Nuestros investigadores

Domingo Francisco Javier Díez Martínez

Clínica Universidad de Navarra. Clínica Universidad de Navarra
. Universidad de Navarra
Ciencias Cardiovasculares
Ciencias Cardiovasculares. Fundación para la Investigación Médica Aplicada
Índice H
57, (WoS, 27/04/2018)

Publicaciones científicas más recientes (desde 2010)

Autores: Ferreira, J. P.; Machu, J. L.; Girerd, N. ; et al.
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.
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: Trippel, T. D.; Van Linthout, S.; Westermann, D.; et al.
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: Moreno, MU; Gavira, Juan José; et al.
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: Díez, J;
ISSN 1879-0844  Vol. 19  Nº 2  2017  págs. 167 - 176
Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter-regulatory hormones of the RAAS and SNS, and endothelin-1 become over-activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.
Autores: Schelbert, E. B.; Fridman, Y.; Wong, T. C.; et al.
ISSN 2380-6583  Vol. 2  Nº 9  2017  págs. 995 - 1006
IMPORTANCE Amongmyriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte-extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function. OBJECTIVE To investigate whethermyocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes. DESIGN, SETTING, AND PARTICIPANTS Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19). EXPOSURES Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures. MAIN OUTCOME AND MEASURES Baseline BNP; subsequent hospitalization for heart failure or death. RESULTS Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were "at risk"for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences inMF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not. CONCLUSIONS AND RELEVANCE Amongmyriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediatingMF represent therapeutic targets in HFpEF warrants further evaluation.
Autores: Ravassa, S; López, B; Querejeta, R.; et al.
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: Beloqui, Óscar; Moreno, MU; San José, Gorka; et al.
ISSN 1071-5762  Vol. 51  Nº 4  2017  págs. 389 - 396
Vascular calcification is a common feature in atherosclerosis and associates with cardiovascular events. Oxidative stress may be involved in the pathogenesis of vascular calcification. Previous studies have shown that the phagocytic NADPH oxidase is associated with atherosclerosis. The objective of the present study was to investigate the association between phagocytic NADPH oxidase-mediated superoxide production and coronary artery calcium (CAC). NADPH oxidase-mediated superoxide production was determined by chemiluminescence and CAC by computed tomography in 159 asymptomatic men free of overt clinical atherosclerosis. Multivariate linear regression analyses were used to assess the relationship between CAC and NADPH oxidase-mediated superoxide production. Compared with individuals in the lowest score of CAC (= 0 Agatston units), those in the upper score (> 400 Agatston units) showed higher superoxide production (p < 0.05). In correlation analysis, superoxide production positively (p < 0.01) correlated with CAC, which in multivariate analysis remained significant after adjusting for age, HDL-cholesterol, triglycerides, body mass index, smoking, arterial hypertension and diabetes mellitus. In conclusion, in a population of men without clinically overt atherosclerotic disease, increased NADPH oxidase-mediated superoxide production associated with enhanced CAC. Albeit descriptive, these findings suggest a potential involvement of phagocytic NADPH oxidase-mediated oxidative stress in CAC.
Autores: Barba, Joaquín; Guembe MJ; et al.
ISSN 1885-5857  Vol. 70  Nº 4  2017  págs. 254-260
In a subsample of the general population, EAT measured by echocardiography increased significantly and independently with age. Increased EAT thickness was independently associated with MS and with low high-density lipoprotein cholesterol, high triglycerides, and elevated waist circumference as individual criteria.
Autores: Echegaray, K.; Andreu, I.; Lazkano, A.; et al.
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.
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: Pérez del Villar, C.; Savvatis, K.; López, B; et al.
ISSN 0008-6363  Vol. 113  Nº 8  2017  págs. 906 - 914
Aim To address the mechanisms responsible for the increase in LV filling pressures induced by acute hypertension transients in patients with heart failure with preserved ejection fraction ( HFpEF) Methods and results Multiple-beat pressure-volume loops were recorded during inferior vena cava occlusion in 39 HFpEF patients and 20 controls during handgrip and atrial pacing. We measured the contribution of relaxation, elastic recoil, and stiffness to instantaneous diastolic pressure using a novel processing method. Fibrosis was quantified from endomyo-cardial biopsies. HFpEF patients showed higher diastolic pressures and stiffness constant than controls (P < 0.05 for all). As opposed to controls, all intrinsic global diastolic properties were sensitive to acute changes in systolic pressure in the HFpEF group. In fact, the stiffness constant increased by more than 50% during handgrip in HFpEF patients (P < 0.05), tightly related to changes in systolic pressure (fixed-effect = 0.26mm Hg per mm Hg [95% CI = 0.15-0.37]; P < 0.0001). Incomplete relaxation contributed to increasing pressure before atrial contraction, but changes in end-diastolic pressure was mostly caused by the increase in stiffness. The degree of pressure-sensitivity of stiffness correlated with myocardial collagen volume and crosslinking (R = 0.40 to 0.82 for all). Conclusion Acute chamber stiffening is the main mechanism responsible for rising late-diastolic pressures when HFpEF patients undergo hypertension transients. This stiffening behaviour is related to impaired dynamic systolic-diastolic interactions and correlates with matrix remodelling. Ventricular-vascular relationships are a promising target in HFpEF and should be taken into account when assessing diastolic function.
Autores: Beaumont Javier; López, B; Ravassa, S; et al.
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: Ravassa, S; Gallego, C. ; Querejeta, R.; et al.
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 587 - 588
Autores: González, A; Pueyo, Jesús Ciro; et al.
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 123
Autores: González, A; López, B; Ravassa, S; et al.
ISSN 1388-9842  Vol. 19  Nº Supl. 1  2017  págs. 9 - 10
Autores: Díez, J; Ruilope, L. M;
ISSN 2055-6837  Vol. 2  Nº 2  2016  págs. 119 - 130
Acute heart failure (AHF) is a complex clinical syndrome characterized by fluid overload and haemodynamic abnormalities (short-term clinical consequences) and the development of end-organ damage (long-term consequences). Current therapies for the treatment of AHF, such as loop diuretics and vasodilators, help to relieve haemodynamic imbalance and congestion, but have not been shown to prevent (and may even contribute to) end-organ damage, or to provide long-term clinical benefit. Serelaxin is the recombinant form of human relaxin-2, a naturally occurring hormone involved in mediating haemodynamic changes during pregnancy. Preclinical and clinical studies have investigated the effects mediated by serelaxin and the suitability of this agent for the treatment of patients with AHF. Data suggest that serelaxin acts via multiple pathways to improve haemodynamics at the vascular, cardiac, and renal level and provide effective congestion relief. In addition, this novel agent may protect the heart, kidneys, and liver from damage by inhibiting inflammation, oxidative stress, cell death, and tissue fibrosis, and stimulating angiogenesis. Serelaxin may therefore improve both short- and long-term outcomes in patients with AHF. In this review, we examine the unique mechanisms underlying the potential benefits of serelaxin for the treatment of AHF, in particular, those involved in mediating end-organ protection.
