding induced pulmonary arterial wall thickness to increase and correlates negatively with effort intolerance and positively with E/e' and left atrial area. We described dysregulated pathways in LV and RV remodelling and RR after AVR. Importantly we showed important RV-side effects of aortic constriction, highlighting the impact that LV-reverse remodelling has on both ventricles.
- Galectin-3 inhibition with modified citrus pectin in hypertension(2021) Liu, E. (Elizabeth); Zampierollo, G. (Giovanna); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Lau, E.S. (Emily S.); Paniagua, S.M. (Samantha M.); Sarma, A.A. (Amy A.); Wang, T.J. (Thomas J.); Ho, J. E. (Jennifer H.)We investigated the effect of galectin-3 (Gal-3) inhibition with modified citrus pectin on markers of collagen metabolism in a proof-of-concept randomized placebo-controlled trial of participants with elevated Gal-3 levels and hypertension. Although higher Gal-3 levels were associated with female sex, diabetes, and reduced glomerular filtration rate in cross-sectional analyses, treatment with modified citrus pectin did not change collagen markers. The effect of Gal-3 inhibition among individuals with heart failure warrants further investigation. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
- The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy - A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy(2021) Brunner-La-Rocca, H.P. (Hans-Peter); Abdul-Hamid, M.A. (Myrurgia A.); Wang, P. (Ping); Empel, V.P.M. (Vanessa P. M.) van; Raafs, A.G. (Anne G.); Diez-Martinez, J. (Javier); Verdonschot, J.A.J. (Job A. J.); Hazebroek, M.R. (Mark R.); Adriaans, B.P. (Bouke P.); Bekkers, S.C.A.M. (Sebastian C. A. M.); Henkens, M.T.H.M. (Michiel T. H. M.); Heymans, S. (Stephane); Brunner, H.G. (Han G.); González-Miqueo, A. (Aránzazu); Derks, K. (Kasper); Knackstedt, C. (Christian)Aims To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients. Methods and results We quantified fibrosis in 209 DCM patients at three levels: (i) non-invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino-terminal propeptide of procollagen type III (PIIINP) and carboxy-terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life-threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90-6.60; P < 0.001 and PICP 1.02, 95% CI 1.01-1.03; P = 0.001]. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log-rank P < 0.001). RNA-sequencing and gene enrichment analysis of EMB showed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE-/PICP-). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles. Conclusion The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro-fibrotic and pro-inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.
- Cartilage intermediate layer protein 1 (CILP1): a novel mediator of cardiac extracellular matrix remodelling(2017) Veld, R.C. (Roel C.) op't; Nieuwenhoven, F.A. (Frans A.) van; Diez-Martinez, J. (Javier); Heymans, S. (Stephane); Munts, C. (Chantal); Schroen, B. (Blanche); Bilsen, M. (Marc) van; González-Miqueo, A. (Aránzazu)Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r2¿=¿0.83) and non-structural (e.g. TGFB3 r2¿=¿0.75) ECM proteins. Gene enrichment analysis further underscored the involvement of CILP1 in human cardiac ECM remodelling and TGFß signalling. Myocardial CILP1 protein levels were significantly elevated in human infarct tissue and in aortic valve stenosis patients. CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Cardiac fibroblasts were found to be the primary source of cardiac CILP1 expression. Recombinant CILP1 inhibited TGFß-induced ¿SMA gene and protein expression in cardiac fibroblasts. In addition, CILP1 overexpression in HEK293 cells strongly (5-fold p¿<¿0.05) inhibited TGFß signalling activity. In conclusion, our study identifies CILP1 as a new cardiac matricellular protein interfering with pro-fibrotic TGFß signalling, and as a novel sensitive marker for cardiac fibrosis.
- Atherosclerosis: Is it time for a new name?(2009) Beloqui, O. (Óscar); Diez-Martinez, J. (Javier)
- The activity of circulating dipeptidyl peptidase-4 is associated with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus(2013) Huerta, A. (Ana); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Ravassa, S. (Susana); Barba, J. (Joaquín); Gonzalez, A. (Arantxa); Coma-Canella, I. (Isabel)Background: Patients with type 2 diabetes mellitus (T2DM) present subclinical left ventricular systolic and/or diastolic dysfunction (LVD). Dipeptidyl peptidase-4 (DPP4) inactivates peptides that possess cardioprotective actions. Our aim was to analyze whether the activity of circulating DPP4 is associated with echocardiographically defined LVD in asymptomatic patients with T2DM. Methods: In this cross-sectional study, we examined 83 T2DM patients with no coronary or valve heart disease and 59 age and gender-matched non-diabetic subjects. Plasma DPP4 activity (DPP4a) was measured by enzymatic assay and serum amino-terminal pro-brain natriuretic peptide (NT-proBNP) was measured by enzyme-linked immunosorbent assay. LV function was assessed by two-dimensional echocardiographic imaging, targeted M-mode recordings and Doppler ultrasound measurements. Differences in means were assessed by t-tests and one-way ANOVA. Associations were assessed by adjusted multiple linear regression and logistic regression analyses. Results: DPP4a was increased in T2DM patients as compared with non-diabetic subjects (5855 ± 1632 vs 5208 ± 957 pmol/min/mL, p < 0.05). Clinical characteristics and echocardiographic parameters assessing LV morphology were similar across DPP4a tertiles in T2DM patients. However, prevalence of LVD progressively increased across incremental DPP4a tertiles (13%, 39% and 71%, all p < 0.001). Multivariate regression analysis confirmed the independent associations of DPP4a with LVD in T2DM patients (p < 0.05). Similarly, multiple logistic regression analysis showed that an increase of 100 pmol/min/min plasma DPP4a was independently associated with an increased frequency of LVD with an adjusted odds ratio of 1.10 (95% CI, 1.04 to 1.15, p = 0.001). Conclusions: An excessive activity of circulating DPP4 is independently associated with subclinical LVD in T2DM patients. Albeit descriptive, these findings suggest that DPP4 may be involved in the mechanisms of LVD in T2DM.
- Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice(2013) Benetos, A.(Athanase); Lacolley, P. (Patrick); Calvier, L. (Laurent); Diez-Martinez, J. (Javier); Fay, R. (Reynaud); Zannad, F. (Faiez); Lopez-Andres, N. (Natalia); Rossignol, P.(Patrick); Labat, C. (Carlos)Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month- old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic, inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1–null mice was studied. Vascular smooth muscle cells were treated with CT-1 (10 −9 mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic modulus curve of old CT-1–null mice was shifted rightward as compared with wild-type mice, indicating decreased arterial stiffness. Media thickness and wall fibrosis were lower in CT-1–null mice. CT-1–null mice showed decreased levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins, and antioxidant enzyme activities were increased. CT-1–null mice displayed a 5-month increased median longevity compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic, senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the aging process
- Association of phagocytic NADPH oxidase activity with hypertensive heart disease: a role for cardiotrophin-1?(2014) Landecho, M.F. (Manuel F.); Moreno, M.U. (María Ujué); Pejenaute, Á. (Ángel); Beloqui, O. (Óscar); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Zalba, G. (Guillermo)Left ventricular hypertrophy (LVH) is an independent marker of mortality in hypertension. Although the mechanisms contributing to LVH are complex, inflammation and oxidative stress may favor its development. We analyzed the association of the phagocytic NADPH oxidase–mediated superoxide anion release and LVH in patients with essential hypertension and the role of cardiotrophin-1 (CT-1) and interleukin-6 (IL-6), cytokines implicated in cardiac growth. Blood pressure, echocardiography data, and serum CT-1 and IL-6 levels were obtained in 140 subjects: 18 normotensives without LVH, 42 hypertensives without LVH, and 80 hypertensives with LVH. The NADPH oxidase–dependent superoxide production was assessed by chemiluminescence in peripheral blood mononuclear cells. Peripheral blood mononuclear cells were stimulated with CT-1 in vitro. Superoxide anion production by peripheral blood mononuclear cells associated with LVH and correlated with the left ventricular mass index. Serum CT-1 and IL-6 levels, which associated with the left ventricular mass index, correlated with superoxide production. Serum CT-1 and IL-6 levels were correlated. CT-1 stimulated NADPH oxidase superoxide production in peripheral blood mononuclear cells, which resulted in an increased release of IL-6. Our results show that superoxide anion production by the phagocytic NADPH oxidase associates with hypertensive heart disease, being significantly enhanced in hypertensive patients with LVH. This may be attributable to the activation of the NADPH oxidase by CT-1 and the subsequent release of IL-6. The phagocytic NADPH oxidase may be a therapeutic target in hypertensive heart disease
- Association of cardiotrophin-1 with myocardial fibrosis in hypertensive patients with heart failure(2014) Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Gonzalez, A. (Arantxa); Rabago, G. (Gregorio); Larman, M. (Mariano)Cardiotrophin-1 has been shown to be profibrogenic in experimental models. The aim of this study was to analyze whether cardiotrophin-1 is associated with left ventricular end-diastolic stress and myocardial fibrosis in hypertensive patients with heart failure. Endomyocardial biopsies from patients (n=31) and necropsies from 7 control subjects were studied. Myocardial cardiotrophin-1 protein and mRNA and the fraction of myocardial volume occupied by collagen were increased in patients compared with controls ( P <0.001). Cardiotrophin-1 overexpression in patients was localized in cardiomyocytes. Cardiotrophin-1 protein was correlated with collagen type I and III mRNAs ( r =0.653, P <0.001; r =0.541, P <0.01) and proteins ( r =0.588, P <0.001; r =0.556, P <0.005) in all subjects and with left ventricular end-diastolic wall stress ( r =0.450; P <0.05) in patients. Plasma cardiotrophin-1 and N-terminal pro-brain natriuretic peptide and serum biomarkers of myocardial fibrosis (carboxy-terminal propeptide of procollagen type I and amino-terminal propeptide of procollagen type III) were increased ( P <0.001) in patients compared with controls. Plasma cardiotrophin-1 was correlated with N-terminal pro-brain natriuretic peptide ( r =0.386; P <0.005), carboxy- terminal propeptide of procollagen type I ( r =0.550; P <0.001), and amino-terminal propeptide of procollagen type III ( r =0.267; P <0.05) in all subjects. In vitro, cardiotrophin-1 stimulated the differentiation of human cardiac fibroblast to myofibroblasts ( P <0.05) and the expression of procollagen type I ( P <0.05) and III ( P <0.01) mRNAs. These findings show that an excess of cardiotrophin-1 is associated with increased collagen in the myocardium of hypertensive patients with heart failure. It is proposed that exaggerated cardiomyocyte production of cardiotrophin-1 in response to increased left ventricular end-diastolic stress may contribute to fibrosis through stimulation of fibroblasts in heart failure of hypertensive origin