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Respuestas del miocardio al estrés biomecánico

2012-08-17T00:09:05Z

Title: Respuestas del miocardio al estrés biomecánico Author(s) : Diez, J. (Javier); Lopez, B. (Begoña); Gonzalez, A. (Arantxa); Ardanaz, N. (Noelia); Fortuño, M.A. (María Antonia) Abstract: El estrés biomecánico del miocardio hace referencia a la situación que se genera cuando, debido a la hipertensión, la hipoxia u otras formas de daño miocárdico, están aumentadas las demandas de trabajo cardíaco y/o se ha perdido miocardio funcionante. Como consecuencia del estrés biomecánico se producen diversas respuestas que afectan a todas las células miocárdicas, en particular a los cardiomiocitos. El resultado final de las mismas son distintas modificaciones fenotípicas que inicialmente son compensadoras (p. ej., hipertrofia), pero que si persiste el estrés pueden mediar la transición de la hipertrofia a la insuficiencia cardíaca (p. ej., apoptosis y fibrosis). Esta revisión se centra en la descripción de las distintas fases de las respuestas miocárdicas al estrés, así como en la consideración de los hallazgos más recientes sobre los mecanismos moleculares implicados en el desarrollo de insuficiencia cardíaca.

Atherosclerosis: Is it time for a new name?

2012-07-20T00:11:33Z

Title: Atherosclerosis: Is it time for a new name? Author(s) : Paramo, J.A. (José Antonio); Beloqui, O. (Óscar); Diez, J. (Javier)

Blockade of TGF-β 1 Signalling Inhibits Cardiac NADPH Oxidase Overactivity in Hypertensive Rats

2012-07-05T00:09:46Z

Title: Blockade of TGF-β 1 Signalling Inhibits Cardiac NADPH Oxidase Overactivity in Hypertensive Rats Author(s) : Miguel-Carrasco, J.L. (José Luis); Baltanas, A. (Ana); Cebrian, C. (Carolina); Moreno, M.U. (María Ujué); Lopez, B. (Begoña); Hermida, N. (Nerea); Gonzalez, A. (Arantxa); Dotor, J. (Javier); Borras-Cuesta, F. (Francisco); Diez, J. (Javier); Fortuño, A. (A.); Zalba, G. (Guillermo) Abstract: NADPH oxidases constitute a major source of superoxide anion (·O(2) (-)) 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.

Decreased excretion of nitrate and nitrite in essential hypertensives with renal vasoconstriction

2012-05-11T18:20:29Z

Title: Decreased excretion of nitrate and nitrite in essential hypertensives with renal vasoconstriction Author(s) : Sierra, M. (Milagros); Gonzalez, A. (Alvaro); Gomez-Alamillo, C. (Carlos); Monreal, I. (Ignacio); Huarte, E. (Emma); Gil, A. (Antonio); Sanchez-Casajus, A. (Angel); Diez, J. (Javier) Abstract: Most hypertensive patients exhibit increased renal vascular resistance (RVR). This study was designed to investigate whether there exists any relationship between RVR and the production of nitric oxide (NO) in patients with essential hypertension. The study was performed in 49 non-treated patients with mild-to-moderate essential hypertension, and 20 age- and sex-matched normotensive subjects on a controlled sodium diet. Renal hemodynamics was measured in terms of the clearance of para-aminohippuric acid and inulin. Urinary excretion of nitrate and nitrite (NO3- plus NO2-) was determined as an index of NO production. As compared with normotensives, hypertensive patients exhibited higher (P < 0.001) RVR and lower (P < 0.05) urinary excretion of NO3- plus NO2-. With the 100% confidence (upper) limit of the normotensive population as a cut-off point, a subgroup of 30 hypertensives had an abnormally high RVR. The excretion of NO3- plus NO2- was lower (P < 0.005) in hypertensives with high RVR than in normotensives and the remaining hypertensives. No differences were found in the urinary excretion of NO3- plus NO2- between normotensives and hypertensives with normal RVR. Statistically significant associations were seen between diastolic blood pressure and RVR (r = 0.341, P < 0.05) and urinary excretion of NO3- plus NO2- (r = -0.387, P < 0.01) in all hypertensives. These results indicate that there is a subgroup (61%) of hypertensive patients with diminished urine levels of NO3- plus NO2- in which RVR is abnormally increased. Thus, it is suggested that in essential hypertension a diminished renal ability to produce NO by the endothelium may be involved in exaggerated renal vasoconstriction.

Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds

2012-05-11T18:19:28Z

Title: Prevalence of left ventricular diastolic dysfunction in European populations based on cross-validated diagnostic thresholds Author(s) : Kloch-Badelek, M. (Malgorzata); Kuznetsova, T. (Tatiana); Sakiewicz, W. (Wojciech); Tikhonoff, V. (Valerie); Ryabikov, A. (Andrew); Gonzalez, A. (Arantxa); Lopez, B. (Begoña); Thijs, L. (Lutgarde); Jin, Y. (Yu); Malyutina, S. (Sofía); Stolarz-Skrzypek, K. (Katarzyna); Casiglia, E. (Edoardo); Diez, J. (Javier); Narkiewicz, K. (Krzysztof); Kawecka-Jaszcz, K. (Kalina); Staessen, J.A. (Jan A.) Abstract: 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%.

Cardiotrophin-1 in hypertensive heart disease

2012-05-11T18:18:58Z

Title: Cardiotrophin-1 in hypertensive heart disease Author(s) : Gonzalez, A. (Arantxa); Lopez, B. (Begoña); Ravassa, S. (Susana); Beaumont, J. (Javier); Zudaire, A. (Amaia); Gallego, I. (Idoia); Brugnolaro, C. (Cristina); Diez, J. (Javier) Abstract: 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.

The influence of obesity on the assessment of carotid intima-media thickness

2012-05-11T18:17:30Z

Title: The influence of obesity on the assessment of carotid intima-media thickness Author(s) : Gallego-Perez-Larraya, J. (Jaime); Irimia, P. (Pablo); Martinez-Vila, E. (Eduardo); Barba, J. (Joaquín); Guembe, M.J. (María Jesús); Varo, N. (Nerea); Castellano, J.M. (José María); Viñes, J.J. (José Javier); Diez, J. (Javier) Abstract: 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 45-75, 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.

Contribution of circulating biomarkers to unravel the role of extracellular matrix in hypertensive cardiac remodelling

2012-05-11T18:16:28Z

Title: Contribution of circulating biomarkers to unravel the role of extracellular matrix in hypertensive cardiac remodelling Author(s) : Beaumont, J. (Javier); Gonzalez, A. (Arantxa); Lopez, B. (Begoña); Ravassa, S. (Susana); Diez, J. (Javier)

Angiotensin converting enzyme inhibition prevents polyploidization of cardiomyocytes in spontaneously hypertensive rats with left ventricular hypertrophy

2012-06-20T07:09:40Z

Title: Angiotensin converting enzyme inhibition prevents polyploidization of cardiomyocytes in spontaneously hypertensive rats with left ventricular hypertrophy Author(s) : Panizo-Santos, A. (Ángel); Sola, J.J. (Jesús J.); Pardo-Mindan, F.J. (Francisco Javier); Hernandez, M. (M.); Cenarruzabeitia, E. (Edurne); Diez, J. (Javier) Abstract: Polyploidization of cardiomyocyte nuclei is a physiological phenomenon that increases in pathological conditions such as myocardial hypertrophy. The purpose of this study was to evaluate the potential benefit of the angiotensin converting enzyme (ACE) inhibitor quinapril in reversing the polyploidization of cardiomyocyte nuclei in spontaneously hypertensive rats (SHR) with established left ventricular hypertrophy (LVH). Sixteen week-old male SHR were treated with oral quinapril (average dose 10 mg/kg per day) for 20 weeks. Sixteen- and 36-week-old untreated SHR and 16- and 36-week-old normotensive Wistar-Kyoto (WKY) rats were used as controls. Nuclear polyploidization was determined by DNA flow cytometry of frozen tissues from the left ventricle, at least 20 000 nuclei being measured in each sample. The rates of tetraploidy in the 16- and 36-week-old SHR groups were 2·8 per cent (range 2·16-3 per cent) and 5·4 per cent (range 4·9–5·9 per cent), respectively. Treated SHR had a similar rate of DNA tetraploidy to the 16- and 36-week-old WKY rat groups: 1·8 per cent (range 1·5–2·3 per cent), 1·55 per cent (range 1·5–1·6 per cent), and 1·5 per cent (range 1·4–1·6 per cent), respectively. The differences in the percentage of tetraploid cardiomyocytes between the SHR untreated groups and the SHR treated group were statistically significant (P<0·05). Regression of LVH and normalization of blood pressure were observed in treated rats. These results indicate that DNA tetraploidy in the myocardium of SHR increases with hypertrophy and decreases on quinapril treatment. It is suggested that ACE inhibition modifies nuclear processes involved in myocyte growth in arterial hypertension.

