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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 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).

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Formación de Profesorado y Educación. Departamento de Didáctica y Teoría de la Educación. Fecha de lectura: 26-06-2017, El ciudadano de hoy debe desenvolverse en la nueva sociedad de la información y la comunicación, para ello, debe enfrentarse a nuevas habilidades, nuevos desafíos como saber buscar, gestionar y transformar la información que se le presenta para poder comunicarla; en segundo lugar, saber manejar la tecnología; en un tercer lugar desarrollar distintas alfabetizaciones -ya no vale solamente con saber escribir y leer-; este ciudadano ha de ser competente digital. Es el docente quien tiene no solo la obligación de presentar estas competencias sino, además, de él depende la responsabilidad de formar al ciudadano del futuro por lo que le convierte en ser responsable directo de su educación. En este estudio de tesis se pretende reconocer, averiguar y profundizar en la competencia digital que adquieren los alumnos universitarios en las Facultades de Formación del Profesorado en España para poder detectar los elementos de mejora en la calidad de la enseñanza mediante la adecuada y eficiente integración de las TIC. Consta de tres fases principales: (1) marco teórico donde se desarrolla el marco conceptual, (2) marco metodológico donde se desarrolla los pasos a seguir en la investigación, (3) análisis de datos y resultados, (4) discusión y conclusiones. Los resultados revelan que el alumno universitario está influenciado por sus propias creencias, pensamiento y emociones que las TIC les despierta, por ello, no adquieren la competencia digital para su desempeño laboral docente. Asimismo, el docente universitario reclama más formación en didáctica de las TIC para sus asignaturas desde la experiencia real de otros docentes., The citizen of today has to know how to get on in this new society of information and communication, therefore, they have to face, how to confront new abilities and skills, new goals and challenges such as: to know how to surf the internet in search of information, manage and transform the information to be able to communicate. Secondly, to know how to manage the technology and finally, how to develop different types of literacy – it is not enough to know how to write or to read – this citizen has to deal with Digital Competence. The teacher not only must have these skills, but also he has the responsibility to educate our future citizens and be directly responsible of their education. This research tries to recognize, discover and delve into the Digital Competence students who are now preparing themselves to be Primary school teachers, acquire in the different Universities in Spain to be able to detect the elements for improving the quality of teaching through an appropriate and efficient integration of ICT. This research has been divided into three main parts: (1) Theoretical frame where the conceptual frame is developed. (2) methodological frame where different steps of the investigation are followed (3) data and result analysis (4) discussion and conclusions. Results reveal that university students are influenced for their own beliefs, thoughts and feelings that ICT spark (generate) them, for that, they don’t acquire the Digital Competence for their job performance in didactic of ICT for their subject from the real experience of others teacher.

Myocardial interstitial fibrosis contributes to left ventricular dysfunction leading to the development of heart failure. Basic research has provided abundant evidence for the cellular and molecular mechanisms behind this lesion and the pathways by which it imparts a detrimental impact on cardiac function. Translation of this knowledge, however, to improved diagnostics and therapeutics for patients with heart failure has not been as robust. This is partly related to the paucity of biomarkers to accurately identify myocardial interstitial fibrosis and to the lack of personalized antifibrotic strategies to treat it in an effective manner. This paper summarizes current knowledge of the mechanisms and detrimental consequences of myocardial interstitial fibrosis, discusses the potential of circulating and imaging biomarkers available to recognize different phenotypes of this lesion and track their clinical evolution, and reviews the currently available and potential future therapies that allow its individualized management in heart failure patients.

Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r2 = 0.83) and non-structural (e.g. TGFB3 r2 = 0.75) ECM proteins. Gene enrichment analysis further underscored the involvement of CILP1 in human cardiac ECM remodelling and TGFβ signalling. Myocardial CILP1 protein levels were significantly elevated in human infarct tissue and in aortic valve stenosis patients. CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Cardiac fibroblasts were found to be the primary source of cardiac CILP1 expression. Recombinant CILP1 inhibited TGFβ-induced αSMA gene and protein expression in cardiac fibroblasts. In addition, CILP1 overexpression in HEK293 cells strongly (5-fold p

Cardiovascular diseases are the number one of death globally. According to the World Health organization 17.7 million people died from cardiovascular diseases in 2015, representing 31% of all global deaths. In these diseases the cardiac homeostasis is disrupted by a non-appropriate myocardium remodelling. The cardiac extracellular matrix (ECM) provides not only the biochemical environment but also a natural scaffold surrounding and connecting cardiac cells and distributing mechanical forces throughout the organ. Thus, the properties of the ECM are essential for the maintenance of the functional myocardium. Alterations in cardiac ECM structure associated with heart failure influence cell-matrix and cell-cell adhesions modifying cell shape and mechanotransduction.The need to understand the cardiac ECM remodelling mechanisms that allow us to identify new therapeutic targets lead us to create biomimetic scaffolds which emulate the structure, topography, mechanics and chemical composition of ECM.Here, we present the development of modulable materials for the manufacturing, by using photopolymerizable materials, of structured hydrogels with myocardium properties of stiffness and elastic modulus in physiological and pathological conditions.

Objective Sarcomeric gene mutation carriers without overt left ventricular hypertrophy (G+/LVH−) can harbour subclinical changes in cardiovascular structure and function that precede the development of hypertrophic cardiomyopathy (HCM). We sought to investigate if circulating biomarkers of cardiovascular stress and collagen metabolism among G+/LVH− individuals, measured at rest and following exercise provocation, yield further insights into the underlying biology of HCM. Methods We studied 76 individuals with overt HCM, 50 G+/LVH− individuals and 41 genotype-negative related controls enrolled in a cross-sectional, multicentre observational study (HCMNet). Biomarkers of cardiac stress (N-terminal pro-B-type natriuretic peptide, NT-proBNP; high-sensitivity troponin I, hsTnI; soluble ST2) and fibrosis (carboxy-terminal propeptide of procollagen type I; C-terminal telopeptide of type I collagen; galectin-3; periostin) were measured. Results Individuals with overt HCM had elevated NT-proBNP and hsTnI compared with G+/LVH− subjects and controls at rest, along with an exaggerated increase in NT-proBNP and hsTnI in response to exercise. We found no detectable differences in resting or exercise-provoked biomarker profiles of cardiovascular stress and fibrosis among G+/LVH− individuals compared with healthy controls despite subtle echocardiographic differences in cardiac structure and function. Conclusion Dynamic exercise testing exaggerated resting differences in natriuretic peptides and troponin elevations among individuals with overt HCM. In contrast, we found no differences in biomarker profiles of cardiovascular stress and fibrosis among G+/LVH− individuals compared with controls even after maximal exercise provocation. Our findings highlight the need for continued investigation into early phenotypes of sarcomeric gene mutations and the evolution of HCM.

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-β1-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.

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 subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P

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 in vitro studies miR-19b inhibition increased (p

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.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.Mean age was 75 years, blood pressure 134/80 mm Hg, ejection fraction 34%, serum PICP 81 μg/L and CITP 8.3 μg/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 μg/L change 1.01, P = 0.012) and left ventricular end-diastolic volume (odds ratio per 1 mL change 0.98, P0.001) were independently associated with coexisting AF.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.