Autores: Díez, J; González, A; Ravassa, S;
ISSN 0735-1097  Vol. 67  Nº 13  2016  págs. 1569 - 1571
Autores: Nilsson, P. M.; Díez, J;
ISSN 1473-5598  Vol. 34  Nº 2  2016  págs. 184 - 187
Autores: Díez, J; Bayés-Genis, A.;
ISSN 1520-765X  Vol. 18  Nº Supl. G  2016  págs. G33 - G42
Patients hospitalized with acutely decompensated heart failure (ADHF) are often critically ill and require immediate treatment to stabilize their haemodynamic status. Despite improving the signs and symptoms of ADHF, currently available therapies have failed to demonstrate improvements in post-discharge outcomes, such as mortality and rehospitalization, and to address the impact of end-organ damage. Furthermore, attempts to develop therapies to treat patients with ADHF over the past 10 to 20 years have been largely unsuccessful, further compounding the problem. Recent evidence supporting a variety of novel therapies, such as serelaxin and natriuretic peptides, may signal a new hope on the horizon for patients with ADHF.
Autores: Beaumont Javier; López, B; Ravassa, S; et al.
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: Huerta, Ana; López, B; Ravassa, S; et al.
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: Weber, K. T.; Díez, J;
ISSN 1941-3289  Vol. 9  Nº 8  2016  págs. e003315
Autores: López, B; Ravassa, S; González, A; et al.
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: Yang, J.; Savvatis, K.; Kang, J. S.; et al.
ISSN 2041-1723  Vol. 7  2016  págs. 13710
Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-beta 2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-beta 2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.
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.
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.
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: Wilcox, J. E.; Fonarow, G. C.; Ardehali, H.; et al.
ISSN 0735-1097  Vol. 3  Nº 9  2015  págs. 661 - 669
Myocardial recovery in heart failure (HF) is possible, but its determinants are not fully defined. At least partial functional improvement is possible with current evidence-based therapies. However, once significant HF symptoms develop, patients have varied trajectories, including: 1) structural and functional recovery; 2) stabilization (remission); and 3) acceleration to end-stage HF/death. All 3 trajectories may be interrupted by sudden death. These trajectories may represent the interplay of heterogeneous causality, genetic predeterminants, and disease phenotypes. Enhanced phenotypic description with cardiac magnetic resonance imaging, molecular imaging, or circulating biomarkers of the heterogeneous HF population may provide insights regarding specific biological targets amenable to existing and novel therapeutic strategies. The identification of patients in "remission," before progression to the end stage of predominantly nonviable tissue (e.g., fibrosis), has implications for clinical practice and future trials because such patients may be more likely to experience myocardial recovery (cardiac reserve). The identification of dysfunctional but viable myocardium and its diverse pathophysiological causes may provide opportunities to investigate existing and novel therapeutics aimed at enhancing myocardial recovery
Autores: Díez, J;
ISSN 0014-2565  Vol. 215  Nº 6  2015  págs. 320 - 321
Autores: Schelbert, E. B.; Piehler, K. M.; Zareba, K. M.; et al.
ISSN 2047-9980  Vol. 4  Nº 12  2015  págs. e002613
BACKGROUND: Myocardial fibrosis (MF) in noninfarcted myocardium may be an interstitial disease pathway that confers vulnerability to hospitalization for heart failure, death, or both across the spectrum of heart failure and ejection fraction. Hospitalization for heart failure is an epidemic that is difficult to predict and prevent and requires potential therapeutic targets associated with outcomes. METHOD AND RESULTS: We quantified MF with cardiovascular magnetic resonance extracellular volume fraction (ECV) measures in 1172 consecutive patients without amyloidosis or hypertrophic or stress cardiomyopathy and assessed associations with outcomes using Cox regression. ECV ranged from 16.6% to 47.8%. Over a median of 1.7 years, 111 patients experienced events after cardiovascular magnetic resonance, 55 had hospitalization for heart failure events, and there were 74 deaths. ECV was more strongly associated with outcomes than "nonischemic" MF observed with late gadolinium enhancement, thus ECV quantified MF in multivariable models. Adjusting for age, sex, renal function, myocardial infarction size, ejection fraction, hospitalization status, and heart failure stage, higher ECV was associated with hospitalization for heart failure (hazard ratio 1.77; 95% CI 1.32 to 2.36 for every 5% increase in ECV), death (hazard ratio 1.87 95% CI 1.45 to 2.40) or both (hazard ratio 1.85, 95% CI 1.50 to 2.27). ECV improved classification of persons at risk and improved model discrimination for outcomes (eg, hospitalization for heart failure: continuous net reclassification improvement 0.33, 95% CI 0.05 to 0.66; P=0.02; 0.16, 95% CI 0.01 to 0.33; P=0.02; integrated discrimination improvement 0.037, 95% CI 0.008 to 0.073; P<0.01). CONCLUSION: MF measured by ECV is associated with hospitalization for heart failure, death, or both. MF may represent a principal phenotype of cardiac vulnerability that improves risk stratification. Because MF can be reversible, cells and enzymes regulating collagen could be potential therapeutic targets.
Autores: Rivera-Torres, J; Guzman-Martinez, G; Villa-Bellosta, R; et al.
