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Publicaciones científicas más recientes (desde 2010)

Autores: Ferreira, J. P.; Machu, J. L.; Girerd, N. ; et al.
Revista: ESC HEAR FAILURE
ISSN 2055-5822  Vol. 5  Nº 1  2018  págs. 139-148
AIMS: Myocardial fibrosis alters the cardiac architecture favouring the development of cardiac dysfunction, including arrhythmias and heart failure. Reducing myocardial fibrosis may improve outcomes through the targeted diagnosis and treatment of emerging fibrotic pathways. The European-Commission-funded 'FIBROTARGETS' is a multinational academic and industrial consortium with the main aims of (i) characterizing novel key mechanistic pathways involved in the metabolism of fibrillary collagen that may serve as biotargets, (ii) evaluating the potential anti-fibrotic properties of novel or repurposed molecules interfering with the newly identified biotargets, and (iii) characterizing bioprofiles based on distinct mechanistic phenotypes involving the aforementioned biotargets. These pathways will be explored by performing a systematic and collaborative search for mechanisms and targets of myocardial fibrosis. These mechanisms will then be translated into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. METHODS AND RESULTS: The FIBROTARGETS consortium has merged data from 12 patient cohorts in a common database available to individual consortium partners. The database consists of >12 000 patients with a large spectrum of cardiovascular clinical phenotypes. It integrates community-based population cohorts, cardiovascular risk cohorts, and heart failure cohorts. CONCLUSIONS: The FIBROTARGETS biomarker programme is aimed at exploring fibrotic pathways allowing the bioprofiling of patients into specific 'fibrotic' phenotypes and identifying new therapeutic targets that will potentially enable the development of novel and tailored anti-fibrotic therapies for heart failure.
Autores: Treibel, T. A.; López, B; González, A; et al.
Revista: EUROPEAN HEART JOURNAL
ISSN 0195-668X  Vol. 39  Nº 8  2018  págs. 699 - 709
Aims To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n=80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyo-cardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P<0.001) compared with controls, and higher (P<0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P<0.001) but not ECV. Both LGE and ECV correlated independently (P<0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix.
Autores: Verjans, R. ; Peters,T. ; Beaumont Javier; et al.
Revista: HYPERTENSION
ISSN 0194-911X  Vol. 71  Nº 2  2018  págs. 280 - 288
Pressure overload causes cardiac fibroblast activation and transdifferentiation, leading to increased interstitial fibrosis formation and subsequently myocardial stiffness, diastolic and systolic dysfunction, and eventually heart failure. A better understanding of the molecular mechanisms underlying pressure overload-induced cardiac remodeling and fibrosis will have implications for heart failure treatment strategies. The microRNA (miRNA)-221/222 family, consisting of miR-221-3p and miR-222-3p, is differentially regulated in mouse and human cardiac pathology and inversely associated with kidney and liver fibrosis. We investigated the role of this miRNA family during pressure overload-induced cardiac remodeling. In myocardial biopsies of patients with severe fibrosis and dilated cardiomyopathy or aortic stenosis, we found significantly lower miRNA-221/222 levels as compared to matched patients with nonsevere fibrosis. In addition, miRNA-221/222 levels in aortic stenosis patients correlated negatively with the extent of myocardial fibrosis and with left ventricular stiffness. Inhibition of both miRNAs during AngII (angiotensin II)-mediated pressure overload in mice led to increased fibrosis and aggravated left ventricular dilation and dysfunction. In rat cardiac fibroblasts, inhibition of miRNA-221/222 derepressed TGF-ß (transforming growth factor-ß)-mediated profibrotic SMAD2 (mothers against decapentaplegic homolog 2) signaling and downstream gene expression, whereas overexpression of both miRNAs blunted TGF-ß-induced profibrotic signaling. We found that the miRNA-221/222 family may target several genes involved in TGF-ß signaling, including JNK1 (c-Jun N-terminal kinase 1), TGF-ß receptor 1 and TGF-ß receptor 2, and ETS-1 (ETS proto-oncogene 1). Our findings show that heart failure-associated downregulation of the miRNA-221/222 family enables profibrotic signaling in the pressure-overloaded heart.
Autores: Trippel, T. D.; Van Linthout, S.; Westermann, D.; et al.
Revista: EUROPEAN JOURNAL OF HEART FAILURE
ISSN 1388-9842  Vol. 20  Nº 3  2018  págs. 460 - 470
Aim Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial remodelling including severe pro-fibrotic changes contributing to an increase in left ventricular stiffness and diastolic dysfunction. Serum C-terminal propeptide of procollagen type I (PIP) strongly correlates with the turnover of extracellular cardiac matrix proteins and fibrosis. Torasemide, but not furosemide, was described to reduce collagen type I synthesis in clinically unstable patients with heart failure with reduced ejection fraction. We evaluated whether its effect translated to HFpEF patients with type 2 diabetes mellitus (T2DM) and abnormal basal PIP levels. Methods and results We performed a relatively small, single-centre, randomised, double-blind, two-arm parallel-group, active controlled clinical trial in 35 HFpEF patients with T2DM to determine the effects of a 9-month treatment with torasemide vs. furosemide on changes of serum PIP levels. Patients with increased PIP levels (>= 110 ng/mL), or evidence of structural changes with a left atrial volume index (LAVI) > 29 mL/m(2) and abnormal PIP levels (>= 70 ng/mL), were eligible to participate. Fifteen patients were female (42%), mean age was 69 years, body mass index was 34.7 kg/m(2), 83% were in New York Heart Association class II/III. Echocardiographic characteristics showed a mean left ventricular ejection fraction of > 60%, a left ventricular mass index > 120 g/m(2), an E/e' ratio of 14, and a LAVI of 40 mL/m(2) ...
Autores: Gyongyosi, M. ; Winkler, J. ; Ramos, I. ; et al.
Revista: EUROPEAN JOURNAL OF HEART FAILURE
ISSN 1388-9842  Vol. 19  Nº 2  2017  págs. 177 - 191
Myocardial fibrosis refers to a variety of quantitative and qualitative changes in the interstitial myocardial collagen network that occur in response to cardiac ischaemic insults, systemic diseases, drugs, or any other harmful stimulus affecting the circulatory system or the heart itself. Myocardial fibrosis alters the architecture of the myocardium, facilitating the development of cardiac dysfunction, also inducing arrhythmias, influencing the clinical course and outcome of heart failure patients. Focusing on myocardial fibrosis may potentially improve patient care through the targeted diagnosis and treatment of emerging fibrotic pathways. The European Commission funded the FIBROTARGETS consortium as a multinational academic and industrial consortium with the primary aim of performing a systematic and collaborative search of targets of myocardial fibrosis, and then translating these mechanisms into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. This review focuses on those methodological and technological aspects considered and developed by the consortium to facilitate the transfer of the new mechanistic knowledge on myocardial fibrosis into potential biomedical applications.
Autores: Moreno, MU; Gavira, Juan José; et al.
Revista: MEDICAL CLINICS OF NORTH AMERICA
ISSN 0025-7125  Vol. 101  Nº 1  2017  págs. 43-52
The chronic hemodynamic load imposed by hypertension on the left ventricle leads to lesions in the myocardium that result in structural remodeling, which provides support for alterations in cardiac function, perfusion, and electrical activity that adversely influence the clinical evolution of hypertensive heart disease. Management must include detecting, reducing, and reversing left ventricular hypertrophy, as well as the detection and repair of microscopic lesions responsible for myocardial remodeling. Reducing the burden associated with hypertensive heart disease can be targeted using personalized treatment. The noninvasive, biomarker-mediated identification of subsets of patients with hypertensive heart disease is essential to provide personalized treatment.