AIMS Myocardial 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. METHODS We 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 134/80 mmHg, ejection fraction 34%, and median BNP 210 ng/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. RESULTS Increased 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

See related article, pp 350–360 Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminates in tissue fibrosis. When this process progresses for a prolonged period of time, parenchymal scarring and ultimately cellular dysfunction and organ failure ensue. In this conceptual framework, renal fibrosis corresponds to the replacement of renal functional tissue by extracellular matrix proteins, mainly fibrillary collagens, which lead to chronic kidney disease (CKD) and ultimately to chronic kidney failure that represents the end-stage renal disease. The concept of reversing CKD has been intensively researched during the past decade. Indeed, because the prevalence of end-stage renal disease is constantly on the rise, the lack of established antifibrotic therapies is a considerable unmet need in clinical practice. To date, the possibility of effective antifibrotic treatment has been established in experimental models of CKD, and although multiple antifibrotic compounds targeting various components of the fibrotic pathway are being assessed in clinical trials, the available results show that they are ineffective or only slightly successful to prevent or reverse renal fibrosis. Hence, it is essential to understand the pathogenesis of renal fibrosis and to discover and better understand new strategies for treating this lesion from its earliest phases. As in other organs, the mechanistic hallmark of renal fibrosis is the accumulation of a large number of matrix-producing cells or myofibroblasts. These cells are derived from diverse origins, such as resident fibroblasts, vascular …

We thank Dr. Nadir for his interest in RELIEF-AS (Regression of Myocardial Fibrosis After Aortic Valve Replacement) [(1)][1] and the potential impact of the renin-angiotensin system (RAS) on myocardial remodeling. Dr. Nadir postulates that RAS inhibition may accelerate regression of myocardial

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-β1 (TGF-β1). We investigated whether a chronic treatment with P144, a peptide synthesized from type III TGF-β1 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-β1-stimulated NRK52E exhibited a significant increase in NADPH oxidase expression and activity as well as a TGF-β1-dependent intrace...

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

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 P 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.

Aims 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. Methods and results 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. Conclusion 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 OPN–LOX 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.

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.

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 endomyocardial biopsies. HFpEF patients showed higher diastolic pressures and stiffness constant than controls (P

Heart failure (HF) is a leading cause of morbidity and mortality and generates high health care–related costs, putting a great burden on both patients and society. HF therapy given on the basis of counteracting neurohormonal activation appears to have reached a plateau, thus highlighting the need

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 r =0.474; P r =0.625; P r =0.410; P r =0.612; P r =0.538; P r =0.535; P r =−0.343; P r =−0.430; P r =0.421; P

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 TGF-β 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-β 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-β 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-β 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-β 1.

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.

Resumen El sistema renina-angiotensina desempena un papel determinante en la aparicion de complicaciones cardiovasculares y renales en el contexto de la diabetes mellitus. Las acciones del sistema reninaangiotensina incluyen no solo las dependientes de la produccion de angiotensina II, sino tambien las resultantes de la activacion del sistema renina-pro-renina/receptor de la pro-renina. En los ultimos anos, diversos estudios clinicos y experimentales senalan la implicacion del sistema renina-pro-renina/receptor de la pro-renina en el dano de organos diana en la diabetes mellitus. Este articulo revisa los principales estudios que han contribuido a una mayor comprension de dicho sistema y de su papel como posible diana terapeutica en la diabetes mellitus.

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.

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.

Heart failure is a complex syndrome and is one of the main causes of morbidity and mortality in developed countries. Despite considerable research effort in recent years, heart failure prevention and treatment strategies still suffer significant limitations. New theoretical and technical approaches are, therefore, required. It is in this context that the “omic” sciences have a role to play in heart failure. The incorporation of “omic” methodologies into the study of human disease has substantially changed biological approaches to disease and has given an enormous impetus to the search for new disease mechanisms, as well as for novel biomarkers and therapeutic targets. The application of genomics, proteomics, and metabonomics to heart failure research could increase our understanding of the origin and development of the different processes contributing to this syndrome, thereby enabling the establishment of specific diagnostic profiles and therapeutic templates that could help improve the poor prognosis associated with heart failure. This brief review contains a short description of the fundamental principles of the “omic” sciences and an evaluation of how these new techniques are currently contributing to research into human heart failure. The focus is mainly on the analysis of gene expression microarrays in the field of genomics and on studies using two-dimensional electrophoresis with mass spectrometry in the area of proteomics.