ISSN 0263-6352  Vol. 33  Nº 4  2015  págs. 843 - 850
OBJECTIVE: The Notch pathway has been linked to pulmonary hypertension, but its role in systemic hypertension and, in particular in left ventricular hypertrophy (LVH), remains poorly understood. The main objective of this work was to analyse the effect of inhibiting the Notch pathway on the establishment and maintenance of angiotensin II (Ang-II)-induced arterial hypertension and LVH in adult mice with inducible genetic deletion of ¿-secretase, and to test preclinically the therapeutic efficacy of ¿-secretase inhibitors (GSIs). BASIC METHODS: We analysed Ang-II responses in primary cultures of vascular smooth muscle cells obtained from a novel mouse model with inducible genetic deletion of the ¿-secretase complex, and the effects of GSI treatment on a mouse cardiac cell line. We also investigated Ang-II-induced hypertension and LVH in our novel mouse strain lacking the ¿-secretase complex and in GSI-treated wild-type mice. Moreover, we analysed vascular tissue from hypertensive patients with and without LVH. MAIN RESULTS: Vascular smooth muscle cells activate the Notch pathway in response to Ang-II both 'in vitro' and 'in vivo'. Genetic deletion of ¿-secretase in adult mice prevented Ang-II-induced hypertension and LVH without causing major adverse effects. Treatment with GSI reduced Ang-II-induced hypertrophy of a cardiac cell line 'in vitro' and LVH in wild-type mice challenged with Ang-II. We also report elevated expression of the Notch target HES5 in vascular tissue from hypertensive patients with LVH compared with those without LVH. CONCLUSION: The Notch pathway is activated in the vasculature of mice with hypertension and LVH, and its inhibition via inducible genetic ¿-secretase deletion protects against both conditions. Preliminary observations in hypertensive patients with LVH support the translational potential of these findings. Moreover, GSI treatment protects wild-type mice from Ang-II-induced LVH without affecting blood pressure. Our results unveil the potential use of GSIs in the treatment of hypertensive patients with LVH.
Autores: Ho, C. Y.; Lakdawala, N. K.; Cirino, A. L.; et al.
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; Kuznetsova, T.; Varo, N; et al.
ISSN 0167-5273  Vol. 185  2015  págs. 177 - 185
BACKGROUND/OBJECTIVES: The validation of effective screening tools for the identification of patients with subclinical myocardial remodelling is a major clinical need. Thus, we explored the associations of circulating biomarkers of cardiomyocyte injury and stress with subclinical cardiac remodelling and dysfunction, and with biomarkers reflecting collagen turnover. METHODS: We randomly recruited 727 subjects from a general population (51.2% women; mean age 51.3 years). Measurements included echocardiographic left atrial (LA) and left ventricular (LV) structure and function, quantification of high sensitivity cardiac Troponin T (hs-cTnT), NT-proBNP, and biomarkers of collagen types I and III turnover. RESULTS: In unadjusted and adjusted analyses, the prevalence of LA enlargement (LAE), LV hypertrophy (LVH) and LV diastolic dysfunction (LVDD) increased with higher hs-cTnT (P ¿ 0.031). NT-proBNP was independently associated with LVDD (P=0.009). Both biomarkers combined yielded significant integrated discrimination and net reclassification improvements (P ¿ 0.014 and P ¿ 0.009, respectively) for LAE, LVH and LVDD, over the conventional risk factors, and were independently and positively associated with biomarkers of collagen type I turnover. In a sensitivity analysis, after excluding participants with previous cardiac diseases, our findings remained consistent. CONCLUSIONS: Our population-based study suggested that subclinical LV and LA remodelling were associated with hs-cTnT, and that, in combination with NT-proBNP, hs-cTnT showed incremental diagnostic utility over the conventional risk factors. Both biomarkers were associated with biomarkers of collagen type I turnover. Thus, biomarkers of cardiomyocyte microinjury and hemodynamic stress may stimulate fibrosis-related mechanisms and facilitate the diagnosis of subclinical LA and LV remodelling and dysfunction in the general population.
Autores: Ravassa, S; Beaumont Javier; Huerta, Ana; et al.
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: López, B; González, A; Querejeta, R.; et al.
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: Senni, M.; Paulus, W. J.; Gavazzi, A.; et al.
ISSN 0195-668X  Vol. 35  Nº 40  2014  págs. 2797 - 2815
The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.
Autores: Díez, J;
ISSN 1175-3277  Vol. 14  Nº 4  2014  págs. 275 - 285
Abstract Acute heart failure (AHF) is characterized by high morbidity and mortality and high costs. Although the treatment of AHF has not changed substantially in recent decades, it is becoming clear that treatment strategies for AHF need to address both the immediate hemodynamic abnormalities giving rise to congestion as well as prevent organ damage that can influence long-term prognosis. Serelaxin, the recombinant form of human relaxin-2, a naturally occurring peptide hormone, has been found to significantly improve symptoms and signs of AHF, prevent in-hospital worsening heart failure, as well as significantly improve 180-day cardiovascular and all-cause mortality after a 48-h infusion commenced within 16 h of presentation (RELAX-AHF study). Available data suggest that the clinical benefits may be attributable to a potential combination of multiple actions of serelaxin, including improving systemic, cardiac, and renal hemodynamics, and protecting cells and organs from damage via anti-inflammatory, anti-cell death, anti-fibrotic, anti-hypertrophic, and pro-angiogenic effects. This manuscript describes the short- and long-term effects of serelaxin in AHF patients, analyzing how these effects can be explained by taking into account the range of hemodynamic and non-hemodynamic actions of serelaxin. In addition, this paper also addresses several aspects related to the role of serelaxin in the therapy of AHF that remain to be clarified and warrant further investigation.
Autores: Díez, J;
ISSN 1551-7136  Vol. 10  Nº 2  2014  págs. 233 - 242
Hypertensive heart disease (HHD) has been considered the adaptive hypertrophy of the left ventricle wall to increased blood pressure. Recent findings in hypertensive animals and patients now challenge this paradigm by showing that HHD also results from pathologic structural remodeling of the myocardium in response to hemodynamic and nonhemodynamic factors that are altered in arterial hypertension. The possibility that hypertensive patients predisposed to develop heart failure may be detected before the appearance of clinical manifestations provides a new way to prevent this major arterial complication.
Autores: García-Dorado, D.; Díez, J; Cinca, J.; et al.
ISSN 0300-8932  Vol. 67  Nº 4  2014  págs. 254 - 258
Autores: Löfsjögard, J.; Persson, H.; Díez, J; et al.
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: Moreno, MU; San José, Gorka; Pejenaute, Á.; et al.
ISSN 0194-911X  Vol. 63  Nº 3  2014  págs. 468 - 474
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.
Autores: Löfsjögard, J.; Kahan,T.; Díez, J; et al.
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: Lucas, E. ; Jurado-Pueyo, M. ; Fortuño, María Antonia; et al.
ISSN 0925-4439  Vol. 1842  Nº 12 Pt A  2014  págs. 2448 - 2456
G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, we have explored the interconnections among a systemic insulin resistant status, GRK2 dosage and cardiac insulin sensitivity in adult (9 month-old) animals. GRK2(+/-) mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where insulin resistance develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as insulin resistance, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.
