Search

High/ultrahigh-pressure (HP/UHP) metamorphic complexes, such as eclogite and blueschist, are generally regarded as significant signature of paleo-subduction zones and paleo-suture zones. Glaucophane eclogites have been recently identified within the Lancang Group characterized by accretionary melange in the Changning-Menglian suture zone, at Bangbing in the Shuangjiang area of southeastern Tibetan Plateau. The authors report the result of petrological, mineralogical and metamorphism investigations of these rocks, and discuss their tectonic implications. The eclogites are located within the Suyi blueschist belt and occur as tectonic lenses in coarse-grained garnet muscovite schists. The major mineral assemblage of the eclogites includes garnet, omphacite, glaucophane, phengite, clinozoisite and rutile. Eclogitic garnet contains numerous inclusions, such as omphacite, glaucophane, rutile, and quartz with radial cracks around. Glaucophane and clinozoisite in the matrix have apparent optical and compositional zonation. Four stages of metamorphic evolution can be determined: The prograde blueschist facies (M1), the peak eclogite facies (M2), the decompression blueschist facies (M3) and retrograde greenschist facies (M4). Using the Grt-Omp-Phn geothermobarometer, a peak eclogite facies metamorphic P-T condition of 3000–3270 MPa and 617–658°C was determined, which is typical of low-temperature ultrahigh-pressure metamorphism. The comparison of the geological characteristics of the Bangbing glaucophane eclogites and the Mengku lawsonite-bearing retrograde eclogites indicates that two suites of eclogites may have formed from significantly different depths or localities to create the tectonic melange in a subduction channel during subduction of the Triassic Changning-Menglian Ocean. The discovery of the Bangbing glaucophane eclogites may represent a new oceanic HP/UHP metamorphic belt in the Changning-Menglian suture zone. ©2021 China Geology Editorial Office.

The welded joint of steel structure is prone to occur fatigue fracture under dynamic loads. In this paper, an experimental study on the fatigue performance of base material, butt weld, and cross fillet weld of high-strength steels were investigated. The S-N curve was fitted, and the corresponding fatigue life was predicted. Results corroborate that the base material of high-strength steel possess high fatigue resistance. AISC360 and EC3 standard design curves are applicable for the evaluation of the butt weld fatigue performance of Q460D and possess adequate safety margin, but only suitable for low-fatigue life estimation of Q690D butt weld. With respect to cross fillet weld, AISC360 design curve not only is suitable for the fatigue life analysis of Q460D and Q690D but also has enough safety margins, while EC3 and BS7608 codes possess relatively low fatigue limit. In addition, a quantitative analysis on fatigue fracture was conducted on the basis of fatigue damage theory, and the fatigue crack propagation law was disclosed on the basis of fracture morphology. The crack propagation law before instant fracture is consistent with damage development, and the fatigue striation width increases gradually with damage development. The fast crack propagation stage accounts for a small proportion in the fatigue life, thereby indicating that this stage is insufficiently developed.

To observe the therapeutic effect of "Tiaoyi Sanjiao" （regulating and tonifying the triple energizer）acupuncture and moxibustion in the treatment of cancer-related fatigue of advanced non-small cell lung cancer and observe its influence on lymphocyte count.The cancer-related fatigue patients with advanced non-small cell lung cancer who met the inclusive criteria were randomly divided into 2 groups, with 77 cases in each group. Patients in the control group were treated with conventional Chinese and Western medicine. In the treatment group, on the base of the treatment as the control group, "Tiaoyi Sanjiao" acupuncture and moxibustion was applied（mild moxibustion at Danzhong ［CV17］, Zhongwan［CV12］, Qihai［CV6］, bilateral Zusanli［ST36］, and acupuncture at bilateral Xuehai［SP10］, Waiguan［SJ5］, Taichong［LR3］）. KPS score, Piper scale, percentage and absolute count of lymphocyte subsets of the two groups before and after treatment were observed.Compared with pre-treatment, the KPS scores of both groups were significantly increased after treatment ("Tiaoyi Sanjiao" acupuncture and moxibustion can significantly alleviate the fatigue state and improve the quality of life in patients with advanced non-small cell lung cancer, which may be achieved by regulating the number of lymphocytes and improving immune function.