La insuficiencia cardiaca es un sindrome complejo y una de las principales causas de morbilidad y mortalidad en los paises occidentales. A pesar del enorme esfuerzo realizado en los ultimos anos, todavia existen importantes limitaciones en la prevencion y el tratamiento de la insuficiencia cardiaca, por lo que se impone un nuevo enfoque conceptual y practico. En este contexto se inscribe la aplicacion de las ciencias «omicas» a la insuficiencia cardiaca. La incorporacion de la metodologia «omica» al estudio de las enfermedades humanas ha modificado sustancialmente el enfoque biologico y ha estimulado enormemente la investigacion de nuevos mecanismos, asi como de biomarcadores y dianas terapeuticas. La aplicacion de la genomica, la proteomica y la metabonomica al estudio de la insuficiencia cardiaca puede facilitar la comprension del origen y el desarrollo de las distintas entidades que configuran dicho sindrome, con lo que se propiciaria el establecimiento de perfiles diagnosticos y patrones terapeuticos diferenciales que pueden mejorar el mal pronostico que la insuficiencia cardiaca conlleva. En esta breve revision se definen brevemente aspectos basicos sobre las ciencias «omicas» y se evalua el estado actual de la aplicacion de estas nuevas tecnologias a la investigacion de la insuficiencia cardiaca humana, centrandose principalmente en los analisis de microarrays de expresion genica en el campo de la genomica y los estudios de electroforesis bidimensional acoplada a espectrometria de masas en el ambito de la proteomica.

Cardiotrophin-1 is a cytokine that induces hypertrophy and dysfunction in cardiomyocytes and has been shown to be increased in hypertensive patients. The objective of this study was to evaluate the association of cardiotrophin-1 with heart failure (HF) in hypertensive patients and its usefulness as a biomarker of stage C heart failure. Hypertensive patients without cardiac abnormalities (stage A, n = 64), with left ventricular hypertrophy (LVH) (stage B, n = 58), and with left ventricular hypertrophy and clinical manifestations of chronic heart failure (stage C, n = 39) were studied. Plasma cardiotrophin-1 was measured by an enzyme-linked inmunosorbent assay. Plasma cardiotrophin-1 progressively increased (P < 0.001), along with progression of heart failure stages, in hypertensive patients. Plasma cardiotrophin-1 was directly (r = 0.416, P < 0.001) and inversely (r = 0.263, P < 0.01) correlated with left ventricular (LV) mass index and ejection fraction, respectively, in all hypertensive patients. These associations were independent of a number of potential confounding factors. Receiver operating characteristic curves showed that a cut-off of 48.72 fmol/ml for cardiotrophin-1 provided higher sensitivity for diagnosing stage C heart failure than a cut-off of 375.54 pg/ml for amino-terminal probrain natriuretic peptide (NT-proBNP) (80% vs. 72%). Sixty-four percent of stage C hypertensive patients with NT-proBNP values below 375.54 pg/ml value exhibited cardiotrophin-1 values above 49.16 fmol/ml. These findings indicate that plasma cardiotrophin-1 is associated with progression of heart failure in hypertensive patients. Cardiotrophin-1 measurement may provide additional information to that afforded by NT-proBNP to diagnose stage C heart failure in these patients.

The aim of this study was to investigate whether torasemide modifies collagen cross-linking in the failing human heart. We analyzed the degree of cross-linking and the expression of the enzyme lysyl oxidase, which regulates cross-linking, in the myocardium of patients with chronic heart failure at baseline and after 8 months of treatment with either torasemide or furosemide in addition to their standard heart failure therapy. Whereas lysyl oxidase protein expression was very scarce in normal hearts, it was highly expressed in failing hearts. Cross-linking was increased ( P P =0.021 and P =0.034) in torasemide-treated patients and remained unchanged in furosemide-treated patients. In addition, more ( P =0.009) patients showed normalization of left ventricular chamber stiffness in the torasemide subgroup than in the furosemide subgroup after treatment. Lysyl oxidase expression correlated with cross-linking ( r =0.661; P r =0.452; P =0.002) in all patients. These findings show for the first time that lysyl oxidase overexpression is associated with enhanced collagen cross-linking in the failing human heart. In addition, we report that the ability of torasemide to correct both lysyl oxidase overexpression and enhanced collagen cross-linking results in normalization of left ventricular chamber stiffness in patients with heart failure. Lysyl oxidase may thus represent a target for reduction of stiff collagen and improvement of left ventricular mechanical properties in heart failure patients.