Autores: López, B; González, A; Querejeta, R.; et al.
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.
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: Jacobs, L.; Thijs, L.; Jin, Y.; et al.
ISSN 1674-8301  Vol. 28  Nº 5  2014  págs. 349 - 359
Heart failure is common in older people and its prevalence is increasing. The Heart 'omics' in AGEing (HOMAGE) project aims to provide a biomarker approach that will improve the early diagnosis of heart failure. A large clinical database, based on (1) prospective population studies or (2) cross-sectional, prospective studies or randomized controlled trials (RCTs) of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising 'omics'-based biomarkers to identify the risk of developing heart failure and/or comorbidities. Population studies, patient cohorts and RCTs are eligible for inclusion in the common database, if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors. Currently, the HOMAGE database includes 43,065 subjects, from 20 studies in eight European countries, including healthy subjects from three population studies in France, Belgium and Italy (n ¿=¿ 7,124), patients with heart failure (n ¿=¿ 4,312) from four cohorts in the UK, Spain and Switzerland and patients at high risk for cardiovascular disease (n ¿=¿ 31,629) in 13 cohorts. It is anticipated that more partners will join the consortium and enlarge the pooled data. This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure
Autores: Beaumont Javier; López, B; et al.
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: García-Cenador, M. B.; López-Novoa, J. M.; Díez, J; et al.
ISSN 0929-8673  Vol. 20  Nº 2  2013  págs. 246 - 256
Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although many effects of CT-1 have been described on the heart, CT-1has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFR beta) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated.
Autores: Ravassa, S; Barba, Joaquín; Coma, María Isabel; et al.
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: San José, Gorka; Moreno, MU; et al.
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: Moreno, MU; López, B; González, A; et al.
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: Calvier, L.; Labat, C.; Fay, R.; et al.
ISSN 0194-911X  Vol. 61  Nº 1  2013  págs. 120 - 129
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.
Autores: Ravassa, S; Beloqui, Óscar; Varo, N; et al.
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.
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.
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.
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: Ravassa, S; Díez, J;
ISSN 0008-6363  Vol. 94  Nº 2  2012  págs. 316 - 323
During myocardial infarction (MI), a variety of mechanisms contribute to the activation of cell death processes in cardiomyocytes, determining the final MI size, subsequent mortality, and post-MI remodelling. The deleterious mechanisms accompanying the ischaemic and reperfusion phases in MI include deprivation of oxygen, nutrients, and survival factors, accumulation of waste products, generation of oxygen free radicals, calcium overload, neutrophil infiltration of the ischaemic area, depletion of energy stores, and opening of the mitochondrial permeability transition pore, all of which contribute to the activation of apoptosis and necrosis in cardiomyocytes. During the last few years, glucagon-like peptide-1 (GLP-1) (7-36)-based therapeutic strategies have been incorporated into the treatment of patients with type 2 diabetes mellitus. Cytoprotection is among the pleiotropic actions described for GLP-1 in different cell types, including cardiomyocytes. This paper reviews the most relevant experimental and clinical studies that have contributed to a better understanding of the molecular mechanisms and intracellular pathways involved in the cardioprotection induced by GLP-1, analysing in depth its potential role as a therapeutic target in the ischaemic and reperfused myocardium as well as in other pathologies that are associated with myocardial remodelling and heart failure.
Autores: Ravassa, S; Díez, J;
ISSN 0188-9796  Vol. 59  Nº 9  2012  págs. 561 - 569
La activación de diferentes procesos de muerte celular en los cardiomiocitos tras un infarto de miocardio (IM) contribuye al tamaño final del infarto, a la mortalidad subsecuente y al remodelado postinfarto en los supervivientes. Los diversos mecanismos deletéreos activados durante las fases de isquemia y reperfusión en el IM incluyen la privación de oxígeno, la disponibilidad reducida de nutrientes y factores de supervivencia, la acumulación de residuos, la generación de especies reactivas del oxígeno, la sobrecarga de calcio, la infiltración por neutrófilos en el área isquémica, la depleción energética, y la apertura del poro de transición de permeabilidad mitocondrial, todos ellos mecanismos de activación de apoptosis y necrosis en los cardiomiocitos. En los últimos años, las terapias basadas en el péptido similar al glucagón tipo 1 [GLP-1 (7-36) amida] han adquirido mayor relevancia como tratamiento metabólico de la diabetes mellitus tipo 2. Entre las acciones atribuidas a GLP-1 destaca la preservación de la viabilidad en diferentes tipos celulares, entre ellos los cardiomiocitos. Este artículo revisa los principales estudios experimentales que han contribuido a una mayor comprensión de la citoprotección inducida por GLP-1 en el miocardio y de sus efectos en la función cardiaca, ahondando en el estudio de su papel como diana terapéutica, no solo en el contexto de la diabetes mellitus sino también en otras patologías que cursan con remodelado cardiaco.
Autores: González, A; López, B; Ravassa, S; et al.
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.
ISSN 0263-6352  Vol. 30  Nº 1  2012  págs. 34 - 37
Autores: Díez, J; Hermida, José;
ISSN 1538-7933  Vol. 10  Nº 9  2012  págs. 1733-1735
Autores: Díez, J;
ISSN 0025-7753  Vol. 138  Nº 4  2012  págs. 155 - 156
Autores: Ruiz-Hurtado, G.; Gómez-Hurtado, N.; Fernández-Velasco, M.; et al.
ISSN 1755-3245  Vol. 96  Nº 1  2012  págs. 81 - 89
AIMS: Plasma levels of cardiotrophin-1 (CT-1) are elevated in several cardiovascular diseases and are correlated with the severity of the pathology. However, the mechanisms by which this inflammatory cytokine participates in the pathology of the heart are not completely understood. It is well established that alterations in intracellular calcium ([Ca(2+)](i)) handling are involved in cardiac dysfunction during heart failure, but it is unknown whether CT-1 modulates [Ca(2+)](i) handling in adult cardiomyocytes. Here we have analyzed for the first time the effects of CT-1 on [Ca(2+)](i) homeostasis in adult rat cardiomyocytes. METHODS AND RESULTS: L-type calcium current (I(CaL)) was recorded using patch-clamp techniques, and [Ca(2+)](i) transients and Ca(2+) sparks were viewed by confocal microscopy. Treatment of cardiomyocytes with 1 nM CT-1 for 20-60 min induced a significant increase in I(CaL) density, [Ca(2+)](i) transients, and cell shortening compared with control cells. Our study reveals that CT-1 increases I(CaL) by a protein kinase A-dependent mechanism, and Ca(2+) sparks by a Ca(2+)/calmodulin kinase II-dependent and protein kinase A-independent mechanism. Cardiomyocytes treated with CT-1 exhibited a higher occurrence of arrhythmogenic behaviour, manifested as spontaneous Ca(2+) waves and aftercontractions. CONCLUSION: Our findings provide evidence that cardiomyocytes treated with CT-1 present high spontaneous Ca(2+) release during diastole, a mechanism linked to arrhythmogenicity in the pathologic heart.