Autores: Ravassa, S; López, B; Querejeta, R.; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 1473-5598  Vol. 35  Nº 4  2017  págs. 853 - 861
OBJECTIVE: Myocardial fibrosis is associated with alterations in the cross-linking and deposition of collagen type I (CCL and CD, respectively). We aimed to evaluate whether the combination of circulating biomarkers of CCL [the carboxy-terminal telopeptide of collagen type I to matrix metalloproteinase-1 ratio (CITP¿:¿MMP-1)] and CD [the carboxy-terminal propeptide of procollagen type I (PICP)] identifies myocardial fibrosis phenotypes with distinct clinical outcome in hypertensive patients with heart failure. METHODS: Endomyocardial biopsies and blood samples from 38 patients (small cohort), and blood samples from 203 patients (large cohort) were analyzed. Myocardial CCL and CD were assessed by histological methods. Serum PICP, CITP, and MMP-1 were determined by ELISA. RESULTS: Small cohort: CITP¿:¿MMP-1 cutoff 1.968 or less and PICP cutoff at least 110.8¿ng/ml were used for predicting high CCL and severe CD, respectively. Large cohort: as defined by the above thresholds, patients were categorized into four subgroups based on the presence (+) or absence (-) of high CCL and severe CD. Compared with CCL-CD-, the adjusted hazard ratios for a composite end point of heart failure hospitalization or cardiovascular death over 5 years in CCL-CD+, CCL+CD-, and CCL+CD+ were 1.11 (P¿=¿0.79), 1.99 (P¿=¿0.07), and 2.18 (P¿=¿0.04), respectively (P for trend¿=¿0.005). In addition, the categorization based on CCL and CD yielded integrated discrimination (P¿=¿0.03) and net reclassification..
Autores: Echegaray, K.; Andreu, I.; Lazkano, A.; et al.
Revista: REVISTA ESPAÑOLA DE CARDIOLOGIA
ISSN 0300-8932  Vol. 70  Nº 10  2017  págs. 832 - 840
Introducción y objetivos Se ha estudiado la localización anatómica, las propiedades biomecánicas y el fenotipo molecular del colágeno miocárdico tisular en 40 pacientes con estenosis aórtica grave, fracción de eyección conservada y síntomas de insuficiencia cardiaca. Métodos Se obtuvieron 2 biopsias transmurales de la pared libre del ventrículo izquierdo. La fracción del volumen de colágeno (FVC) se cuantificó mediante rojo picrosirio y la rigidez, mediante el módulo elástico de Young (YEM) evaluado con microscopia de fuerza atómica en regiones misiales y no misiales. Las FVC de tipos I y III se cuantificaron mediante microscopia confocal en áreas con determinación del YEM. Resultados Comparados con sujetos de control, la FVC misial y no misial y el cociente FVC no misial:misial (p < 0,05) estaban incrementados en los pacientes. El cociente entre la velocidad pico de la onda E mitral y la velocidad E del anillo lateral mitral de los pacientes se correlacionaba con la FVC no misial (r = 0,330; p = 0,046) y con el cociente FVC no misial:misial (r = 0,419; p = 0,012). El cociente FVCI:FVCIII y el YEM aumentaban (p ¿ 0,001) en regiones no misiales respecto de las misiales, con correlación entre ellos (r = 0,895; p < 0,001). Conclusiones En la estenosis aórtica grave con fracción de eyección conservada y síntomas de insuficiencia cardiaca, la disfunción diastólica se asocia con un depósito no misial de colágeno aumentado, predominantemente de tipo I y con mayor rigidez. Las características del colágeno tisular pueden contribuir a la disfunción diastólica en estos pacientes.
Autores: Beaumont Javier; San José, Gorka; Moreno, MU; et al.
Revista: SCIENTIFIC REPORTS
ISSN 2045-2322  Vol. 7  2017  págs. 41865
Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-beta(1)-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts.
Autores: Beaumont Javier; López, B; Ravassa, S; et al.
Revista: SCIENTIFIC REPORTS
ISSN 2045-2322  Vol. 7  2017  págs. 40696
This study analyzed the potential associations of 7 myocardial fibrosis-related microRNAs with the quality of the collagen network (e.g., the degree of collagen fibril cross-linking or CCL) and the enzyme lysyl oxidase (LOX) responsible for CCL in 28 patients with severe aortic stenosis (AS) of whom 46% had a diagnosis of chronic heart failure (HF). MicroRNA expression was analyzed in myocardial and blood samples. From the studied microRNAs only miR-19b presented a direct correlation (p < 0.05) between serum and myocardium. Compared to controls both myocardial and serum miR-19b were reduced (p < 0.01) in AS patients. In addition, miR-19b was reduced in the myocardium (p < 0.01) and serum (p < 0.05) of patients with HF compared to patients without HF. Myocardial and serum miR-19b were inversely correlated (p < 0.05) with LOX, CCL and LV stiffness in AS patients. In in vitro studies miR-19b inhibition increased (p < 0.05) connective tissue growth factor protein and LOX protein expression in human fibroblasts. In conclusion, decreased miR-19b may be involved in myocardial LOX up-regulation and excessive CCL, and consequently increased LV stiffness in AS patients, namely in those with HF. Serum miR-19b can be a biomarker of these alterations of the myocardial collagen network in AS patients, particularly in patients with HF.
Autores: Lofsjogard, J., (Autor de correspondencia); Kahan, T.; López, B; et al.
Revista: AMERICAN JOURNAL OF CARDIOLOGY
ISSN 0002-9149  Vol. 119  Nº 12  2017  págs. 2042 - 2048
Disturbances of collagen metabolism may alter the myocardial collagen network and contribute to cardiac remodeling and prognosis in heart failure (HF). Collagen type I synthesis and degradation can be assessed indirectly by the circulating biomarkers carboxy-terminal propeptide (PICP) and carboxy-terminal telopeptide (CITP), respectively. We examined the associations between PICP and CITP and long-term mortality in patients with HF. The Optimizing Congestive Heart Failure Outpatient Clinic (OPTIMAL) project studied patients aged >= 60 years with New York Heart Association class II to IV and HF with reduced ejection fraction (EF) hospitalized with acute HF during 1996 to 1999. On entry, mean age was 75 years, blood pressure 134/80 mm Hg, EF 34%, brain natriuretic peptide 312 pg/ml; 55% had atrial fibrillation. Dates of mortality were collected from administrative databases and medical records up until 2008. Follow-up was 9 to 13 years in all 132 patients, and mean survival was 5.5 +/- 4.0 years. Baseline PICP tended to be higher, CITP was higher, and the PICP:CITP ratio was lower in the 102 deceased, compared with the 30 patients alive. Multivariable Cox regression analyses including 2 established risk factor models performed for all-cause (n = 101) and cardiovascular mortality (n = 61) show PICP and CITP to be independent predictors for all-cause and cardiovascular mortality. In,conclusion, disturbances of collagen type I metabolism have independent prognostic implications for long-term all-cause and cardiovascular mortality in patients with HF with reduced EF. The results suggest excessive degradation to be the predominant disturbance associated with untoward prognosis and adds information on possible target mechanisms for future therapy. (C) 2017 Elsevier Inc. All rights reserved.
