Determination of aortic valve area in valvular aortic stenosis by direct measurement using intracardiac echocardiography: A comparison with the gorlin and continuity equations

AbstractObjectives. This study sought to 1) show that intracardiac echocardiography can allow direct measurement of the aortic valve area, and 2) compare the directly measured aortic valve area from intracardiac echocardiography with the calculated aortic valve area from the Gorlin and continuity equations.Background. Intracardiac echocardiography has been used in the descriptive evaluation of the aortic valve; however, direct measurement of the aortic valve area using this technique in a clinical setting has not been documented. Despite their theoretical and practical limitations, the Gorlin and continuity equations remain the current standard methods for determining the aortic valve orifice area.Methods. Seventeen patients underwent intracardiac echocardiography for direct measurement of the aortic valve area, including four patients studied both before and after valvuloplasty, for a total of 21 studies. Immediately after intracardiac echocardiography, hemodynamic data were obtained from transthoracic echocardiography and cardiac catheterization.Results. Adequate intracardiac echocardiographic images were obtained in 17 (81%) of 21 studies. The average aortic valve area (mean ± SD) determined by intracardiac echocardiography for the 13 studies in the Gorlin analysis group was 0.59 ± 0.18 cm2(range 0.37 to 1.01), and the average aortic valve area determined by the Gorlin equation was 0.62 ± 0.18 cm2(range 0.31 to 0.88). The average aortic valve area determined by intracardiac echocardiography for the 17 studies in the continuity analysis group was 0.66 ± 0.23 cm2(range 0.37 to 1.01), and that for the continuity equation was 0.62 ± 0.22 cm2(range 0.34 to 1.06). There was a significant correlation between the aortic valve area determined by intracardiac echocardiography and the aortic valve area calculated by the Gorlin (r = 0.78, p = 0.002) and continuity equations (r = 0.82, p < 0.0001).Conclusions. In the clinical setting, intracardiac echocardiography can directly measure the aortic valve area with an accuracy similar to the invasive and noninvasive methods currently used. This study demonstrates a new, quantitative use for intracardiac echocardiographic imaging with many potential clinical applications

The CSN3 subunit of the COP9 signalosome interacts with the HD region of Sos1 regulating stability of this GEF protein

Sos1 is an universal, widely expressed Ras guanine nucleotide-exchange factor (RasGEF) in eukaryotic cells. Its N-terminal HD motif is known to be involved in allosteric regulation of Sos1 GEF activity through intramolecular interaction with the neighboring PH domain. Here, we searched for other cellular proteins also able to interact productively with the Sos1 HD domain. Using a yeast two-hybrid system, we identified the interaction between the Sos1 HD region and CSN3, the third component of the COP9 signalosome, a conserved, multi-subunit protein complex that functions in the ubiquitin-proteasome pathway to control degradation of many cellular proteins. The interaction of CSN3 with the HD of Sos1 was confirmed in vitro by GST pull-down assays using truncated mutants and reproduced in vivo by co-immunoprecipitation with the endogenous, full-length cellular Sos1 protein. In vitro kinase assays showed that PKD, a COP9 signalosome-associated-kinase, is able to phosphorylate Sos1. The intracellular levels of Sos1 protein were clearly diminished following CSN3 or PKD knockdown. A sizable fraction of the endogenous Sos1 protein was found ubiquitinated in different mammalian cell types. A significant reduction of RasGTP formation upon growth factor stimulation was also observed in CSN3-silenced as compared with control cells. Our data suggest that the interaction of Sos1 with the COP9 signalosome and PKD plays a significant role in maintenance of cellular Sos1 protein stability and homeostasis under physiological conditions and raises the possibility of considering the CSN/PKD complex as a potential target for design of novel therapeutic drugs.We thank R Brent for the pJG45-HeLa library and R. Jorge for help with yeast two-hybrid screening. J.M.R. received grant support from MINECO-FEDER (SAF2016-78852-R), ISCIII-MINECO (FIS-Intrasalud PI13/00703) and Spanish Association against Cancer (AECC). E.S. and A.F.M. were supported by grants from ISCIII-MINECO (FIS PI16/02137), JCyL (SA043U16-UIC 076) and Solorzano Foundation. E.S. and J.M.R. were also supported by ISCIII-RETIC (groups RTICC-RD12/0036/0001 and RTICC-RD12/0036/0021, respectively) and by CIBERONC (groups CB16/12/00352 and CB16/12/00273, respectively). Research co-financed by FEDER funds.S