Autores: Rousseau, A.; Akhtar, R.; Calvier, L.; et al.
ISSN 0194-911X  Vol. 60  Nº 2  2012  págs. 563 - 573
Cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family, is increased in hypertension and in heart failure. We aimed to study the precise role of CT-1 on cardiac, vascular, and renal function; morphology; and remodeling in early stages without hypertension. CT-1 (20 ¿g/kg per day) or vehicle was administrated to Wistar rats for 6 weeks. Cardiac and vascular functions were analyzed in vivo using M-mode echocardiography, Doppler, and echo tracking device and ex vivo using a scanning acoustic microscopy method. Cardiovascular and renal histomorphology were measured by immunohistochemistry, RT-PCR, and Western blot. Kidney functional properties were assessed by serum creatinine and neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. Without alterations in blood pressure levels, CT-1 treatment increased left ventricular volumes, reduced fractional shortening and ejection fraction, and induced myocardial dilatation and myocardial fibrosis. In the carotid artery of CT-1-treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward, and the acoustic speed of sound in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen, and fibronectin content were increased by CT-1 treatment. CT-1-treated rats presented unaltered serum creatinine concentrations but increased urinary and serum neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. This paralleled a glomerular and tubulointerstitial fibrosis accompanied by renal epithelial-mesenchymal transition. CT-1 is a new potent fibrotic agent in heart, vessels, and kidney able to induce cardiovascular-renal dysfunction independent from blood pressure. Thus, CT-1 could be a new target simultaneously integrating alterations of heart, vessels, and kidney in early stages of heart failure.
Autores: López, B; Querejeta, R.; González, A; et al.
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: Gállego, Jaime; Irimia, Pablo; Martínez Vila, E.; et al.
ISSN 0091-2751  Vol. 40  Nº 8  2012  págs. 479 - 485
Background. The assessment of carotid intima-media thickness (CIMT) may improve cardiovascular risk prediction. The optimal protocol for CIMT measurement is unclear. CIMT may be measured in the common carotid artery (CCA), carotid bifurcation (CB), and internal carotid artery (ICA), but measurements from CB and ICA are more difficult to obtain. We studied the influence of body mass index (BMI) and atheroma plaques on the capacity to obtain CIMT measurements at different carotid sites. Methods. Using an automatic system, CIMT was measured in 700 subjects aged 4575, in the near and far walls of CCA, CB, and ICA bilaterally. The presence of atheroma plaques, BMI and vascular risk factors were recorded. Results. CIMT measurements in CCA were possible in all except one subject. It was not possible to obtain CIMT measurements at CB or ICA in 24.1% of normal weight and 58.8% of obese subjects. The likelihood of obtaining CIMT measurement at all carotid sites decreased as the BMI increased. Atheroma plaques in a carotid segment did not preclude CIMT measurement at this site. Conclusions. CIMT measurements in distal carotid segments are more challenging in obese subjects. Measuring CIMT at CCA remains feasible in obese subjects and should be the primary endpoint in these subjects. Nevertheless, CB and ICA measurements, when feasible, would improve risk classification.
Autores: Moreno, MU; López, B; et al.
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.
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: Delles, C.; Díez, J; Dominiczak, A.;
ISSN 1862-8346  Vol. 5  Nº 5 - 6  2011  págs. 222 - 232
Cardiovascular disease (CVD) is the major cause of mortality and morbidity worldwide. Diagnosis of CVD and risk stratification of patients with CVD remains challenging despite the availability of a wealth of non-invasive and invasive tests. Clinical proteomics analyses a large number of peptides and proteins in biofluids. For clinical applications, the urinary proteome appears particularly attractive due to the relative low complexity compared with the plasma proteome and the noninvasive collection of urine. In this article, we review the results from pilot studies into urinary proteomics of coronary artery disease and discuss the potential of urinary proteomics in the context of pathogenesis of CVD.
Autores: Ravassa, S; González, A; Díez, J;
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;
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: Díez, J;
ISSN 0895-7061  Vol. 24  Nº 6  2011  págs. 626 - 627
Autores: González, A; Ravassa, S; Beaumont Javier; et al.
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: Herzog, C. A.; Asinger, R. W.; Berger, A. K.; et al.
ISSN 0085-2538  Vol. 80  Nº 6  2011  págs. 572 - 586
Cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) is high, and the presence of CKD worsens outcomes of cardiovascular disease (CVD). CKD is associated with specific risk factors. Emerging evidence indicates that the pathology and manifestation of CVD differ in the presence of CKD. During a clinical update conference convened by the Kidney Disease: Improving Global Outcomes (KDIGO), an international group of experts defined the current state of knowledge and the implications for patient care in important topic areas, including coronary artery disease and myocardial infarction, congestive heart failure, cerebrovascular disease, atrial fibrillation, peripheral arterial disease, and sudden cardiac death. Although optimal strategies for prevention, diagnosis, and management of these complications likely should be modified in the presence of CKD, the evidence base for decision making is limited. Trials targeting CVD in patients with CKD have a large potential to improve outcomes.
Autores: Díez, J; López, B; Beaumont Javier; et al.
ISSN 0263-6352  Vol. 29  Nº 4  2011  págs. 660 - 662
Autores: Díez, J;
ISSN 0263-6352  Vol. 29  Nº 2  2011  págs. 204 - 206
Autores: Montserrat, L.; López, B; González, A; et al.