Autores: Ravassa, S; Gallego, C. ; Querejeta, R.; et al.
Revista: EUROPEAN JOURNAL OF HEART FAILURE
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 587 - 588
Autores: González, A; Pueyo, Jesús Ciro; et al.
Revista: EUROPEAN JOURNAL OF HEART FAILURE
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 123
Autores: González, A; López, B; Ravassa, S; et al.
Revista: EUROPEAN JOURNAL OF HEART FAILURE
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 9 - 10
Autores: Díez, J; González, A; Ravassa, S;
Revista: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ISSN 0735-1097  Vol. 67  Nº 13  2016  págs. 1569 - 1571
Autores: Huerta, Ana; López, B; Ravassa, S; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 34  Nº 1  2016  págs. 130 - 138
OBJECTIVES: Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. METHODS: One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. RESULTS: Compared with controls, cystatin C was increased (P¿<¿0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P¿<¿0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P¿<¿0.01), TIMP-1 and osteopontin (P¿<¿0.001) and inversely correlated with MMP-1:TIMP-1 (P¿<¿0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P¿<¿0.01) and TIMP-1 (P¿<¿0.0
Autores: Beaumont Javier; López, B; Ravassa, S; et al.
Revista: CLINICAL SCIENCE
ISSN 0143-5221  Vol. 130  Nº 23  2016  págs. 2139 - 2149
MicroRNAs have been associated with cardiomyocyte apoptosis, a process involved in myocardial remodelling in aortic valve (Av) stenosis (AS). Our aim was to analyse whether the dysregulation of myocardial microRNAs was related to cardiomyocyte apoptosis in AS patients. Endomyocardial biopsies were obtained from 28 patients with severe AS (based on pressure gradients and Av area) referred for Av replacement and from necropsies of 10 cardiovascular disease-free control subjects. AS patients showed an increased (P<0.001) cardiomyocyte apoptotic index (CMAI) compared with controls. Two clusters of patients were identified according to the CMAI: group 1 (CMAI ¿ 0.08%; n=16) and group 2 (CMAI > 0.08%; n=12). Group 2 patients presented lower cardiomyocyte density (P<0.001) and ejection fraction (P<0.05), and higher troponin T levels (P<0.05), prevalence of heart failure (HF; P<0.05) and NT-proBNP levels (P<0.05) than those from group 1. miRNA expression profile analysed in 5 patients randomly selected from each group showed 64 microRNAs down-regulated and 6 up-regulated (P<0.05) in group 2 compared with group 1. Those microRNAs with the highest fold-change were validated in the full two groups corroborating that miR-10b, miR-125b-2* and miR-338-3p were down-regulated (P<0.05) in group 2 compared with group 1 and control subjects. These three microRNAs were inversely correlated (P<0.05) with the CMAI. Inhibition of miR-10b induced an increase (P<0.05) of apoptosis and increased expression (P<0.05) of apoptosis protease-activating factor-1 (Apaf-1) in HL-1 cardiomyocytes. In conclusion, myocardial down-regulation of miR-10b may be involved in increased cardiomyocyte apoptosis in AS patients, probably through Apaf-1 up-regulation, contributing to cardiomyocyte damage and to the development of HF.
Autores: López, B; Ravassa, S; González, A; et al.
Revista: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ISSN 0735-1097  Vol. 67  Nº 3  2016  págs. 251 - 260
BACKGROUND: Excessive myocardial collagen cross-linking (CCL) determines myocardial collagen's resistance to degradation by matrix metalloproteinase (MMP)-1 and interstitial accumulation of collagen fibers with impairment of cardiac function. OBJECTIVES: This study sought to investigate whether CCL and a newly identified biomarker of this alteration are associated with hospitalization for heart failure (HHF) or cardiovascular death in patients with HF and arterial hypertension in whom other comorbidities were excluded. METHODS: Endomyocardial biopsies and blood samples from 38 patients (invasive study), and blood samples from 203 patients (noninvasive study) were analyzed. Mean follow-ups were 7.74 ± 0.58 years and 4.72 ± 0.11 years, respectively. Myocardial CCL was calculated as the ratio between insoluble and soluble collagen. The ratio between the C-terminal telopeptide of collagen type I (CITP) and matrix metalloproteinase-1 (CITP:MMP-1) was determined in blood samples. RESULTS: Invasive study: CCL was increased (p < 0.001) in patients compared with controls. Patients were categorized according to normal or high CCL values. Patients with high CCL exhibited higher risk for subsequent HHF (log-rank test p = 0.022), but not for cardiovascular death. CITP:MMP-1 was inversely associated with CCL (r = -0.460; p = 0.005) in all patients. Receiver operating characteristic curves rendered a CITP:MMP-1 cutoff ¿1.968 (80% sensitivity and 76% specificity) for predicting high CCL. Noninvasive study: Patients were categorized according to CITP:MMP-1 ratio values as normal ratio (>1.968) or low ratio (¿1.968). Patients with a low ratio exhibited higher risk for HHF (log-rank test p = 0.014), which remained significant after adjustment for relevant covariables (adjusted hazard ratio: 2.22; 95% CI: 1.37 to 3.59, p = 0.001). In addition, CITP:MMP-1-based categorization yielded significant integrated discrimination and net reclassification improvements (p = 0.003 and p = 0.009, respectively) for HHF over relevant risk factors. CITP:MMP-1 was not associated with the risk of cardiovascular death. CONCLUSIONS: Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF.
Autores: Zhang, Z. Y. ; Ravassa, S; Yang, W. Y.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 11  Nº 12  2016  págs. e0167582
Current knowledge on the pathogenesis of diastolic heart failure predominantly rests on case-control studies involving symptomatic patients with preserved ejection fraction and relying on invasive diagnostic procedures including endomyocardial biopsy. Our objective was to gain insight in serum and urinary biomarkers reflecting collagen turnover and associated with asymptomatic diastolic LV dysfunction. We randomly recruited 782 Flemish (51.3% women; 50.5 years). We assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus. By sequencing urinary peptides, we identified 70 urinary collagen fragments. In serum, we measured carboxyterminal propeptide of procollagen type 1 (PICP) as marker of collagen I synthesis and tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1), an inhibitor of collagen-degrading enzymes. In multivariable-adjusted analyses with Bonferroni correction, we expressed effect sizes per 1-SD in urinary collagen I (uCI) or collagen III (uCIII) fragments. In relation to uCI fragments, e' decreased by 0.183 cm/s (95% confidence interval, 0.017 to 0.350; p = 0.025), whereas E/e' increased by 0.210 (0.067 to 0.353; p = 0.0012). E/e' decreased with uCIII by 0.168 (0.021 to 0.316; p = 0.018). Based on age-specific echocardiographic criteria, 182 participants (23.3%) had subclinical diastolic LV dysfunction. Partial least squares discriminant analysis contrasting normal vs. diastolic LV dysfunction confirmed the aforementioned associations with the uCI and uCIII fragments. PICP and TIMP-1 increased in relation to uCI (p<0.0001), whereas these serum markers decreased with uCIII (p <= 0.0006). Diastolic LV dysfunction was associated with higher levels of TIMP-1 (653 vs. 696 ng/mL; p = 0.013). In a general population, the non-invasively assessed diastolic LV function correlated inversely with uCI and serum markers of collagen I deposition, but positively with uCIII. These observations generalise previous studies in patients to randomly recruited people, in whom diastolic LV function ranged from normal to subclinical impairment, but did not encompass overt diastolic heart failure.