Galectin- 3 (Gal-3), a member of the β-galactoside lectin family, has an important role in immune regulation. In hypertensive rats and heart failure patients, Gal-3 is considered a marker for an unfavorable prognosis. Nevertheless, the role and mechanism of Gal-3 action in hypertension-induced target organ damage are unknown. We hypothesized that, in angiotensin II (ANG II)-induced hypertension, genetic deletion of Gal-3 prevents left ventricular (LV) adverse remodeling and LV dysfunction by reducing the innate immune responses and myocardial fibrosis. To induce hypertension, male C57BL/6J and Gal-3 knockout (KO) mice were infused with ANG II (3 µg·min-1·kg-1 sc) for 8 wk. We assessed: 1) systolic blood pressure by plethysmography, 2) LV function and remodeling by echocardiography, 3) myocardial fibrosis by histology, 4) cardiac CD68+ macrophage infiltration by histology, 5) ICAM-1 and VCAM-1 expression by Western blotting, 6) plasma cytokines, including interleukin- 6 (IL-6), by enzyme-linked immunosorbent assay, and 7) regulatory T (Treg) cells by flow cytometry as detected by their combined expression of CD4, CD25, and FOXP3. Systolic blood pressure and cardiac hypertrophy increased similarly in both mouse strains when infused with ANG II. However, hypertensive C57BL/6J mice suffered impaired ejection and shortening fractions. In these mice, the extent of myocardial fibrosis and macrophage infiltration was greater in histological sections, and cardiac ICAM-1, as well as plasma IL-6, expression was higher as assessed by Western blotting. However, all these parameters were blunted in Gal-3 KO mice. Hypertensive Gal-3 KO mice also had a higher number of splenic Treg lymphocytes. In conclusion, in ANG II-induced hypertension, genetic deletion of Gal-3 prevented LV dysfunction without affecting blood pressure or LV hypertrophy. This study indicates that the ANG II effects are, in part, mediated or triggered by Gal-3 together with the related intercellular signaling (ICAM-1 and IL-6), leading to cardiac inflammation and fibrosis. Fil: González, Germán Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Henry Ford Hospital; Estados Unidos Fil: Rhaleb, N.-E.. Henry Ford Hospital; Estados Unidos. Wayne State University; Estados Unidos Fil: D'Ambrosio, Martin A.. Henry Ford Hospital; Estados Unidos Fil: Nakagawa, Pablo. Henry Ford Hospital; Estados Unidos Fil: Liao, Tang Dong. Henry Ford Hospital; Estados Unidos Fil: Peterson, Edward L.. Henry Ford Hospital; Estados Unidos Fil: Leung, Pablo. Henry Ford Hospital; Estados Unidos Fil: Dai, Xiangguo. Henry Ford Hospital; Estados Unidos Fil: Janic, Branislava. Henry Ford Hospital; Estados Unidos Fil: Liu, Yun He. Henry Ford Hospital; Estados Unidos Fil: Yang, Xiao Ping. Henry Ford Hospital; Estados Unidos Fil: Carretero, Oscar A.. Henry Ford Hospital; Estados Unidos

We present a method to unify the calculation of Green’s functions for an electromagnetic (EM) transmitting source embedded in a homogeneous stratified medium. A virtual interface parallel to layer interfaces is introduced through the source location. The potentials for Green’s function are derived by decomposing the partial wave solutions to Helmholtz’s equations into upward and downward within boundaries. The amplitudes of the potentials in each stratum are obtained recursively from the initial amplitudes at the source level. The initial amplitudes are derived by coupling with the transmitting sources and following the discontinuity of the tangential electric and magnetic fields at the source interface. Only the initial terms are related to the transmitting sources and thus need to be modified for different transmitters, whereas the kernel connected with the stratified media stays unchanged. Hence, the present method can be easily applied to EM transmitting sources with little modification. The application of the proposed method to the marine controlled-source electromagnetic method (MCSEM) demonstrates its simplicity and flexibility.

Steel plate shear wall (SPSW) systems have dual characteristics, the frame and infill wall action. The connection flexibility of frame joint not only changes the force and moment distribution, but also increases the lateral displacement and weakens the overall stability in SPSW structure. This paper presents the influence of hinged, rigid and semi-rigid connection joints on the behavior of SPSW structures. The bearing capacity, energy dissipation mechanism, failure mode, stress and deformation development process of the semi-rigid composite frame with steel plate shear walls under different stiffener forms were studied using experimental tests and finite element analysis. It was observed that with stiffeners the specimen yield load increased about 20% on the elastic stage, the ultimate bearing capacity of the diagonal stiffener was about 5% larger than the cross stiffener on the plastic stage, but the overall failure modes were basically the same. Additionally, the quantitative indications of the effect of joint stiffness on load carrying capacity were presented.