Vasoconstriction of the afferent arteriole and defective renal synthesis of nitric oxide in essential hypertension

2012-05-11T18:08:57Z

Title: Vasoconstriction of the afferent arteriole and defective renal synthesis of nitric oxide in essential hypertension Author(s) : Gomez-Alamillo, C. (Carlos); Sanchez-Casajus, A. (Angel); Sierra, M. (M.); Huarte, E. (E.); Diez, J. (Javier) Abstract: This study was designed to investigate whether some relation exists between afferent arteriolar resistance (AAR) and the renal production of nitric oxide (NO) and prostacyclin (PGI2) in 21 patients with untreated essential hypertension and 20 normotensive controls. All subjects were studied in conditions of an unlimited Na+ diet both basally and after a four-hour amino acid infusion. AAR was calculated using Gomez's equations. Renal production of NO and PGI2 were assessed by radioimmunoassay of the urinary excretion of cGMP and 6-keto-PGF1 alpha, respectively. Baseline AAR was higher (P < 0.01) in hypertensives than in normotensives. The baseline urinary excretion of 6-keto-PGF1 alpha and cGMP were similar in the two groups of subjects. AAR diminished (P < 0.005) in normotensives and remained unchanged in hypertensives after amino acid infusion. Urinary excretion of 6-keto-PGF1 alpha was increased similarly in the two groups of subjects after infusion. Urinary excretion of cGMP remained unchanged in normotensives and decreased by 31% in hypertensives after infusion. These findings suggest that afferent vasoconstriction present in hypertensive patients is unresponsive to the vasodilatory manoeuvre of amino acid infusion. This lack of response may be due to a defective renal synthesis of NO in these patients.

Beneficial aspects of vascular apoptosis in hypertensive heart disease

2012-05-11T17:53:32Z

Title: Beneficial aspects of vascular apoptosis in hypertensive heart disease Author(s) : Diez, J. (Javier); Fortuño, A. (A.); Gonzalez, A. (Arantxa); Ravassa, S. (Susana); Zalba, G. (Guillermo) Abstract: Arterial hypertension may be viewed as a generalized vascular disorder, with an imbalance between proliferation and apoptosis of vascular smooth muscle cells. As a consequence exaggerated accumulation of these cells may result leading to an encroachment of the tunica media into the lumen. This geometric abnormality of the vessel wall may play a critical role in the long-term maintenance of elevated blood pressure and development of hypertensive endorgan damage. In this short paper, we summarize data on alterations in the growth and death of vascular smooth muscle cells in the small coronary arteries in hypertension.

NADPH oxidase-mediated oxidative stress

2012-05-11T17:52:54Z

Title: NADPH oxidase-mediated oxidative stress Author(s) : Zalba, G. (Guillermo); San-Jose, G. (Gorka); Moreno, M.U. (María Ujué); Fortuño, A. (A.); Diez, J. (Javier) Abstract: Increased vascular production of reactive oxygen species, especially superoxide anion, significantly contributes to the oxidative stress associated with hypertension. An enhanced superoxide production causes an increased inactivation of nitric oxide that diminishes nitric oxide bioavailability, thus contributing to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that NADPH oxidases play a major role as the most important sources of superoxide anion in phagocytic and vascular cells. Several experimental observations have described an enhanced superoxide generation as a result of NADPH oxidase activation in hypertension. Although these enzymes respond to stimuli such as vasoactive factors, growth factors, and cytokines, recent data suggest a significant role of the genetic background in the modulation of the expression of its different components. Several polymorphisms have been identified in the promoter and in the coding region of CYBA, the gene that encodes the essential subunit of the NADPH oxidase p22phox, some of which seem to influence significantly the activity of these enzymes in the context of cardiovascular diseases. Among CYBA polymorphisms, genetic investigations have provided a novel marker, the -930(A/G) polymorphism, which determines the genetic susceptibility of hypertensive patients to oxidative stress.