The P34G mutation reduces the transforming activity of K-Ras and N-Ras in NIH 3T3 cells but not of H-Ras

Retraction in The P34G mutation reduces the transforming activity of K-Ras and N-Ras in NIH 3T3 cells but not of H-Ras. [J Biol Chem. 2018]Ras proteins (H-, N-, and K-Ras) operate as molecular switches in signal transduction cascades controlling cell proliferation, differentiation, or apoptosis. The interaction of Ras with its effectors is mediated by the effector-binding loop, but different data about Ras location to plasma membrane subdomains and new roles for some docking/scaffold proteins point to signaling specificities of the different Ras proteins. To investigate the molecular mechanisms for these specificities, we compared an effector loop mutation (P34G) of three Ras isoforms (H-, N-, and K-Ras4B) for their biological and biochemical properties. Although this mutation diminished the capacity of Ras proteins to activate the Raf/ERK and the phosphatidylinositol 3-kinase/AKT pathways, the H-Ras V12G34 mutant retained the ability to cause morphological transformation of NIH 3T3 fibroblasts, whereas both the N-Ras V12G34 and the K-Ras4B V12G34 mutants were defective in this biological activity. On the other hand, although both the N-Ras V12G34 and the K-Ras4B V12G34 mutants failed to promote activation of the Ral-GDS/Ral A/PLD and the Ras/Rac pathways, the H-Ras V12G34 mutant retained the ability to activate these signaling pathways. Interestingly, the P34G mutation reduced specifically the N-Ras and K-Ras4B in vitro binding affinity to Ral-GDS, but not in the case of H-Ras. Thus, independently of Ras location to membrane subdomains, there are marked differences among Ras proteins in the sensitivity to an identical mutation (P34G) affecting the highly conserved effector-binding loop.This work was supported in part by Programa General del Conocimiento (BMC2001-0057), Intramural Instituto de Salud Carlos III (ISCIII) (01/16), and SAF2003-02604 (Ministerio de Ciencia y Tecnología) grants (to J. M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.S

Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome

OBJECTIVE—Acute hyperglycemia on admission for acute coronary syndrome worsens the prognosis in patients with and without known diabetes. Postulated mechanisms of this observation include prothrombotic effects. The aim of this study was to evaluate the effect of elevated glucose levels on blood clotting in acute coronary syndrome patients

Left ventricular dysfunction measured by tissue Doppler imaging and strain rate imaging in hypertensive adolescents

Purpose : Left ventricular (LV) hypertrophy and impaired diastolic function may occur early in systemic hypertension. Diastolic dysfunction is associated with increased cardiovascular risk. Tissue Doppler imaging (TDI)-derived tissue velocity and strain rate are new parameters for assessing diastolic dysfunction. The aim of this study is to determine whether TDI and strain rate imaging (SRI) would improve the ability to recognize early impaired diastolic and systolic functions compared with conventional echocardiography in hypertensive adolescents. Methods : We included 38 hypertensive patients with systolic blood pressure above 140 mmHg or diastolic blood pressure above 90 mmHg. Ejection fraction and myocardial performance index (MPI) were estimated by conventional echocardiography. Peak systolic myocardial velocity, early diastolic myocardial velocity (Em), and peak late diastolic myocardial velocity (Am) were obtained by using TDI and SRI. Results : In the hypertensive group, interventricular septal thickness was significantly increased on M-mode echocardiography. Em&#47;Am was significantly decreased at the mitral valve annulus. Among hypertensive subjects, the E strain rate at basal, mid, and apex was significantly decreased. Systolic strain was significantly decreased at the septum in the hypertensive group. Conclusion : Strain rate might be a useful new parameter for the quantification of both regional and global LV functions and could be used in long-term follow up in hypertensive patients. Early identification by SRI of subjects at risk for hypertensive and ventricular dysfunction may help to stratify risk and guide therapy. Further studies, including serial assessment of LV structure and function in a larger number of adolescents with hypertension, is necessary