Interstitial and perivascular fibrosis is a constant finding in heart biopsies and necropsy studies in patients with chronic kidney disease and hypertension, namely in those with left ventricular hypertrophy. Fibrosis is the result of the unbalance between exaggerated collagen synthesis and unchanged or depressed collagen degradation. A number of factors linked to hypertension and the progressive deterioration of renal function may facilitate such an unbalance. Patients with chronic kidney disease and hypertension are prone to develop diastolic heart failure, and myocardial fibrosis has been suggested as a major determinant of disturbances in diastolic function in these patients. Thus, the therapeutic strategies aimed to reduce cardiac fibrosis may provide a particular cardioprotective benefit in patients with chronic kidney disease. In this regard, recent data suggest that the loop diuretic torasemide reduces myocardial fibrosis and ameliorates cardiac function in patients with chronic heart failure through local mechanisms beyond its effects on the renal excretion of fluid and electrolytes and systemic hemodynamics.

It is time to recognize that the quality, not quantity, of myocardium in hypertensive heart disease is responsible for adverse cardiovascular events. Experimental and clinical available data indicate that myocardial fibrosis due to the exaggerated accumulation of collagen type I and type III fibers predisposes to an enhanced risk of diastolic and/or systolic ventricular dysfunction, symptomatic heart failure, ischemic heart disease, and arrhythmias in patients with hypertensive heart disease. Thus, management of these patients must not only focus on detection and regression of left ventricular hypertrophy. Far more sensible are interventions aimed to detect and target hypertensive myocardial fibrosis. The available data on the use of biochemical and/or imaging methodologies to address excessive accumulation of collagen fibers in the myocardium of hypertensive patients are promising. On the other hand, preliminary data suggest that the goal of reducing myocardial fibrosis is achievable in patients with hypertensive heart disease treated with specific antihypertensive agents. Collectively, these findings set the stage for larger trials where-in noninvasive measures and reparative strategies of myocardial fibrosis to prevent heart failure could prove useful.

Desde el punto de vista molecular, la cardiopatia hipertensiva se caracteriza por un conjunto de cambios en la expresion de genes y proteinas del miocardio que provocan una serie de modificaciones en su composicion, dando lugar a su remodelado estructural y geometrico, asi como a alteraciones de su funcion, perfusion y actividad electrica. El remodelado es la consecuencia tanto de la sobrecarga mecanica hipertensiva como de la activacion local de diversos factores humorales que afectan a los cardiomiocitos (facilitando su muerte por apoptosis) y a la matriz extracelular miocardica (dando lugar a cambios en la cuantia y el deposito de las fibras de colageno). La relevancia clinica de estas lesiones radica en que contribuyen a la transicion de la hipertrofia ventricular izquierda a la insuficiencia cardiaca en los pacientes con cardiopatia hipertensiva. Hallazgos recientes senalan nuevos mecanismos de apoptosis y fibrosis (p. ej., alteraciones del receptor alfa activado por proliferadores de peroxisomas) en el ventriculo hipertenso que abren vias nuevas para la prevencion de la insuficiencia cardiaca en los pacientes con cardiopatia hipertensiva.

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.