Autores: López, B; González, A; Ravassa, S; et al.
Revista: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ISSN 0735-1097  Vol. 65  Nº 22  2015  págs. 2449 - 2456
Myocardial fibrosis impairs cardiac function, in addition to facilitating arrhythmias and ischemia, and thus influences the evolution and outcome of cardiac diseases. Its assessment is therefore clinically relevant. Although tissue biopsy is the gold standard for the diagnosis of myocardial fibrosis, a number of circulating biomarkers have been proposed for the noninvasive assessment of this lesion. A review of the published clinical data available on these biomarkers shows that most of them lack proof that they actually reflect the myocardial accumulation of fibrous tissue. In this "call to action" article, we propose that this absence of proof may lead to misinterpretations when considering the incremental value provided by the biomarkers with respect to traditional diagnostic tools in the clinical handling of patients. We thus argue that strategies are needed to more strictly validate whether a given circulating biomarker actually reflects histologically proven myocardial fibrosis before it is applied clinically.
Autores: Heymans, S; González, A; Pizard, A; et al.
Revista: EUROPEAN JOURNAL OF HEART FAILURE
ISSN 1388-9842  Vol. 17  Nº 8  2015  págs. 764 - 771
Myocardial fibrosis is the result of excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation. It causes cardiac dysfunction, arrhythmias, and ischaemia, and thereby determines the clinical course and outcome of cardiac patients even when adequately treated. Therefore, further research is needed to identify and better understand the factors that trigger and maintain the myocardial fibrotic response against different injuries in a variety of cardiac diseases. Here, we will focus on the following major areas of research: molecules that stimulate the differentiation of fibroblasts into myofibroblasts and subsequently alter collagen turnover (e.g. cardiotrophin-1, galectin-3, NADPH oxidases, and neutrophil gelatinase-associated lipocalin), microRNA-induced alterations of collagen gene expression, and matricellular protein- and lysyl oxidase-mediated alterations of collagen cross-linking and deposition.
Autores: Ho, C. Y.; Lakdawala, N. K.; Cirino, A. L.; et al.
Revista: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ISSN 0735-1097  Vol. 3  Nº 2  2015  págs. 180 - 188
OBJECTIVES: The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers. BACKGROUND: HCM is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. METHODS: In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. RESULTS: Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular (LV) end-diastolic diameter improved toward normal in the diltiazem group but decreased further in controls (change in z-scores, +0.6 vs. -0.5; p < 0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group but increased in controls (-0.02 vs. +0.15; p = 0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, 2 in each treatment group. CONCLUSIONS: Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982).
Autores: Ravassa, S; Beaumont Javier; Huerta, Ana; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 81  2015  págs. 1 - 12
Oxidative stress (OS) contributes to cardiovascular damage in type 2 diabetes mellitus (T2DM). The peptide glucagon-like peptide-1 (GLP-1) inhibits OS and exerts cardiovascular protective actions. Our aim was to investigate whether cardiac remodeling (CR) and cardiovascular events (CVE) are associated with circulating GLP-1 and biomarkers of OS in T2DM patients. We also studied GLP-1 antioxidant effects in a model of cardiomyocyte lipotoxicity. We examined 72 T2DM patients with no coronary or valve heart disease and 14 nondiabetic subjects. A median of 6 years follow-up information was obtained in 60 patients. Circulating GLP-1, dipeptidyl peptidase-4 activity, and biomarkers of OS were quantified. In T2DM patients, circulating GLP-1 decreased and OS biomarkers increased, compared with nondiabetics. Plasma GLP-1 was inversely correlated with serum 3-nitrotyrosine in T2DM patients. Patients showing high circulating 3-nitrotyrosine and low GLP-1 levels exhibited CR and higher risk for CVE, compared to the remaining patients. In palmitate-stimulated HL-1 cardiomyocytes, GLP-1 reduced cytosolic and mitochondrial oxidative stress, increased mitochondrial ATP synthase expression, partially restored mitochondrial membrane permeability and cytochrome c oxidase activity, blunted leakage of creatine to the extracellular medium, and inhibited oxidative damage in total and mitochondrial DNA. These results suggest that T2DM patients with reduced circulating GLP-1 and exacerbated OS may exhibit CR and be at higher risk for CVE. In addition, GLP-1 exerts antioxidant effects in HL-1 palmitate-overloaded cardiomyocytes. It is proposed that therapies aimed to increase GLP-1 may counteract OS, protect from CR, and prevent CVE in patients with T2DM.
Autores: García, R. ; Nistal, J. F. ; Merino, D. ; et al.
Revista: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
ISSN 0925-4439  Vol. 1852  Nº 7  2015  págs. 1520 - 1530
Transforming growth factor-ß (TGF-ß) induces miR-21 expression which contributes to fibrotic events in the left ventricle (LV) under pressure overload. SMAD effectors of TGF-ß signaling interact with DROSHA to promote primary miR-21 processing into precursor miR-21 (pre-miR-21). We hypothesize that p-SMAD-2 and -3 also interact with DICER1 to regulate the processing of pre-miR-21 to mature miR-21 in cardiac fibroblasts under experimental and clinical pressure overload. The subjects of the study were mice undergoing transverse aortic constriction (TAC) and patients with aortic stenosis (AS). In vitro, NIH-3T3 fibroblasts transfected with pre-miR-21 responded to TGF-ß1 stimulation by overexpressing miR-21. Overexpression and silencing of SMAD2/3 resulted in higher and lower production of mature miR-21, respectively. DICER1 co-precipitated along with SMAD2/3 and both proteins were up-regulated in the LV from TAC-mice. Pre-miR-21 was isolated bound to the DICER1 maturation complex. Immunofluorescence analysis revealed co-localization of p-SMAD2/3 and DICER1 in NIH-3T3 and mouse cardiac fibroblasts. DICER1-p-SMAD2/3 protein-protein interaction was confirmed by in situ proximity ligation assay. Myocardial up-regulation of DICER1 constituted a response to pressure overload in TAC-mice. DICER mRNA levels correlated directly with those of TGF-ß1, SMAD2 and SMAD3. In the LV from AS patients, DICER mRNA was up-regulated and its transcript levels correlated directly with TGF-ß1, SMAD2, and SMAD3. Our results support that p-SMAD2/3 interacts with DICER1 to promote pre-miR-21 processing to mature miR-21. This new TGFß-dependent regulatory mechanism is involved in miR-21 overexpression in cultured fibroblasts, and in the pressure overloaded LV of mice and human patients.
Autores: López, B; González, A; Querejeta, R.; et al.