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: Ravassa, S; Carr, R. D.; Díez, J;
ISSN 0363-6135  Vol. 300  Nº 4  2011  págs. H1361 - H1372
Activation of apoptosis contributes to cardiomyocyte dysfunction and death in diabetic cardiomyopathy. The peptide glucagon-like peptide-1 (GLP-1), a hormone that is the basis of emerging therapy for type 2 diabetic patients, has cytoprotective actions in different cellular models. We investigated whether GLP-1 inhibits apoptosis in HL-1 cardiomyocytes stimulated with staurosporine, palmitate, and ceramide. Studies were performed in HL-1 cardiomyocytes. Apoptosis was induced by incubating HL-1 cells with staurosporine (175 nM), palmitate (135 ¿M), or ceramide (15 ¿M) for 24 h. In staurosporine-stimulated HL-1 cardiomyocytes, phosphatidylserine exposure, Bax-to-Bcl-2 ratio, Bad phosphorylation (Ser(136)), BNIP3 expression, mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, DNA fragmentation, and mammalian target of rapamycin (mTOR)/p70S6K phosphorylation (Ser(2448) and Thr(389), respectively) were assessed. Apoptotic hallmarks were also measured in the absence or presence of low (5 mM) and high (10 mM) concentrations of glucose. In addition, phosphatidylserine exposure and DNA fragmentation were analyzed in palmitate- and ceramide-stimulated cells. Staurosporine increased apoptosis in HL-1 cardiomyocytes. GLP-1 (100 nM) partially inhibited staurosporine-induced mitochondrial membrane depolarization and completely blocked the rest of the staurosporine-induced apoptotic changes. This cytoprotective effect was mainly mediated by phosphatidylinositol 3-kinase (PI3K) and partially dependent on ERK1/2. Increasing concentrations of glucose did not influence GLP-1-induced protection against staurosporine. Furthermore, GLP-1 inhibited palmitate- and ceramide-induced phosphatidylserine exposure and DNA fragmentation. Incretin GLP-1 protects HL-1 cardiomyocytes against activation of apoptosis. This cytoprotective ability is mediated mainly by the PI3K pathway and partially by the ERK1/2 pathway and seems to be glucose independent. It is proposed that therapies based on GLP-1 may contribute to prevent cardiomyocyte apoptosis.
Autores: Moreno, MU; San José, Gorka; Fortuño, Ana; et al.
ISSN 1945-0494  Vol. 3  2011  págs. 1467 - 1474
Oxidative stress is implicated in diabetes. The NADPH oxidases are the main source of superoxide in phagocytic and vascular cells, and p22phox is a key subunit. Genetic variants of CYBA, the human p22phox gene, associate with cardiovascular disease. We investigated the association of the A640G polymorphism with diabetes and its impact on phagocytic NADPH oxidase-dependent superoxide production and subclinical atherosclerosis. We studied 1212 subjects in which clinical parameters including carotid intima-media thickness (cIMT) were assessed. The A640G polymorphism was genotyped by TaqMan probes. In 496 subjects, the NADPH oxidase-dependent superoxide production in peripheral blood mononuclear cells was assessed by chemiluminescence. The GG genotype prevalence was significantly higher in type 2 diabetic patients than in non-diabetic subjects. Peripheral blood mononuclear cells from diabetic GG patients presented higher NADPH oxidase-dependent superoxide production than those of diabetic AA/AG patients. Within the diabetic group, GG patients presented higher cIMT levels than AA/AG patients. The A640G CYBA polymorphism may be a marker of oxidative stress risk and may be indicative of subclinical atherosclerosis in type 2 diabetes.
Autores: San José, Gorka; Rodríguez, C.; et al.
ISSN 0008-6363  Vol. 92  Nº 2  2011  págs. 247 - 255
Aims Cardiotrophin-1 (CT-1) is a cytokine of the interleukin-6 superfamily which is up-regulated in cardiac diseases, in part via hypoxia-dependent mechanisms. However, no evidence for a direct regulation of CT-1 gene (CTF1) promoter by hypoxia inducible factor-1 (HIF-1) has been provided. Methods and results Hypoxia increased CT-1 mRNA levels in the murine adult cardiomyocyte cell line HL-1 in a time-dependent manner. Interestingly, in a murine model (C57BL/6), we show that systemic hypoxia also significantly up-regulated CT-1 in myocardial tissue. The effect of hypoxia on CT-1 expression was mediated through a transcriptional mechanism, since hypoxia increased luciferase activity of constructs containing CTF1 promoter sequences. The increase in CT-1 levels was significantly reduced by drugs that prevent calcium mobilization, such as lercanidipine, or that inhibit the activation of the PI3K/Akt pathway (wortmannin) or mammalian target of rapamycin (rapamycin). The CT-1 elevation was similarly induced by HIF-1 alpha over-expression in co-transfection experiments and prevented by HIF-1 alpha silencing. The direct interaction of HIF-1 alpha with the CTF1 promoter was confirmed through site-directed mutagenesis of hypoxia response elements, electrophoreric mobility shift, and ChIP assays. Hypoxia induced HL-1 apoptosis (measured as annexin-V binding or caspase 3/7 activity) which was increased when CT-1 was silenced in knocked-down cells by lentiviral vectors. Conclusion Hypoxia increased CT-1 levels in cardiac cells (in vitro and in vivo) through a direct regulation of CTF1 promoter by HIF-1 alpha. This CT-1 activation by hypoxia may protect cells from apoptosis, thus supporting a protective role for CT-1 as a survival factor for cardiomyocytes.
Autores: Beaumont Javier; López, B; et al.
ISSN 0263-6352  Vol. 29  Nº 5  2011  págs. 876 - 883
Objective: To analyze whether genetic variants of PPARA are associated with the development of stage C heart failure. Methods: We analyzed the distribution of the rs1800206, rs4253778 and rs135551 polymorphisms in genomic DNA extracted from peripheral blood cells of 534 patients in different heart failure stages and 63 healthy individuals. The mRNA expression of the peroxisome proliferator-activated receptor (PPAR)¿ target genes long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was measured in myocardial biopsies of a subgroup of stage B and C patients. Functional studies were performed in HL-1 cardiomyocytes. Results: The V162 allele of the rs1800206 polymorphism was more frequent in stage C patients than in stage A and B patients and healthy individuals. Patients with the V162 allele exhibited decreased myocardial LCHAD and MCAD mRNA expression as compared to L162 homozygote patients. In addition, stage C patients exhibited lower myocardial LCHAD and MCAD mRNA expression than stage B patients. Cardiomyocytes transfected with the V162 allele presented decreased PPAR¿ transcriptional activity, LCHAD mRNA expression and ATP production compared to cardiomyocytes transfected with the L162 variant. Conclusions: These findings suggest that the V162 allele of the human PPARA gene can be a new risk factor in the development of stage C heart failure, likely via depressed cardiac PPARalfa activity.
Autores: Martín-Fernández, B.; Rossignol, P.; Zannad, F.; et al.
