Myocardial Relaxation Is Accelerated by Fast Stretch, Not Reduced Afterload

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the speed of myocardial relengthening at end systole (end systolic strain rate), and not afterload, modulates relaxation rate and tested this hypothesis using electrically-stimulated trabeculae from mice, rats, and humans. We used load-clamp techniques to vary afterload and end systolic strain rate independently. Our data show that the rate of relaxation increases monotonically with end systolic strain rate but is not altered by afterload. Computer simulations mimic this behavior and suggest that fast relengthening quickens relaxation by accelerating the detachment of cross-bridges. The relationship between relaxation rate and strain rate is novel and upends the prevailing theory that afterload modifies relaxation. In conclusion, myocardial relaxation is mechanically modified by the rate of stretch at end systole. The rate of myocardial relengthening at end systole may be a new diagnostic indicator or target for treatment of diastolic dysfunction

Delayed Sternal Closure Does Not Reduce Complications Associated with Coagulopathy and Right Ventricular Failure After Left Ventricular Assist Device Implantation

Delayed sternal closure (DSC) is occasionally adopted after implantation of left ventricular assist device (LVAD). Recent studies suggest that DSC be used for high risk group of patients with coagulopathy, hemodynamic instability or right ventricular failure. However, whether DSC is efficacious for bleeding complication or right ventricular failure is not known. This study is single center analysis of 52 patients, who underwent LVAD implantation. Of those 52 patients, 40 consecutive patients underwent DSC routinely. The sternum was left open with vacuum assist device after implantation of LVAD. Perioperative outcome of the patients who underwent routine DSC were compared with 12 patients who had immediate sternal closure (IC). Mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level of IC group and DSC group were 2.7 and 2.6, respectively. Postoperative bleeding (643 vs. 1469 ml, p \u3c 0.001), duration of inotropic support (109 vs. 172 h, p = 0.034), and time to extubation (26 vs. 52 h, p = 0.005) were significantly increased in DSC group. Length of ICU stay (14 vs. 15 days, p = 0.234) and hospital stay (28 vs. 20 days, p = 0.145) were similar. Incidence of right ventricular failure and tamponade were similar in the two groups. Routine DSC after implantation of an LVAD did not prove to be beneficial in reducing complications associated with coagulopathy and hemodynamic instability including cardiac tamponade or right ventricular failure. We suggest that DSC be selectively applied for patients undergoing LVAD implant

Diaphragm Abnormalities in Patients with End-Stage Heart Failure: NADPH Oxidase Upregulation and Protein Oxidation

Patients with heart failure (HF) have diaphragm abnormalities that contribute to disease morbidity and mortality. Studies in animals suggest that reactive oxygen species (ROS) cause diaphragm abnormalities in HF. However, the effects of HF on ROS sources, antioxidant enzymes, and protein oxidation in the diaphragm of humans is unknown. NAD(P)H oxidase, especially the Nox2 isoform, is an important source of ROS in the diaphragm. Our main hypothesis was that diaphragm from patients with HF have heightened Nox2 expression and p47phox phosphorylation (marker of enzyme activation) that is associated with elevated protein oxidation. We collected diaphragm biopsies from patients with HF and brain-dead organ donors (controls). Diaphragm mRNA levels of Nox2 subunits were increased 2.5–4.6-fold over controls (p \u3c 0.05). Patients also had increased protein levels of Nox2 subunits (p47phox, p22phox, and p67phox) and total p47phox phosphorylation, while phospho-to-total p47phox levels were unchanged. The antioxidant enzyme catalase was increased in patients, whereas glutathione peroxidase and superoxide dismutases were unchanged. Among markers of protein oxidation, carbonyls were increased by ~40% (p \u3c 0.05) and 4-hydroxynonenal and 3-nitrotyrosines were unchanged in patients with HF. Overall, our findings suggest that Nox2 is an important source of ROS in the diaphragm of patients with HF and increases in levels of antioxidant enzymes are not sufficient to maintain normal redox homeostasis. The net outcome is elevated diaphragm protein oxidation that has been shown to cause weakness in animals

Synthetic High-Resolution Line Spectra of Star-Forming Galaxies Below 1200A

We have generated a set of far-ultraviolet stellar libraries using spectra of OB and Wolf-Rayet stars in the Galaxy and the Large and Small Magellanic Cloud. The spectra were collected with the Far Ultraviolet Spectroscopic Explorer and cover a wavelength range from 1003.1 to 1182.7A at a resolution of 0.127A. The libraries extend from the earliest O- to late-O and early-B stars for the Magellanic Cloud and Galactic libraries, respectively. Attention is paid to the complex blending of stellar and interstellar lines, which can be significant, especially in models using Galactic stars. The most severe contamination is due to molecular hydrogen. Using a simple model for the H$_2$ line strength, we were able to remove the molecular hydrogen lines in a subset of Magellanic Cloud stars. Variations of the photospheric and wind features of CIII 1176, OVI 1032, 1038, PV 1118, 1128, and SIV 1063, 1073, 1074 are discussed as a function of temperature and luminosity class. The spectral libraries were implemented into the LavalSB and Starburst99 packages and used to compute a standard set of synthetic spectra of star-forming galaxies. Representative spectra are presented for various initial mass functions and star formation histories. The valid parameter space is confined to the youngest ages of less than 10 Myr for an instantaneous burst, prior to the age when incompleteness of spectral types in the libraries sets in. For a continuous burst at solar metallicity, the parameter space is not limited. The suite of models is useful for interpreting the restframe far-ultraviolet in local and high-redshift galaxies.Comment: 33 pages including 13 figures, accepted for publication in Ap