This paper investigates the influence of a piezoelectric (PE) particle pair on the crack-tip parameters. The I-integral is employed to solve the crack-tip stress intensity factors (SIFs) and electric displacement intensity factors (EDIFs) of a PE/dielectric material. The I-integral can decouple mixed-mode SIFs and EDIFs, and moreover, it is domain-independent for material interfaces, which greatly facilitate the extraction of the crack-tip field intensity factors for PE particulate composites by adopting an integral domain with arbitrary interfaces. Finally, a cracked dielectric plate reinforced by a pair of PE particles is studied to investigate the influences of the particle pair on the SIFs and EDIFs.

Objective: Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II). Methods: Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks. Results: Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio. Conclusion: In conclusion, absence of interleukin -6 did not alter the development of Ang II-high salt-induced hypertension and cardiac hypertrophy, but it prevented the development of cardiac dysfunction, myocardial inflammation, and fibrosis. This indicates that interleukin-6 plays an important role in hypertensive heart damage but not in the development of hypertension. Fil: González, Germán Esteban. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Henry Ford Hospital; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rhaleb, Nour Eddine. Henry Ford Hospital; Estados Unidos Fil: D'Ambrosio, Martin A.. Henry Ford Hospital; Estados Unidos Fil: Nakagawa, Pablo. Henry Ford Hospital; Estados Unidos Fil: Liu, Yunhe. Henry Ford Hospital; Estados Unidos Fil: Leung, Pablo. Henry Ford Hospital; Estados Unidos Fil: Dai, Xiangguo. Henry Ford Hospital; Estados Unidos Fil: Yang, Xiao Ping. Henry Ford Hospital; Estados Unidos. Wayne State University; Estados Unidos Fil: Peterson, Edward L.. Henry Ford Hospital; Estados Unidos Fil: Carretero, Oscar A.. Henry Ford Hospital; Estados Unidos

Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS−/−), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by Nω-nitro-l-arginine methyl ester (l-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS−/− mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MI+vehicle, and MI+l-NAME (100 mg·kg−1·day−1 in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/d t/instant pressure) in response to isoproterenol (100 ng·kg−1·min−1 iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS−/− compared with WT mice. l-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS−/− mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.

Pressure-overload left ventricular hypertrophy (LVH) is characterized by an increase in myocyte size and fibrosis. However, it is not clear how each of these components affects hypertensive heart disease (HHD). We have shown in 2 different rat models of hypertension that cardiac fibrosis can be reduced with N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), an antifibrotic peptide normally present in mammals. To assess how inhibition of fibrosis affects HHD, spontaneously hypertensive rats (SHR) and normotensive controls (WKY) were treated with Ac-SDKP or vehicle. Cardiac systolic and diastolic function were assessed using in vivo pressure-volume (PV) analysis. Left ventricle passive compliance was also determined ex vivo. We found that in SHR, Ac-SDKP normalized left ventricle total collagen content and interstitial collagen fraction without changing myocyte diameter or left ventricle mass. In WKY, collagen did not change significantly after treatment. Ac-SDKP did not affect left ventricle diastolic function, determined in vivo and ex vivo in SHR and WKY, whereas systolic function was significantly decreased in SHR treated with Ac-SDKP and unchanged in treated WKY. We concluded that in adult SHR, reducing left ventricle collagen deposition with Ac-SDKP does not improve diastolic function, whereas it decreases systolic performance. These findings suggest that total left ventricle collagen reduction per se does not necessarily benefit cardiac function. In HHD, other factors besides collagen quantity, such as myocyte hypertrophy and/or collagen type or cross-link, might be targeted to improve cardiac function.