ISSN 0363-6135  Vol. 301  Nº 6  2011  págs. H2372 - H2382
Hyperaldosteronim is associated with left ventricular (LV) hypertrophy (LVH) and fibrosis. Cardiotrophin (CT)-1 is a cytokine that induces myocardial remodeling. We investigated whether CT-1 mediates aldosterone (Aldo)-induced myocardial remodeling in two experimental models. Wistar rats were treated with Aldo-salt (1 mg·kg(-1)·day(-1)) with or without spironolactone (200 mg·kg(-1)·day(-1)) for 3 wk. Wild-type (WT) and CT-1-null mice were infused with Aldo (1 mg·kg(-1)·day(-1)) for 3 wk. Hemodynamic parameters were analyzed. LVH, fibrosis, inflammation, and CT-1 expression were evaluated in both experimental models by histopathological analysis, RT-PCR, Western blot analysis, and ELISA. Hypertensive Aldo-treated rats exhibited increased LV end-diastolic pressure and -dP/dt compared with controls. The cardiac index, LV cross-sectional area and wall thickness, cardiomyocyte size, collagen deposition, and inflammation were increased in Aldo-salt-treated rats. Myocardial expression of molecular markers assessing LVH and fibrosis as well as CT-l levels were also augmented by Aldo-salt. Spironolactone treatment reversed all the above effects. CT-1 correlated positively with hemodynamic, histological, and molecular parameters showing myocardial remodeling. In WT and CT-1-null mice, Aldo infusion did not modify blood pressure. Whereas Aldo treatment induced LVH, fibrosis, and inflammation in WT mice, the mineralocorticoid did not provoke cardiac remodeling in CT-1-null mice. In conclusion, in experimental hyperaldosteronism, the increase in CT-1 expression was associated with parameters showing LVH and fibrosis. CT-1-null mice were resistant to Aldo-induced LVH and fibrosis. These data suggest a key role for CT-1 in cardiac remodeling induced by Aldo independent of changes in blood pressure levels.
Autores: Díez, J;
ISSN 0014-2565  Vol. 210  Nº Supl. 1  2010  págs. 12 - 17
Recientemente, el Grupo de Trabajo de la Sociedad Europea de Hipertensión sobre el manejo de la hipertensión ha revaluado las guías del año 2007, a partir de la información proporcionada por una serie de estudios publicados en los últimos dos años. Desde el punto de vista renal, las conclusiones más relevantes de dicha revaluación son varias. En primer lugar, se hace énfasis en la importancia de la inclusión del daño renal subclínico al valorar el riesgo cardiovascular total del paciente hipertenso. En segundo lugar, se cuestiona el objetivo terapéutico de conseguir una presión arterial < 130/80 mmHg en los pacientes renales, sean o no diabéticos, y en los pacientes con un alto riesgo cardiovascular, pues no sólo la mayor protección renal no está consistentemente apoyada por las evidencias disponibles, sino que además cobra fuerza la noción de que el fenómeno de la ¿curva en J¿ podría afectar muy desfavorablemente a la enfermedad renal. En tercer lugar, se enfatiza que la combinación de fármacos antihipertensivos ha de hacerse con suma precaución en el paciente hipertenso con afectación renal, especialmente en el caso de las combinaciones de fármacos que interfieren el sistema renina-angiotensina a distintos niveles.
Autores: Díez, J; Fröhlich, ED;
ISSN 0194-911X  Vol. 55  Nº 1  2010  págs.  -
Autores: López, B; González, A; et al.
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;
ISSN 0009-7322  Vol. 121  Nº 14  2010  págs. 1645 - 1654
Autores: Van den Borne, Susanne WM; Díez, J; Blankesteijn, W Matthijs; et al.
ISSN 1759-5002  Vol. 7  Nº 1  2010  págs. 30 - 37
Myofibroblasts have characteristics of fibroblasts and smooth muscle cells: they produce extracellular matrix and are able to contract. In so doing, they can contribute to tissue replacement and interstitial fibrosis following cardiac injury. The scar formed after myocardial injury is no longer considered to be passive tissue; it is an active playground where myofibroblasts play a role in collagen turnover and scar contraction. Maintaining the extracellular matrix in the scar is essential and can prevent dilatation of the infarct area leading to heart failure. On the other hand, extracellular matrix deposition at sites remote from the infarct area can lead to cardiac stiffness, an inevitable process of myocardial remodeling that occurs in the aftermath of myocardial infarction and constitutes the basis of the development of heart failure. Defining molecular targets on myofibroblasts in conjunction with establishing the feasibility of molecular imaging of these cells might facilitate the early detection and treatment of patients who are at risk of developing heart failure after myocardial infarction.
Autores: Díez, J; González, A; Ravassa, S;
ISSN 0194-911X  Vol. 56  Nº 6  2010  págs. 1045 - 1046
Autores: Díez, J;
ISSN 0008-6363  Vol. 87  Nº 4  2010  págs. 591 - 592
Autores: Ho, Caroline; López, B; Coelho, Oscar; et al.
ISSN 0028-4793  Vol. 363  Nº 6  2010  págs. 552 - 563
Autores: Guembe, M. J.; Toledo, Estefanía Ainhoa; Barba, Joaquín; et al.
ISSN 0021-9150  Vol. 211  Nº 2  2010  págs. 612 - 617
OBJECTIVE: To assess the association between the metabolic syndrome (MetSd) and asymptomatic cardiovascular disease and determine if the MetSd or its single risk factors perform better in discriminating prevalent asymptomatic cardiovascular disease. METHODS: A total of 880 community-dwelling subjects (423 with and 457 without MetSd according to ATPIII) underwent a physical examination, an echocardiography and an ultrasound examination of carotid arteries and blood and urine samples were collected. Associations between the subclinical organ damage markers and the MetSd were addressed with non-conditional logistic regression. AUCs of ROCs were used to compare the models' ability to discriminate asymptomatic cardiovascular disease. RESULTS: The MetSd was independently associated with carotid subclinical atherosclerosis, increased left ventricular mass index and cardiac dysfunction. The MetSd did not discriminate prevalent increased carotid intima-media thickness better than abdominal obesity and impaired fasting glucose [AUC=0.75 (95% CI: 0.71-0.78) and 0.75 (0.71-0.79), respectively; p=0.55]. The MetSd performed worse than abdominal obesity in discriminating increased left ventricular mass index among males younger than 65 years [AUC=0.66 (95% CI: 0.62-0.69) and 0.69 (0.66-0.73), respectively; p=0.02]. No differences between the ability of MetSd or its components in discriminating increased left ventricular mass index were observed among older men or women. The discrimination ability for microalbuminuria for the MetSd or impaired fasting glucose was not statistically different [AUC=0.67 (95% CI: 0.60-0.74) and 0.69 (0.62-0.76), respectively; p=0.18]. CONCLUSION: This study supports the association between the MetSd and asymptomatic cardiovascular disease. The construct of the MetSd might not be better than its single components in addressing cardiovascular risk.