Revista: EUROPEAN JOURNAL OF HEART FAILURE
ISSN 1388-9842  Vol. 17  Nº 4  2015  págs. 385 - 392
Aims The aim of this study was to investigate whether galectin-3 (Gal-3) is associated with myocardial histological and molecular parameters related to fibrosis and with the circulating biomarkers of the extracellular generation of mature fibril-forming collagen types I (C-terminal propeptide of procollagen type I, PICP) and III (N-terminal propeptide of procollagen type III, PIIINP) in two independent studies of hypertensive patients with heart failure (HF). Methods and results Endomyocardial biopsies and blood samples from 39 HF patients (invasive study), and blood samples from 220 HF patients (non-invasive study) were analysed. Necropsies (n=7) and blood samples (n=20) from healthy subjects were used as controls. In the invasive study myocardial mRNA and protein expression of Gal-3 and collagen types I and III, plasma Gal-3 and serum PICP and PIIINP were all significantly increased in patients compared with controls. Neither myocardial nor plasma Gal-3 were correlated with myocardial collagen and circulating biomarkers; whereas PICP was correlated with myocardial total (r=0.819, P<0.001) and collagen type I (r=0.744, P<0.001) deposition, PIIINP was not. In the non-invasive study both plasma Gal-3 and serum PICP were increased (P<0.001) in patients compared with controls. No correlation was found between Gal-3 and PICP in HF patients. Conclusions These findings show that although an excess of cardiac and systemic Gal-3 is present in patients with HF of hypertensive origin, this molecule is not associated with histological, molecular and biochemical parameters related to myocardial fibrosis in these patients.
Autores: Löfsjögard, J.; Persson, H.; Díez, J; et al.
Revista: SCANDINAVIAN CARDIOVASCULAR JOURNAL
ISSN 1401-7431  Vol. 48  Nº 5  2014  págs. 299 - 303
Abstract Objectives. Alterations of collagen metabolism present in heart failure promote the fibrotic substrate for the development of atrial fibrillation (AF). Myocardial collagen I synthesis and degradation can be assessed indirectly by circulating biomarkers such as the carboxy terminal propeptide (PICP) and carboxy-terminal telopeptide (CITP), respectively. Design. We examined myocardial collagen type-I metabolism in 143 patients with systolic heart failure (New York Heart Association Class 2-4) in relation to coexisting AF. Results. Mean age was 75 years, blood pressure 134/80 mm Hg, ejection fraction 34%, serum PICP 81 ¿g/L and CITP 8.3 ¿g/L, and median plasma brain natriuretic peptide 215 pg/L; 77 were in AF. PICP and CITP were related to left atrial diameter (r = 0.22, P = 0.013, and r = 0.26, P = 0.003) and CITP to pulmonary capillary wedge pressure and C-reactive protein (r = 0.19, P = 0.044, and r = 0.29, P = 0.003). A logistic regression suggested that PICP (odds ratio per 1 ¿g/L change 1.01, P = 0.012) and left ventricular end-diastolic volume (odds ratio per 1 mL change 0.98, P < 0.001) were independently associated with coexisting AF. Conclusion. Collagen type-I metabolism is associated to left atrial size. Heart failure patients with coexisting AF exhibit more altered collagen type-I metabolism than patients in sinus rhythm. This might represent more severe atrial and ventricular fibrosis.
Autores: Löfsjögard, J.; Kahan,T.; Díez, J; et al.
Revista: JOURNAL OF CARDIOVASCULAR MEDICINE
ISSN 1558-2027  Vol. 15  Nº 6  2014  págs. 463 - 469
AimsMyocardial collagen metabolism can be assessed indirectly by circulating biomarkers. We aimed to examine associations between myocardial collagen type I synthesis and degradation, and echocardiographic, clinical, and B-type natriuretic peptide (BNP) findings in heart failure.MethodsWe studied 57 women and 75 men 60 years or older with systolic heart failure (New York Heart Association II-IV and an ejection fraction 45%). Mean age was 75 years, blood pressure 134/80mmHg, ejection fraction 34%, and median BNP 210ng/l. Analyses of the carboxy-terminal propeptide of procollagen type I (PICP, biomarker of collagen type I synthesis) and the serum carboxy-terminal telopeptide of collagen type I (CITP, biomarker of collagen type I degradation) were measured. Extensive echocardiographic examinations were performed, including variables of dyssynchrony.ResultsIncreased collagen synthesis (PICP) was independently related to increased BNP levels (r=0.24, P=0.018). Furthermore, independent associations were found between PICP and left ventricular size, isovolumic relaxation time, and relative wall thickness. Increased collagen degradation (CITP) was independently related to increased BNP levels (r=0.35, P<0.001). Also, univariable, but not multivariable, associations were found between CITP and E/E' septal and QRS duration.ConclusionBiomarkers of collagen type I synthesis and degradation are independently related to BNP and to indices of left ventricular size and diastolic function in systolic heart failure. It is proposed that BNP may contribute to alterations in collagen type I metabolism in systolic heart failure.
Autores: López, B; González, A; Querejeta, R.; et al.
Revista: HYPERTENSION
ISSN 0194-911X  Vol. 63  Nº 3  2014  págs. 483 - 489
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.
Autores: Araña, M; Gavira, Juan José; Pena, E. ; et al.
Revista: BIOMATERIALS
ISSN 0142-9612  Vol. 35  Nº 1  2014  págs. 143 - 151
Although transplantation of adipose-derived stem cells (ADSC) in chronic myocardial infarction (MI) models is associated with functional improvement, its therapeutic value is limited due to poor long-term cell engraftment and survival. Thus, the objective of this study was to examine whether transplantation of collagen patches seeded with ADSC could enhance cell engraftment and improve cardiac function in models of chronic MI. With that purpose, chronically infarcted Sprague-Dawley rats (n = 58) were divided into four groups and transplanted with media, collagen scaffold (CS), rat ADSC, or CS seeded with rat ADSC (CS-rADSC). Cell engraftment, histological changes, and cardiac function were assessed 4 months after transplantation. In addition, Gottingen minipigs (n = 18) were subjected to MI and then transplanted 2 months later with CS or CS seeded with autologous minipig ADSC (CS-pADSC). Functional and histological assessments were performed 3 months post-transplantation. Transplantation of CS-rADSC was associated with increased cell engraftment, significant improvement in cardiac function, myocardial remodeling, and revascularization. Moreover, transplantation of CS-pADSC in the pre-clinical swine model improved cardiac function and was associated with decreased fibrosis and increased vasculogenesis. In summary, transplantation of CS-ADSC resulted in enhanced cell engraftment and was associated with a significant improvement in cardiac function and myocardial remodeling. (C) 2013 Elsevier Ltd. All rights reserved.
Autores: Beaumont Javier; López, B; et al.
Revista: CLINICAL SCIENCE
ISSN 0143-5221  Vol. 126  Nº 7  2014  págs. 497 - 506
miRNAs (microRNAs) have been shown to play a role in myocardial fibrosis. The present study was designed to analyse whether alterations in miRNA expression contribute to the progression of myocardial fibrosis in AS (aortic valve stenosis) patients through up-regulation of the pro-fibrotic factor TGF-ß1 (transforming growth factor-ß type 1). Endomyocardial biopsies were obtained from 28 patients with severe AS, and from the necropsies of 10 control subjects. AS patients presented increased myocardial CVF (collagen volume fraction) and TGF-ß1 compared with the controls, these parameters being correlated in all patients. Patients were divided into two groups by cluster analysis according to their CVF: SF (severe fibrosis; CVF >15%; n=15) and non-SF (CVF ¿15%; n=13). TGF-ß1 was increased in patients with SF compared with those with non-SF. To analyse the involvement of miRNAs in SF, the miRNA expression profile of 10 patients (four with non-SF and six with SF) was analysed showing that 99 miRNAs were down-regulated and 19 up-regulated in the SF patients compared with the non-SF patients. Those miRNAs potentially targeting TGF-ß1 were validated by real-time RT (reverse transcription)-PCR in the whole test population, corroborating that miR-122 and miR-18b were down-regulated in patients with SF compared with those with non-SF and the control subjects. Additionally, miR-122 was inversely correlated with the CVF, TGF-ß1 and the TGF-ß1-regulated PCPE-1 (procollagen C-terminal proteinase enhancer-1) in all patients. Experiments in human fibroblasts demonstrated that miR-122 targets and inhibits TGF-ß1. In conclusion, for the first time we show that myocardial down-regulation of miR-122 might be involved in myocardial fibrosis in AS patients, probably through TGF-ß1 up-regulation.