Inflammation may play an important role in the pathogenesis of cardiac fibrosis in heart failure (HF) after myocardial infarction (MI). N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring antifibrotic peptide whose plasma concentration is increased 4- to 5-fold by angiotensin-converting enzyme inhibitors. We tested the hypothesis that in rats with HF after MI, Ac-SDKP acts as an anti-inflammatory cytokine, preventing and also reversing cardiac fibrosis in the noninfarcted area (reactive fibrosis), and thus affording functional improvement. We found that Ac-SDKP significantly decreased total collagen content in the prevention group from 23.7±0.9 to 15.0±0.7 μg/mg and in the reversal group from 22.6±2.2 to 14.4±1.6 ( P 2 , P 2 , P 2 , P 2 , P

We previously found that male mice with myocardial infarction (MI) had a high rate of cardiac rupture, which generally occurred at 3 to 5 days after MI. Since matrix metalloproteinases (MMPs) play an important role in infarct healing, tissue repair and extracellular matrix (ECM) remodeling post-MI, we studied the temporal relationship of MMP expression and inflammatory response to cardiac rupture after acute MI. Male C57BL/6J mice were subjected to MI (induced by ligating the left anterior descending coronary artery) and killed 1, 2, 4, 7 or 14 days after MI. MMP-2 and MMP-9 activity in the heart were measured by zymography. Collagen content was measured by hydroxyproline assay. We found that after MI, MMP-9 activity increased as early as 1 day and reached a maximum by 2-4 days, associated with a similar increase in neutrophil and macrophage infiltration in the infarct area. MMP-2 started to increase rapidly within 4 days, reaching a maximum by 7 days and remaining high even at 14 days. Intense macrophage infiltration appeared by 4 days after MI and then gradually decreased within 7 to 14 days. Collagen content was unchanged until 4 days after MI, at which point it increased and remained high thereafter. Our data suggest that in mice, overexpression of MMP-2 and MMP-9 (possibly expressed mainly by neutrophils and macrophages) may lead to excessive ECM degradation in the early phase of MI, impairing infarct healing and aggravating early remodeling which in turn causes cardiac rupture.

We established a mouse model of cardiac dysfunction due to myocardial infarction (MI). For this we ligated the left anterior descending coronary artery in male C57BL/6J mice and assessed healing and left ventricular (LV) remodelling at 1, 2 and 4 days and 1, 2 and 4 weeks after MI. Echocardiography was performed at 1 and 2 weeks and 1, 2, 4 and 6 months after MI. We found that neutrophil infiltration of the infarct border was noticeable at 1-2 days. Marked macrophage infiltration occurred at day 4, while lymphocyte infiltration was apparent at 7-14 days. Massive proliferation of fibroblasts and collagen accumulation began by day 7-14, and scar formation was completed by day 21. LV diastolic dimension increased markedly at 2 weeks and remained at the same level thereafter. LV shortening fraction decreased significantly at 2 weeks and then slowly decreased. In non-infarcted areas of the LV, myocyte cross-sectional area and interstitial collagen fraction increased progressively, reaching a maximum at 4 months. This study provides important qualitative and quantitative information about the natural history of cardiac remodelling after MI in mice.

Background — N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural inhibitor of pluripotent hematopoietic stem cell proliferation. Ac-SDKP plasma concentration is increased 5-fold after angiotensin-converting enzyme inhibition. Here we studied the effect of Ac-SDKP on monocyte/macrophage infiltration, fibroblast proliferation, and collagen deposition in the rat heart in renovascular hypertension. Methods and Results —We investigated whether long-term Ac-SDKP administration would prevent left ventricular (LV) hypertrophy and interstitial collagen deposition in rats with 2-kidney, 1-clip (2K-1C) hypertension. Ac-SDKP (400 μg · kg −1 · d −1 ) did not affect development of hypertension. Mean blood pressure was similar in rats with 2K-1C hypertension whether they were given vehicle or Ac-SDKP and was higher than in controls. Both LV weight and cardiomyocyte size were significantly increased in rats with 2K-1C hypertension compared with controls and were unaffected by Ac-SDKP. Proliferating cell nuclear antigen- and monocyte/macrophage-positive cells were increased in the LV of 2K-1C hypertensive rats; this increase was significantly blunted by Ac-SDKP ( P P P Conclusions —Ac-SDKP inhibited monocyte/macrophage infiltration, cell proliferation, and collagen deposition in the LV of hypertensive rats without affecting blood pressure or cardiac hypertrophy, suggesting that it may be partly responsible for the cardioprotective effect of angiotensin-converting enzyme inhibitors.