Autores: Fortuño, Ana; Moreno, MU; et al.
ISSN 0263-6352  Vol. 28  Nº 9  2010  págs. 1944 - 1950
Autores: Ravassa, S; Garcia-Bolao, I; et al.
ISSN 0008-6363  Vol. 88  Nº 2  2010  págs. 304 - 313
Autores: González, A; López, B; Querejeta, Ramón; et al.
ISSN 0194-911X  Vol. 55  Nº 6  2010  págs. 1418 - 1424
Autores: Kuznetsova, Tatiana; Codd, Veryan; Brouilette, Scott; et al.
ISSN 0002-9262  Vol. 172  Nº 4  2010  págs. 440 - 450
Autores: Moreno, MU; Beloqui, Óscar; et al.
ISSN 0263-6352  Vol. 28  Nº 11  2010  págs. 2219 - 2226
Autores: Coll, B.; Rodríguez, José Antonio; Craver, L.; et al.
ISSN 0085-2538  Vol. 78  Nº 12  2010  págs. 1275 - 1280
Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). As matrix metalloproteinases have a major role in atherosclerosis, we hypothesized that alterations in metalloproteinases-8, -10 and their tissue inhibitor-1 can be associated with the severity of atherosclerosis in patients with kidney disease. This was evaluated in a cross-sectional, observational study of 111 patients with stages I-V kidney disease, 217 patients on dialysis and 50 healthy controls. The severity of atherosclerosis was estimated with the atherosclerosis score (AS), combining the results of ankle-brachial index and carotid ultrasound. Serum levels of the two metalloproteinases and tissue inhibitor-1 were measured by enzyme-linked immunosorbent assay and were significantly increased in patients with kidney disease compared with the healthy controls, and higher in patients on dialysis than in earlier stages of CKD. The severity of the AS was also more prevalent in the dialysis group, in which serum levels of both metalloproteinases and tissue inhibitor-1 were significantly higher. After multivariate analysis, metalloproteinase-10, dialysis, C-reactive protein, age, and male gender were associated with increased risk of atherosclerosis. Thus, patients with CKD exhibit elevated levels of circulating metalloproteinase-10, and this was independently associated with the severity of atherosclerosis and may represent a new biomarker of atherosclerotic diseases.
Autores: García-Guerra, Lucía; Nieto-Vazquez, Iria; Vila-Bedmar, Rocío; et al.
ISSN 0012-1797  Vol. 59  Nº 10  2010  págs. 2407 - 2417
Autores: Fortuño, María Antonia; Díez, J; Zannad, Faiez; et al.
ISSN 0263-6352  Vol. 28  Nº 6  2010  págs. 1261 - 1272
Aims: To investigate cardiotrophin-1 (CT-1) effects and regulation in vascular smooth muscle cells (VSMCs) in vitro and in aortic tunica media ex vivo in normotensive Wistar rats and spontaneously hypertensive rats (SHRs). Methods and Results: CT-1 expression was quantified by real-time reverse-transcription PCR and western blotting. CT-1-activated intracellular pathways were assessed by western bloting analysis. Proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ki67 immunodetection, and cell hypertrophy by planimetry. Extracellular matrix components were quantified by real-time reverse-transcription PCR and western blot, and metalloproteinases activities by zymography. VSMCs from Wistar rats and SHRs expressed spontaneously CT-1 at the mRNA and the protein level, with a two-fold more increase in SHRs. CT-1 phosphorylated p42/44 mitogen-activated protein kinase, p38 mitogen-activated protein kinase, Akt and Stat-3 in both strains. CT-1 stimulated VSMCs proliferation and hypertrophy in both strains, with an enhanced stimulation in SHRs. CT-1 increased the secretion of collagen type I and fibronectin in VSMCs and aortic tunica media of Wistar rats and SHRs, with greater magnitude in SHRs. In SHRs VSMCs in vitro and ex vivo, CT-1 increased the secretion of collagen type III and elastin and the expression of tissue inhibitors of metalloproteinases, without altering metalloproteinase activity. These effects were blocked by CT-1 receptor antibodies. Aldosterone treatment increased CT-1 expression in VSMCs and aortic tunica media from both strains, with a greater magnitude in SHRs. Conclusion: CT-1 induces VSMCs proliferation, hypertrophy and extracellular matrix production, and is upregulated in hypertension and by aldosterone. CT-1 may represent a new target of vascular wall remodeling in hypertension.
Autores: Díez, J;
Libro:  Blood pressure and arterial wall mechanics in cardiovascular diseases
2014  págs. 205 - 213
The structural changes involved in arterial stiffness include cellular changes (namely, smooth muscle cell differentiation) and noncellular changes affecting the extracellular matrix (namely, increased collagen deposition leading to fibrosis of the arterial wall or arteriosclerosis). By altering the geometry and the biomechanical properties of the arterial wall, these changes will contribute to arterial stiffness. A number of pathophysiologic processes develop within the arterial wall that is responsible for its altered structure and stiffening. For instance, increased activity of fibrogenic neurohormones and proinflammatory cytokines and oxidative stress have been shown to play a role in arterial stiffening through mechanisms that affect the metabolism and function of vascular collagen. The possibility is emerging to target the vascular collagen matrix for future pharmacological interventions on arterial stiffness.
Autores: Díez, J;
Libro:  Hernando Nefrología Clínica
2013  págs. 277 - 287
Autores: Díez, J;
Libro:  Hypertension
2013  págs. 152 - 166
Autores: Díez, J;
Libro:  Share care en síndrome cardiorrenal
2012  págs. 6 - 16
Autores: Díez, J; Fortuño, María Antonia; Querejeta, Ramón; et al.
Libro:  New Frontiers in Cardiovascular Research
2010  págs. -
Autores: Zalba, Guillermo; Díez, J;
Libro:  Studies on Cardiovascular Disorders
2010  págs. 169-186



Cardiología y Cirugía Cardiovascular (F.Medicina). 
Universidad de Navarra - Facultad de Medicina.