Arterial hypertension induces numerous alterations in the composition of cardiac tissue, which, in turn, result in structural remodeling of the myocardium. This remodeling is due to a range of pathologic mechanisms associated with mechanical, neurohormonal and cytokine processes that affect both cardiomyocyte and non-cardiomyocyte compartments of the myocardium. One of these processes involves disruption of the equilibrium between the synthesis and degradation of type-I and type-III collagen molecules. The result is excess accumulation of type-I and type-III collagen fibers in interstitial and perivascular spaces in the myocardium. The clinical significance of myocardial fibrosis lies in its contribution to the development of cardiac complications in hypertensive patients. This brief review focuses on the mechanisms of myocardial fibrosis and their clinical consequences. In addition, the techniques used for diagnosing myocardial fibrosis and the main therapeutic strategies for reducing fibrosis are also discussed.

Given the importance of fibrous tissue in leading to myocardial dysfunction and failure in hypertensive heart disease, non-invasive assessment of fibrosis could prove a clinically useful tool in hypertensive patients, particularly given the potential for cardioprotective and cardioreparative pharmacological strategies. In this regard, an emerging experimental and clinical experience holds promise for the assessment of various serum peptides arising from the metabolism of collagen types I and III in arterial hypertension. More specifically, the measurement of serum concentrations of procollagen type I carboxy-terminal propeptide (a peptide that is cleaved from procollagen type I during the synthesis of fibril-forming collagen type I) may provide indirect diagnostic information on both the extent of myocardial fibrosis and the ability of antihypertensive treatment to diminish collagen type I synthesis and reduce myocardial fibrosis in hypertensive patients. The available data set the stage for large and long-term trials to definitively validate this approach.

Changes in the composition of cardiac tissue develop in arterial hypertension and lead to structural remodeling of the myocardium. Structural remodeling is the consequence of a number of pathologic processes, mediated by mechanical, neurohormonal and cytokine routes, occurring in the cardiomyocyte and the noncardiomyocyte compartments of the heart. One of these processes is related to the disruption of the equilibrium between the synthesis and degradation of collagen type I and III molecules, which results in an excessive accumulation of collagen type I and III fibers in the interstitium and the perivascular regions of the myocardium. The clinical relevance of ventricular fibrosis is that it might contribute to the increased cardiac risk of patients with hypertensive heart disease. This review focuses on the mechanisms of hypertensive ventricular fibrosis and its clinical consequences. In addition, we discuss the noninvasive methods for the diagnosis of cardiac fibrosis and the therapeutic strategies aimed to promote its reduction.

Background— We investigated whether increased collagen type I synthesis and deposition contribute to enhancement of myocardial fibrosis and deterioration of cardiac function in patients with hypertensive heart disease (HHD). Methods and Results— We studied 65 hypertensives with left ventricular hypertrophy subdivided into 2 groups: 34 patients without heart failure (HF) and 31 patients with HF. Transvenous endomyocardial biopsies of the interventricular septum were performed to quantify the amount of fibrotic tissue and the extent of collagen type I deposition. The carboxy-terminal propeptide of procollagen type I (PIP), an index of collagen type I synthesis, was measured by radioimmunoassay in serum samples from the coronary sinus and the antecubital vein. Compared with normotensives, the amount of collagen tissue, the extent of collagen type I deposition, and coronary and peripheral PIP were increased ( P P P Conclusions— These findings suggest that an excess of cardiac collagen type I synthesis and deposition may be involved in the enhancement of myocardial fibrosis that accompanies the development of HF in HHD. In addition, our data show that the heart secretes PIP via the coronary sinus into the peripheral circulation in patients with HHD. Thus, PIP determined in peripheral blood can be a useful marker of myocardial fibrosis in these patients.