Autores: San José, Gorka; Moreno, MU; et al.
Revista: ANTIOXIDANTS AND REDOX SIGNALING
ISSN 1523-0864  Vol. 19  Nº 14  2013  págs. 1607 - 1618
Aims: The NADPH oxidases constitute a major source of superoxide anion (·O2¿) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by transforming growth factor-ß1 (TGF-ß1). We investigated whether a chronic treatment with P144, a peptide synthesized from type III TGF-ß1 receptor, inhibited NADPH oxidases in the renal cortex of spontaneously hypertensive rats (SHR). Results: Here, we show that chronic administration of P144 significantly reduced the NADPH oxidase expression and activity as well as the oxidative stress observed in control vehicle-treated SHR (V-SHR). In addition, P144 was also able to reduce the significant increase in the renal fibrosis and in mRNA expression of different components of collagen metabolism, as well as in the levels of connective tissue growth factor observed in V-SHR. Finally, TGF-ß1-stimulated NRK52E exhibited a significant increase in NADPH oxidase expression and activity as well as a TGF-ß1-dependent intracellular pathway that were inhibited in the presence of P144. Innovation: Our experimental evidence suggests that reversing oxidative stress may be therapeutically useful in preventing fibrosis-associated renal damage. We show here that (i) the TGF-ß1-NADPH oxidases axis is crucial in the development of fibrosis in an experimental hypertensive renal disease animal model, and (ii) the use of P144 reverses TGF-ß1-dependent NADPH oxidase activity; thus, P144 may be considered a novel therapeutic tool in kidney disease associated with hypertension. Conclusion: We demonstrate that P144 inhibits NADPH oxidases and prevents oxidative stress in kidneys from hypertensive rats. Our data also suggest that these effects are associated with the renal antifibrotic effect of P144.
Autores: Ravassa, S; Barba, Joaquín; Coma, María Isabel; et al.
Revista: CARDIOVASCULAR DIABETOLOGY
ISSN 1475-2840  Vol. 12  2013  págs. 143
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.
Autores: Moreno, MU; López, B; González, A; et al.
Revista: CLINICAL SCIENCE
ISSN 0143-5221  Vol. 125  Nº 6  2013  págs. 291 - 300
The NADPH oxidases are a key family of ROS (reactive oxygen species)-producing enzymes which may differentially contribute to cardiac pathophysiology. Animal studies show uncertain results regarding the regulation of cardiac Nox4 by pressure overload and no data are available on human myocardial Nox4. In the present study, we evaluated Nox4 expression and its relationship with myocardial remodelling and LV (left ventricular) function in patients with severe AS (aortic valve stenosis). Endomyocardial biopsies from 34 patients with AS were obtained during aortic valve replacement surgery. LV morphology and function were assessed by echocardiography. Myocardial samples from subjects deceased of non-CVDs (cardiovascular diseases) were analysed as controls. Nox4 localization was evaluated by immunohistochemistry and quantified by Western blot. Myocardial capillary density, fibrosis and cardiomyocyte dimensions and apoptosis were assessed histologically to evaluate myocardial remodelling. Nox4 was present in samples from all subjects and expressed in cardiomyocytes, VSMCs (vascular smooth muscle cells), endothelium and fibroblasts. Nox4 levels were reduced 5-fold in AS patients compared with controls (P<0.01). Nox4 levels directly correlated with cardiomyocyte cross-sectional area (r=0.299, P<0.05) and diameter (r=0.406, P<0.05) and capillary density (r=0.389, P<0.05), and inversely with cardiomyocyte apoptosis (r=-0.316, P<0.05) in AS patients. In addition, Nox4 levels correlated with echocardiographic parameters (LV ejection fraction: r=0.353, P<0.05; midwall fractional shortening: r=0.355, P<0.05; deceleration time: r=-0.345, P<0.05) in AS patients. Nox4 is expressed in human myocardium and reduced in AS patients. The observed associations of Nox4 with cardiomyocyte parameters and capillary density in AS patients suggest a potential role of Nox4 deficiency in the myocardial remodelling present in the human pressure-overloaded heart.
Autores: Ravassa, S; Beloqui, Óscar; Varo, N; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 31  Nº 3  2013  págs. 587 - 594
Objectives: Cardiotrophin-1 (CT-1) induces hypertrophic growth and contractile dysfunction in cardiomyocytes. This cross-sectional study was aimed to analyze CT-1 associations with echocardiographically assessed left ventricular systolic properties taking into account the influence of left ventricular growth [i.e. left ventricular hypertrophy (LVH) and inappropriate left ventricular mass (iLVM)] in asymptomatic hypertensive patients. Methods: Serum CT-1 was measured by ELISA in 278 asymptomatic hypertensive patients with a left ventricular ejection fraction more than 50% and in 25 age and sex-matched normotensive patients. Results: Serum CT-1 was increased in hypertensive patients as compared to normotensive patients. CT-1 was directly correlated with parameters of left ventricular mass (LVM) and inversely correlated with parameters assessing myocardial systolic function and left ventricular chamber contractility in hypertensive patients, these associations being independent of a number of potential confounding factors. Interestingly, the associations of CT-1 with myocardial systolic function were independent of LVM even in patients with LVH or iLVM. In addition, there was a significant increment of serum CT-1 in hypertensive patients with LVH or iLVM, especially in those in whom LVH or iLVM were accompanied by impaired myocardial systolic function, as compared to the remaining hypertensive patients and normotensive patients. Plasma amino-terminal pro-brain natriuretic peptide was not correlated with any of the assessed left ventricular systolic parameters in either group of patients. Conclusion: These findings suggest that serum CT-1 is associated with myocardial systolic dysfunction in asymptomatic hypertensive patients, independently of LVM, even in those patients with pathologic left ventricular growth.
Autores: Hamndani, N.; Franssen, C.; Lourenço, A.; et al.
Revista: CIRCULATION-HEART FAILURE
ISSN 1941-3289  Vol. 6  Nº 6  2013  págs. 1239 - 1249
Background Obesity and diabetes mellitus are important metabolic risk factors and frequent comorbidities in heart failure with preserved ejection fraction. They contribute to myocardial diastolic dysfunction (DD) through collagen deposition or titin modification. The relative importance for myocardial DD of collagen deposition and titin modification was investigated in obese, diabetic ZSF1 rats after heart failure with preserved ejection fraction development at 20 weeks. Methods and Results Four groups of rats (Wistar-Kyoto, n=11; lean ZSF1, n=11; obese ZSF1, n=11, and obese ZSF1 with high-fat diet, n=11) were followed up for 20 weeks with repeat metabolic, renal, and echocardiographic evaluations and hemodynamically assessed at euthanization. Myocardial collagen, collagen cross-linking, titin isoforms, and phosphorylation were also determined. Resting tension (F-passive)-sarcomere length relations were obtained in small muscle strips before and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellular matrix to F-passive to be discerned. At 20 weeks, the lean ZSF1 group was hypertensive, whereas both obese ZSF1 groups were hypertensive and diabetic. Only the obese ZSF1 groups had developed heart failure with preserved ejection fraction, which was evident from increased lung weight, preserved left ventricular ejection fraction, and left ventricular DD. The underlying myocardial DD was obvious from high muscle strip stiffness, which was largely (80%) attributable to titin hypophosphorylation. The latter occurred specifically at the S3991 site of the elastic N2Bus segment and at the S12884 site of the PEVK segment. Conclusions Obese ZSF1 rats developed heart failure with preserved ejection fraction during a 20-week time span. Titin hypophosphorylation importantly contributed to the underlying myocardial DD.
