Inhibition of histone deacetylase as a treatment for cardiac hypertrophy

The present invention provides for methods of treating and preventing cardiac hypertrophy. Class II HDACs, which are known to participate in regulation of chromatin structure and gene expression, have been shown to have beneficial effects on cardiac hypertrophy. Surprisingly, the present invention demonstrates that HDAC inhibitors inhibit cardiac hypertrophy by inhibiting fetal cardiac gene expression and interfering with sarcomeric organization.Board of Regents, University of Texas Syste

The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial

Previous trials (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure [MERIT-HF], Cardiac Insufficiency Bisoprolol Study [CIBIS] II) have demonstrated a mortality benefit of β-adrenergic blockade in patients with mild to moderate heart failure. The recent Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial has extended these results to a more advanced patient population. This trial did not, however, include patients who could not reach compensation, patients with far advanced heart failure symptoms, or a significant number of black patients. Future studies of β-blockade may focus on these patients or patients with asymptomatic left ventricular dysfunction

776-1 Selective Down-regulation of Angiotensin II AT1 Receptors in Failing Human Heart: Relationship to β1-Receptor Down-regulation

The renin-angiotensin and adrenergic nervous systems exhibit multiple levels of cross-regulation in heart failure. These systems are bidirectionally activated in concert; i.e. activation of one system activates the other. We compared the behavior of angiotensin II AT1 and AT2 receptors with β1, -and, β2-adrenergic receptors in a high-yield crude membrane fraction prepared from nonfailing and failing human ventricular myocardium. Ang II receptors were measured by 125I saralasin binding, with Bmax determined by saturation binding displaceable by 1μM cold saralasin. AT1 and AT2 receptor fractions were determined by the amount of specific binding displaceable by 1μM losartan. β1-adrenergic receptor density was determined by saturation binding of 125I ICYP, with the, β1 fraction determined by binding displaceable by 0.2μM CGP 20712A. Results in end-stage human left ventricular myocardium failing as a result of idiopathic dilated cardiomyopathy were compared to nonfailing controls taken from age- and gender-matched organ donors not used for transplant because of blood type or body size mismatch: (Receptor density is in fmol/mg±SEM)β1-ARβ2-ARAT1AT2Nonfailing (n=6)59.0±9.420.7±4.04.14±0.621.52±0.43Failing (n = 6)28.3±2.8*17.2±2.61.53±0.57*2.68±0.51*p<0.05The down-regulation of β1 AR and AT1 receptors was significantly related (r=0.62, n=12, p<0.05)Conclusions(1) Compared to β adrenergic receptors ang II receptors are very low density in the human heart. (2) The AT1 receptor sUbtype predominates in the nonfailing human heart. (3) ATl but not AT2 receptors are downregulated in failing heart. (4) Down-regulation of Ang-II AT1 receptor is similar in degree to down-regulation of β1-adrenergic receptors. These data suggest that the AT1 and β1 receptors are respectively exposed to increased concentrations of mutually activatedlinduced norepinephrine and Ang-II in the failing human heart

Performance of the FOS and GHRS Pt/(Cr)-Ne Hollow-cathode Lamps after their Return from Space and Comparison with Archival Data

The Space Telescope European Coordinating Facility (ST-ECF) and National Institute of Standards and Technology (NIST) are collaborating to study hollow cathode calibration lamps as used onboard the Hubble Space Telescope (HST). As part of the STIS Calibration Enhancement (STIS-CE) Project we are trying to improve our understanding of the performance of hollow cathode lamps and the physical processes involved in their long term operation. The original flight lamps from the Faint Object Spectrograph (FOS) and the Goddard High Resolution Spectrograph (GHRS) are the only lamps that have ever been returned to Earth after extended operation in space. We have taken spectra of all four lamps using NIST s 10.7-m normal-incidence spectrograph and Fourier transform spectrometer (FTS) optimized for use in the ultraviolet (UV). These spectra, together with spectra archived from six years of on-orbit operations and pre-launch spectra, provide a unique data set - covering a period of about 20 years - for studying aging effects in these lamps. Our findings represent important lessons for the choice and design of calibration sources and their operation in future UV and optical spectrographs in space