Recent star formation in nearby galaxies from GALEX imaging:M101 and M51

The GALEX (Galaxy Evolution Explorer) Nearby Galaxies Survey is providing deep far-UV and near-UV imaging for a representative sample of galaxies in the local universe. We present early results for M51 and M101, from GALEX UV imaging and SDSS optical data in five bands. The multi-band photometry of compact stellar complexes in M101 is compared to population synthesis models, to derive ages, reddening, reddening-corrected luminosities and current/initial masses. The GALEX UV photometry provides a complete census of young compact complexes on a approximately 160pc scale. A galactocentric gradient of the far-UV - near-UV color indicates younger stellar populations towards the outer parts of the galaxy disks, the effect being more pronounced in M101 than in M51.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Full paper available from http://dolomiti.pha.jhu.edu . Links to full set of papers will be available at http://www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200

Panoramic GALEX FUV and NUV imaging of M31 and M33

We present Galaxy Evolution Explorer (GALEX) far-UV and near-UV mosaic observations covering the entirety of M31 and M33. For both targets, we measure the decline of surface brightness (in FUV and NUV) and changes in FUV--NUV color as a function of galactocentric radius. These UV radial profiles are compared to the distribution of ionized gas traced by H-alpha emission. We find that the extent of the UV emission, in both targets, is greater than the extent of the observed HII regions and diffuse ionized gas. We determine the ultraviolet diffuse fraction in M33 using our FUV observations and compare it to the H-alpha diffuse fraction obtained from wide-field narrow-band imaging. The FUV diffuse fraction appears to be remarkably constant near 0.65 over a large range in galactocentric radius, with departures to higher values in circumnuclear regions and, most notably, at the limit of the H-alpha disk. We suggest that the increase in FUV diffuse fraction at large galactocentric radii could indicate that a substantial portion of the diffuse emission beyond this point is not generated in situ but rather scattered from dust, after originating in the vicinity of the disk's outermost HII regions. Radial variation of the H-alpha diffuse fraction was also measured. We found the H-alpha diffuse fraction generally near 0.4 but rising toward the galaxy center, up to 0.6. We made no attempt to correct our diffuse fraction measurements for position-dependent extinction, so the quoted values are best interpreted as upper limits given the plausibly higher extinction for stellar clusters relative to their surroundings.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Links to the full set of papers will be available at http://www.galex.caltech.edu/PUBLICATIONS/ after November 22, 2004. Individual high-resolution figures can be found at http://dolomiti.pha.jhu.edu/publgoto.htm

GALEX Observations of the Ultraviolet Halos of NGC 253 and M82

We present Galaxy Evolution Explorer (GALEX) images of the prototypical edge-on starburst galaxies M82 and NGC253. Our initial analysis is restricted to the complex of ultraviolet (UV) filaments in the starburst-driven outflows in the galaxy halos. The UV luminosities in the halo are too high to be provided by shock-heated or photoionized gas except perhaps in the brightest filaments in M82, suggesting that most of the UV light is the stellar continuum of the starburst scattered into our line of sight by dust in the outflow. This interpretation agrees with previous results from optical imaging polarimetry in M82. The morphology of the UV filaments in both galaxies shows a high degree of spatial correlation with H-alpha and X-ray emission. This indicates that these outflows contain cold gas and dust, some of which may be vented into the intergalactic medium (IGM). UV light is seen in the ``H-alpha cap'' 11 kpc North of M82. If this cap is a result of the wind fluid running into a pre-existing gas cloud, the gas cloud contains dust and is not primordial in nature but was probably stripped from M82 or M81. If starburst winds efficiently expel dust into the IGM, this could have significant consequences for the observation of cosmologically distant objects.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issue. Links to the full set of papers will be available at http://www.galex.caltech.edu/PUBLICATIONS/ after November 22, 200

A high spatial resolution X-ray and H-alpha study of hot gas in the halos of star-forming disk galaxies. I. Spatial and spectral properties of the diffuse X-ray emission

We present arcsecond resolution Chandra X-ray and ground-based optical H-alpha imaging of a sample of ten edge-on star-forming disk galaxies (seven starburst and three ``normal'' spiral galaxies), a sample which covers the full range of star-formation intensity found in disk galaxies. We use the unprecedented spatial resolution of the Chandra X-ray observatory to robustly remove point sources, and hence obtain the X-ray properties of the diffuse thermal emission alone. The X-ray observations are combined with comparable-resolution H-alpha and R-band imaging, and presented as a mini-atlas of images on a common spatial and surface brightness scale. The vertical distribution of the halo-region X-ray surface brightness is best described as an exponential, with the observed scale heights lying in the range H_eff = 2 -- 4 kpc. The ACIS X-ray spectra of extra-planar emission from all these galaxies can be fit with a common two-temperature spectral model with an enhanced alpha-to-iron element ratio. This is consistent with the origin of the X-ray emitting gas being either metal-enriched merged SN ejecta or shock-heated ambient halo or disk material with moderate levels of metal depletion onto dust. The thermal X-ray emission observed in the halos of the starburst galaxies is either this pre-existing halo medium, which has been swept-up and shock heated by the starburst-driven wind, or wind material compressed near the walls of the outflow by reverse shocks within the wind. In either case the X-ray emission provides us with a powerful probe of the properties of gaseous halos around star-forming disk galaxies.Comment: To appear in April 2004 edition of ApJS. For high resolution version, see http://proteus.pha.jhu.edu/~dks/ Accepted version, now has nuclear and total diffuse emission fluxes and luminosities, a few other minor change

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)