Autores: López, B; González, A; Lindner, D.; et al.
Revista: CARDIOVASCULAR RESEARCH
ISSN 0008-6363  Vol. 99  Nº 1  2013  págs. 111 - 120
We investigated whether the pro-fibrotic matricellular protein osteopontin (OPN) is associated with the enzymes involved in the extracellular synthesis of fibril-forming collagen type I (i.e. procollagen C-proteinase, PCP) and its cross-linking to form insoluble fibrils (i.e. lysyl oxidase, LOX) in heart failure (HF) of hypertensive origin. OPN, PCP, and LOX were assessed by histochemical and molecular methods in the myocardium of 21 patients with hypertensive heart disease (HHD) and HF. Whereas the myocardial expression of OPN was very scarce in control hearts (n 10), it was highly expressed in HF patients (P 0.0001). OPN was directly correlated with LOX (r 0.460, P 0.041), insoluble collagen (r 0.534, P 0.015), pulmonary capillary wedge pressure (r 0.558; P 0.009), and left-ventricular (LV) chamber stiffness (r 0.458, P 0.037), and inversely correlated with LV ejection fraction (r 0.513, P 0.017) in all patients. OPN did not correlate with PCP and other parameters assessing collagen synthesis by fibroblasts or degradation by matrix metalloproteinases. In vitro studies showed that OPN significantly (P 0.05) increases the expression and activity of LOX in human cardiac and dermal fibroblasts. An excess of OPN is associated with increased LOX and insoluble collagen, as well as with LV stiffness and systolic dysfunction in patients with HHD and HF. In addition, OPN up-regulates LOX in human fibroblasts. It is suggested that the OPNLOX axis might facilitate the formation of insoluble collagen (i.e. stiff and resistant to degradation) and the subsequent alteration in LV mechanical properties and function in patients with HHD and HF.
Autores: Ho, C. Y.; Abbasi, S. A.; Neilan, T. G.; et al.
Revista: CIRCULATION-CARDIOVASCULAR IMAGING
ISSN 1941-9651  Vol. 6  Nº 3  2013  págs. 415 - 422
Background-Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations seem to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV). Methods and Results-Sarcomere mutation carriers with LVH (G+/LVH+, n=37) and without LVH (G+/LVH-, n=29), patients with HCM without mutations (sarcomere-negative HCM, n=11), and healthy controls (n=11) underwent contrast cardiac magnetic resonance, measuring T1 times pre- and postgadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared with controls, ECV was increased in patients with overt HCM, as well as G+/LVH-mutation carriers (ECV=0.36 +/- 0.01, 0.33 +/- 0.01, 0.27 +/- 0.01 in G+/LVH+, G+/LVH-, controls, respectively; P <= 0.001 for all comparisons). ECV correlated with N-terminal probrain natriuretic peptide levels (r=0.58; P<0.001) and global E' velocity (r=-0.48; P<0.001). Late gadolinium enhancement was present in >60% of overt patients with HCM but absent from G+/LVH-subjects. Both ECV and late gadolinium enhancement were more extensive in sarcomeric HCM than sarcomere-negative HCM. Conclusions-Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development of myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.
Autores: González, A; López, B; Ravassa, S; et al.
Revista: ENDOCRINE
ISSN 1355-008X  Vol. 42  Nº 1  2012  págs. 9 - 17
Hypertensive heart disease, here defined by the presence of pathologic left ventricular hypertrophy in the absence of a cause other than arterial hypertension, is characterized by complex changes in myocardial structure including enhanced cardiomyocyte growth and non-cardiomyocyte alterations that induce the remodeling of the myocardium, and ultimately, deteriorate left ventricular function and facilitate the development of heart failure. It is now accepted that a number of pathological processes mediated by mechanical, neurohormonal, and cytokine routes acting on the cardiomyocyte and the non-cardiomyocyte compartments are responsible for myocardial remodeling in the context of arterial hypertension. For instance, cardiotrophin-1 is a cytokine member of the interleukin-6 superfamily, produced by cardiomyocytes and non-cardiomyocytes in situations of biomechanical stress that once secreted interacts with its receptor, the heterodimer formed by gp130 and gp90 (also known as leukemia inhibitory factor receptor beta), activating different signaling pathways leading to cardiomyocyte hypertrophy, as well as myocardial fibrosis. Beyond its potential mechanistic contribution to the development of hypertensive heart disease, cardiotrophin-1 offers the opportunity for a new translational approach to this condition. In fact, recent evidence suggests that cardiotrophin-1 may serve as both a biomarker of left ventricular hypertrophy and dysfunction in hypertensive patients, and a potential target for therapies aimed to prevent and treat hypertensive heart disease beyond blood pressure control.
Autores: Beaumont Javier; González, A; López, B; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 30  Nº 1  2012  págs. 34 - 37
Autores: López, B; Querejeta, R.; González, A; et al.
Revista: HYPERTENSION
ISSN 0194-911X  Vol. 60  Nº 3  2012  págs. 677-683
We investigated whether the quality of myocardial collagen associates with elevated left-sided filling pressures in 38 hypertensive patients with stage C chronic heart failure. Filling pressures were assessed invasively measuring pulmonary capillary wedge pressure. Left ventricular chamber stiffness constant was calculated from the deceleration time of the early mitral filling wave. The fraction of myocardial volume occupied by total collagen tissue and collagen type I fibers was assessed histomorphologically. The degree of collagen cross-linking (CCL), which determines the formation of insoluble stiff collagen, was assessed by colorimetric and enzymatic procedures. The expression of lysyl oxidase (LOX), which regulates CCL, was assessed by Western blot. Compared with patients with normal pulmonary capillary wedge pressure (<= 12 mm Hg; n = 16), patients with elevated pulmonary capillary wedge pressure (>12 mm Hg; n = 22) exhibited increases of left ventricular chamber stiffness constant, fraction of myocardial volume occupied by total collagen tissue, fraction of myocardial volume occupied by collagen type I fibers, CCL, insoluble stiff collagen, and LOX. Pulmonary capillary wedge pressure was correlated with left ventricular chamber stiffness constant (r = 0.639; P < 0.001), insoluble stiff collagen (r = 0.474; P < 0.005), CCL (r = 0.625; P < 0.001), and LOX (r = 0.410; P < 0.05) in all of the patients but not with fraction of myocardial volume occupied by total collagen tissue or fraction of myocardial volume occupied by collagen type I fibers. In addition, CCL was correlated with insoluble stiff collagen (r = 0.612; P < 0.005), LOX (r = 0.538; P < 0.01), left ventricular chamber stiffness constant (r = 0.535; P < 0.005), peak filling rate (r =- 0.343; P < 0.05), ejection fraction (r =- 0.430; P < 0.01), and amino-terminal propeptide of brain natriuretic peptide (r = 0.421; P < 0.05) in all of the patients. These associations were independent of confounding factors. These findings indicate that, in hypertensive patients with stage C heart failure, it is only the quality of collagen (ie, degree of cross-linking) that associates with elevated filling pressures. It is suggested that LOX-mediated excessive CCL facilitates the increase in left ventricular stiffness with the resulting elevation of filling pressures in these patients. (Hypertension. 2012; 60: 677-683.) . Online Data Supplement
Autores: Moreno, MU; López, B; et al.