α1Proteinase Inhibitor Regulates CD4+ Lymphocyte Levels and Is Rate Limiting in HIV-1 Disease

Background: The regulation of adult stem cell migration through human hematopoietic tissue involves the chemokine CXCL12 (SDF-1) and its receptor CXCR4 (CD184). In addition, human leukocyte elastase (HLE) plays a key role. When HLE is located on the cell surface (HLE CS), it acts not as a proteinase, but as a receptor for a 1proteinase inhibitor (a 1PI, a 1antitrypsin, SerpinA1). Binding of a1PI to HLECS forms a motogenic complex. We previously demonstrated that a1PI deficiency attends HIV-1 disease and that a1PI augmentation produces increased numbers of immunocompetent circulating CD4 + lymphocytes. Herein we investigated the mechanism underlying the a 1PI deficiency that attends HIV-1 infection. Methods and Findings: Active a 1PI in HIV-1 subjects (median 17 mM, n = 35) was significantly below normal (median 36 mM, p,0.001, n = 30). In HIV-1 uninfected subjects, CD4 + lymphocytes were correlated with the combined factors a1PI, HLECS + lymphocytes, and CXCR4 + lymphocytes (r 2 = 0.91, p,0.001, n = 30), but not CXCL12. In contrast, in HIV-1 subjects with.220 CD4 cells/ml, CD4 + lymphocytes were correlated solely with active a 1PI (r 2 =0.93,p,0.0001, n = 26). The monoclonal anti-HIV-1 gp120 antibody 3F5 present in HIV-1 patient blood is shown to bind and inactivate human a 1PI. Chimpanzee a 1PI differs from human a1PI by a single amino acid within the 3F5-binding epitope. Unlike human a1PI, chimpanzee a1PI did not bind 3F5 or become depleted following HIV-1 challenge, consistent with the normal CD4 + lymphocyte levels and benign syndrome of HIV-1 infected chimpanzees. The presence of IgG-a 1PI immune complexes correlated with decreased CD4 + lymphocytes in HIV-1 subjects

The effect of cardiac resynchronization without a defibrillator on morbidity and mortality: an individual patient data meta-analysis of COMPANION and CARE-HF

AIMS: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality for patients with heart failure, reduced left ventricular ejection fraction, QRS duration >130 ms and in sinus rhythm. The aim of this study was to identify patient characteristics that predict the effect, specifically, of CRT pacemakers (CRT-P) on all-cause mortality or the composite of hospitalization for heart failure or all-cause mortality. METHODS AND RESULTS: We conducted an individual patient data meta-analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization-Heart Failure (CARE-HF) trials. Only patients assigned to CRT-P or control (n = 1738) were included in order to avoid confounding from concomitant defibrillator therapy. The influence of baseline characteristics on treatment effects was investigated. Median age was 67 (59-73) years, most patients were men (70%), 68% had a QRS duration of 150-199 ms and 80% had left bundle branch block. Patients assigned to CRT-P had lower rates for all-cause mortality (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.56-0.81; p < 0.0001) and the composite outcome (HR 0.67, 95% CI 0.58-0.78; p < 0.0001). No pre-specified characteristic, including sex, aetiology of ventricular dysfunction, QRS duration (within the studied range) or morphology or PR interval significantly influenced the effect of CRT-P on all-cause mortality or the composite outcome. However, CRT-P had a greater effect on the composite outcome for patients with lower body surface area and those prescribed beta-blockers. CONCLUSIONS: Cardiac resynchronization therapy-pacemaker reduces morbidity and mortality in appropriately selected patients with heart failure. Benefits may be greater in smaller patients and in those receiving beta-blockers. Neither QRS duration nor morphology independently predicted the benefit of CRT-P. CLINICAL TRIAL REGISTRATION: COMPANION, NCT00180258; CARE-HF, NCT00170300