Biochemical Diagnosis of Hypertensive Myocardial Fibrosis

2012-05-09T00:08:30Z

Title: Biochemical Diagnosis of Hypertensive Myocardial Fibrosis Author(s) : Diez, J. (Javier); Laviades, C. (Concepción); Varo, N. (Nerea); Querejeta, R. (Ramón); Lopez, B. (Begoña) Abstract: A substantial increase in fibrillar collagen has been observed in the left cardiac ventricle of animals and humans with arterial hypertension. Hypertensive myocardial fibrosis is the result of both increased collagen types I and III due to the fact that its synthesis by fibroblasts and myofibroblasts is stimulated and its extracellular collagen degradation unchanged or decreased extracellular collagen degradation. Hemodynamic and non-hemodynamic factors may be involved in the disequilibrium between collagen synthesis and degradation that occurs in hypertension. As shown experimentally and clinically, an exaggerated rise in fibrilar collagen content promotes abnormalities of cardiac function, contributes to the decrease in coronary reserve and facilitates alterations in the electrical activity of the left ventricle. Although microscopic examination of cardiac biopsies is the most reliable method for documenting and measuring myocardial fibrosis, the development of non-invasive methods to indicate the presence of myocardial fibrosis in hypertensive patients would be useful. We have therefore applied a biochemical method based on the measurement of serum peptides derived from the tissue formation when synthesized and degradation of fibrillar collagens to monitor the turnover of these molecules in rats with spontaneous hypertension and patients with essential hypertension.

Apoptosis en las enfermedades cardiovasculares

2012-05-09T00:08:29Z

Title: Apoptosis en las enfermedades cardiovasculares Author(s) : Diez, J. (Javier) Abstract: Apoptosis consists of a distinct form of cell death that displays characteristic alterations in cell morphology and cell fate which are different than death due to oncosis or necrosis. In terms of tissue kinetics, apoptosis may be considered a mechanism that counterbalances the effect of cell proliferation by mitotic division. In fact, deregulated apoptosis has been implicated in the development a wide variety of human diseases. Excessive apoptotic cell death may cause organ atrophy and organ failure. On the other hand, insufficient elimination of redundant cells may lead to organ and tissue structural remodeling. In recent years, apoptosis has become a highly fashionable and competitive area of research. Fortunately, it has not escaped the attention of the cardiovascular community. Sightings of apoptosis have been reported from every corner of cardiovascular medicine ranging from conduction system defects to congestive heart failure, and from atherosclerosis to aneurysms. There is no question that these sightings will eventually be converted into mechanistic etiopathogenic and physiopathological insights and will form the basis for designing new diagnostic modalities and novel therapies.

Myocardial Response to Biomechanical Stress

2012-05-09T00:08:25Z

Title: Myocardial Response to Biomechanical Stress Author(s) : Diez, J. (Javier); Lopez, B. (Begoña); Gonzalez, A. (Arantxa); Ardanaz, N. (Noelia); Fortuño, A. (A.) Abstract: Biomechanical stress of the myocardium is the situation resulting from hypoxia, hypertension, and other forms of myocardial injury, that invariably lead to increased demands for cardiac work and/or loss of functional myocardium. As a consequence of biomechanical stress a number of responses develop involving all the myocardial cells, namely cardiomyocytes. As a result some myocardial phenotypic changes develop that are initially compensatory (i.e., hypertrophy) but which may mediate the eventual decline in myocardial function that occurs with the transition from hypertrophy to failure in conditions of persistent stress (i.e., apoptosis and fibrosis). This review focuses on the steps involved in the response of the myocardium to biomechanical stress and highlights the most recent developments in the molecular mechanisms involved in the development of heart failure.