Structural homogeneity of cardiac tissue is governed by mechanical and humoral factors that regulate cell growth, apoptosis, phenotype, and extracellular matrix turnover. ANGII has endocrine, autocrine, and paracrine properties that influence the behavior of cardiac cells and matrix by AT1 receptor binding. Various paradigms have been suggested, including ANGII-mediated up-regulation of collagen types I and III formation and deposition in cardiac conditions, such as HHD. A growing body of evidence, however, deals with the potential role of aldosterone, either local or systemic, in inducing cardiac fibrosis. Aldosterone might also mediate the profibrotic actions of ANGII. To reduce the risk of heart failure that accompanies HHD, its adverse structural remodeling (eg, myocardial hypertrophy and fibrosis) must be targeted for pharmacologic intervention. Cardioprotective agents must reverse not only the exaggerated growth of cardiac cells, but also regress existing abnormalities in fibrillar collagen. Available experimental and clinical data suggest that agents interfering with ACE, the AT1 receptor, or the mineralocorticoid receptor may provide such a cardioprotective effect.

The balance between cell death and cell survival is a tightly controlled process, especially in terminally differentiated cells, such as the cardiomyocyte. Accumulating data support a role for cardiomyocyte apoptosis in the development of several cardiac diseases, including the transition from hypertensive compensatory hypertrophy to heart failure. This review briefly summarizes the status of the knowledge regarding the death-survival balance of cardiomyocytes in the context of hypertensive heart disease. Several molecular and cellular aspects as well as the most relevant pathophysiological implications are presented. Moreover, diagnosis tools under development and the possibilities for pharmacological intervention are also examined.

Background — This study was designed to investigate whether myocardial collagen content is related to myocardial stiffness in patients with essential hypertension. Methods and Results — The study was performed in 34 patients with hypertensive heart disease. Nineteen of these patients were also evaluated after 12 months of treatment with losartan. Transvenous endomyocardial biopsies of the interventricular septum were performed to quantify collagen volume fraction (CVF). Left ventricular (LV) chamber stiffness (K LV ) was determined from the deceleration time of the early mitral filling wave as measured by Doppler echocardiography. Histological analysis at baseline revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 26 with nonsevere fibrosis. Values of CVF and K LV were significantly higher in the 2 subgroups of hypertensives than in normotensives. In addition, compared with patients with nonsevere fibrosis, patients with severe fibrosis exhibited significantly increased values of CVF and K LV . After treatment, CVF and K LV decreased significantly in patients with severe fibrosis (n=7). None of these parameters changed significantly after treatment in patients with nonsevere fibrosis (n=12). CVF was directly correlated with K LV ( r =0.415, P Conclusions — These findings show a strong association between myocardial collagen content and LV chamber stiffness in patients with essential hypertension. Our results also suggest that the ability of losartan to induce regression of severe myocardial fibrosis is associated with diminution of myocardial stiffness in hypertensive patients.

El estudio de la no volatilidad de una memoria FeRAM de tantalato de bismuto y estroncio, SrBi2Ta2O9 (SBT) en condiciones reales de uso, requiere la caracterizacion ferroelectrica del material en forma de lamina delgada a temperaturas por encima del ambiente. Para ello se han depositado laminas de SBT mediante un metodo sol-gel, sobre substratos de Pt/TiO2/SiO2/Si(100), seleccionandose condensadores de area 5.10-4 cm-2. Basandonos en las medidas de la variacion de la polarizacion con el tiempo (retencion) realizadas a temperatura ambiente y a 75oC, analizamos la viabilidad del material como una FeRAM en condiciones reales de uso

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).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.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.

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.

The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers.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.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.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.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).

Myocardial fibrosis is one of the histologic constituents of myocardial remodeling present in hypertensive patients with hypertensive heart disease. In fact, an exaggerated interstitial and perivascular accumulation of fibrillar collagens type I and type III has been found in the myocardium of patients with arterial hypertension and left ventricular hypertrophy. Hypertensive myocardial fibrosis has been shown to facilitate abnormalities of cardiac function, coronary reserve, and electrical activity that adversely affect the clinical outcome of hypertensive patients. Therefore, development of noninvasive tools for the monitoring of myocardial fibrosis and pharmacological strategies aimed to promote the regression of fibrosis could be of particular relevance in the clinical treatment of patients with hypertensive heart disease.