Revista: OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
ISSN 1942-0900  Vol. 2012  Nº 2012  2012  págs. 8 p.
NADPH oxidases constitute a major source of superoxide anion (center dot O-2(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-beta 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-beta(1) receptor, significantly reduced the cardiac NADPH oxidase expression and activity as well as in the nitrotyrosine levels observed in control spontaneously hypertensive rats (V-SHR) to levels similar to control normotensive Wistar Kyoto rats. In addition, P144 was also able to reduce the significant increases in the expression of collagen type I protein and mRNA observed in hearts from V-SHR. In addition, positive correlations between collagen expression, NADPH oxidase activity, and nitrotyrosine levels were found in all animals. Finally, TGF-beta 1-stimulated Rat-2 exhibited significant increases in NADPH oxidase activity that was inhibited in the presence of P144. It could be concluded that the blockade of TGF-beta 1 with P144 inhibited cardiac NADPH oxidase in SHR, thus adding new data to elucidate the involvement of this enzyme in the profibrotic actions of TGF-beta 1.
Autores: Kloch-Badelek, M.; Kuznetsova, T.; Sakiewicz, W.; et al.
Revista: CARDIOVASCULAR ULTRASOUND
ISSN 1476-7120  Vol. 10  Nº 10  2012 
Background Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence. Methods We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years). Results In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively. Conclusions The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%.
Autores: Ravassa, S; González, A; Díez, J;
Revista: REVISTA ESPAÑOLA DE CARDIOLOGIA. SUPLEMENTO
ISSN 1131-3587  Vol. 11  Nº Supl. 4  2011  págs. 37 - 41
El sistema renina-angiotensina desempeña un papel determinante en la aparición de complicaciones cardiovasculares y renales en el contexto de la diabetes mellitus. Las acciones del sistema reninaangiotensina incluyen no sólo las dependientes de la producción de angiotensina II, sino también las resultantes de la activación del sistema renina-pro-renina/receptor de la pro-renina. En los últimos años, diversos estudios clínicos y experimentales señalan la implicación del sistema renina-pro-renina/receptor de la pro-renina en el daño de órganos diana en la diabetes mellitus. Este artículo revisa los principales estudios que han contribuido a una mayor comprensión de dicho sistema y de su papel como posible diana terapéutica en la diabetes mellitus.
Autores: Frölich, E. D.; González, A; Díez, J;
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 29  Nº 1  2011  págs. 17 - 26
The heart is a remarkably adaptive organ, capable of increasing its minute output and overcoming short-term or prolonged pressure overload. The structural response, in addition to the foregoing functional demands, is that of myocardial hypertrophy. Then, why should an adaptive response increase cardiovascular risk in hypertensive patients with left ventricular hypertrophy (LVH)? Evidence shows that the functional performance of hypertrophied cardiomyocytes is impaired, and that additional alterations develop in cardiomyocytes themselves, the extracellular matrix and the intramyocardial vasculature, leading to myocardial remodelling and providing the basis for the adverse prognosis associated with pathological LVH in hypertensive patients (i.e., hypertensive heart disease, HHD). As molecular information accumulates, the pathophysiological understanding and the clinical approach to HHD are changing. The time has come to develop novel diagnostic and therapeutic strategies aimed at improving the prognosis of HHD on the basis of reversing or even preventing the aforementioned changes in the ventricular myocardium.
Autores: González, A; Ravassa, S; Beaumont Javier; et al.
Revista: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ISSN 0735-1097  Vol. 58  Nº 18  2011  págs. 1833 - 1843
Classical therapy of heart failure is based on treatment of its pre-disposing/triggering factors and of the neurohumoral activation secondary to the deterioration of cardiac function. A new view is emerging that proposes the direct intervention on the pathological structural remodeling of the myocardium as part of heart failure therapy. In fact, in conditions of chronic injury, the cardiomyocytic and the noncardiomyocytic components of the myocardium undergo a series of structural lesions (i.e., cardiomyocyte growth and death, inflammation, alterations of collagen matrix, and microvascular rarefaction) that are governed by a complex interplay of mechanisms. Our increasing knowledge of the role of these mechanisms in remodeling enables us not only to better understand how our more successful therapies work but also to explore novel therapies for the future. In this paper, we will examine recent insights from experimental and pilot clinical studies that have provided new targets for interventions to prevent or reverse inflammation, alterations of collagen matrix, and cardiomyocyte death.
Autores: Díez, J; López, B; Beaumont Javier; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 29  Nº 4  2011  págs. 660 - 662
Autores: Montserrat, L.; López, B; González, A; et al.
Revista: EUROPEAN HEART JOURNAL
ISSN 0195-668X  Vol. 32  Nº 2  2011  págs. 177 - 183
Aims Cardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM). Methods and results The study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spirito's LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P < 0.001) plasma CT-1 levels. Significant correlations were found between CT-1 and maximal LV wall thickness (r = 0.284, P = 0.001) and the Spirito's LVH score (r = 0.287, P = 0.006) in HCM patients. In addition, the levels of CT-1 were higher (P = 0.02) in patients with severe LVH (maximal LV wall thickness >= 30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness <30 mm). Conclusions These findings show that plasma CT-1 is associated with the severity of LVH in patients with HCM. Further studies are required to ascertain whether CT-1 is a diagnostic biomarker of this cardiomyopathy.
Autores: López, B; González, A; et al.
Revista: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
ISSN 0363-6135  Vol. 299  Nº 1  2010  págs. H1 - H9
Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOX-mediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function.
Autores: López, B; González, A; Díez, J;
Revista: CIRCULATION
ISSN 0009-7322  Vol. 121  Nº 14  2010  págs. 1645 - 1654
Autores: Díez, J; González, A; Ravassa, S;
Revista: HYPERTENSION
ISSN 0194-911X  Vol. 56  Nº 6  2010  págs. 1045 - 1046
Autores: Ho, Caroline; López, B; Coelho, Oscar; et al.
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 0028-4793  Vol. 363  Nº 6  2010  págs. 552 - 563
Autores: González, A; López, B; Querejeta, Ramón; et al.
Revista: HYPERTENSION
ISSN 0194-911X  Vol. 55  Nº 6  2010  págs. 1418 - 1424
Autores: Kuznetsova, Tatiana; Codd, Veryan; Brouilette, Scott; et al.
Revista: AMERICAN JOURNAL OF EPIDEMIOLOGY
ISSN 0002-9262  Vol. 172  Nº 4  2010  págs. 440 - 450

ACTIVIDAD DOCENTE

   

Histología B (F.Medicina). 
Universidad de Navarra - Facultad de Medicina.