Abstract —Using B 2 kinin receptor gene knockout mice (B 2 −/− ), we tested the hypothesis that (l) lack of B 2 receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT 1 -ant), whereas lack of B 2 receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B 2 −/− and 129/SvEvTac mice (wild-type control, B 2 +/+ ). An ACEi (ramipril, 2.5 mg/kg/d) or AT 1 -ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B 2 +/+ and B 2 −/− mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B 2 −/− mice (respective values for B 2 +/+ versus B 2 −/− mice: overall increase in ejection fraction, 64±10% versus 21±5% [ P P P P 1 -ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B 2 −/− mice (respective values for B 2 +/+ versus B 2 −/− mice: overall increase in ejection fraction, 46±10% versus 25±9% [ P P P P 1 -ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B 2 −/− mice. We concluded that (1) lack of B 2 kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B 2 receptor play an important role in the cardioprotective effect of ACEi and AT 1 -ant.

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT1-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEi; (d) HF-AT1-ant; (e) HF-ACEi + AT1-ant (half dose of each); and (f) HF-ACEi + AT1-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT1-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT1-ant alone. We concluded that ACEi and AT1-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.

The inducible nitric oxide synthase isoform (iNOS) is upregulated by cytokines and endotoxins in many types of cells, including cardiac myocytes. Nitric oxide (NO) induced by cytokines can be cytotoxic, and has been implicated in the pathophysiology of myocardial infarction, cardiomyopathy, and septic shock. To examine the role of iNOS in the ischemic myocardium, we studied: 1) the time course of expression of iNOS mRNA after myocardial infarction (MI) in male Sprague-Dawley rat hearts and expression of iNOS protein in the infarcted region; 2) whether hypoxia in vitro is a potential mediator of the induction of iNOS mRNA; and 3) whether inhibition of iNOS by two different selective inhibitors (aminoguanidine and S-methylisothiourea sulfate) in vivo influences infarct size. Myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD), and tissue was collected at selected times thereafter from both ligated and sham-operated rats. iNOS mRNA was induced in the infarcted region of the left ventricle for 7 days; iNOS protein was also detected in the infarcted area. We next tested whether hypoxia would induce iNOS in vitro. In cultured neonatal ventricular myocytes, iNOS mRNA was slightly induced by 6 to 24 h of hypoxia; however, iNOS protein was only detected when the cytokine interleukin-1beta was present. To study whether iNOS activity contributed to myocardial damage (eg, infarct size), we administered the first dose of the NOS inhibitors 24 h before LAD occlusion and then a second dose after surgery. Inhibition of iNOS activity with aminoguanidine reduced infarct size by 20% but had no effect on infiltration by neutrophils, whereas the more selective inhibitor S-methylisothiourea sulfate reduced infarct size by 41%. These data suggest that NO derived from the iNOS isoform contributes to some of the myocardial injury following MI, possibly by causing myocardial cell death in areas bordering the ischemic region of the heart.

Myocarditis is commonly associated with cardiotropic infections and has been linked to development of autoimmunity. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases; however, its effect on autoimmune-mediated cardiac diseases remains unknown. We studied the effects of Ac-SDKP in experimental autoimmune myocarditis (EAM), a model of T cell-mediated autoimmune disease. This study was conducted to test the hypothesis that Ac-SDKP prevents autoimmune myocardial injury by modulating the immune responses. Lewis rats were immunized with porcine cardiac myosin and treated with Ac-SDKP or vehicle. In EAM, Ac-SDKP prevented both systolic and diastolic cardiac dysfunction, remodeling as shown by hypertrophy and fibrosis, and cell-mediated immune responses without affecting myosin-specific autoantibodies or antigen-specific T cell responses. In addition, Ac-SDKP reduced cardiac infiltration by macrophages, dendritic cells, and T cells, pro-inflammatory cytokines [interleukin (IL)-1α, tumor necrosis factor-α, IL-2, IL-17] and chemokines (cytokine-induced neutrophil chemoattractant-1, interferon-γ-induced protein 10), cell adhesion molecules (intercellular adhesion molecule-1, L-selectin), and matrix metalloproteinases (MMP). Ac-SDKP prevents autoimmune cardiac dysfunction and remodeling without reducing the production of autoantibodies or T cell responses to cardiac myosin. The protective effects of Ac-SDKP in autoimmune myocardial injury are most likely mediated by inhibition of 1) innate and adaptive immune cell infiltration and 2) expression of proinflammatory mediators such as cytokines, chemokines, adhesion molecules, and MMPs. Fil: Nakagawa, Pablo. Henry Ford Hospital; Estados Unidos Fil: Liu, Yunhe. Henry Ford Hospital; Estados Unidos Fil: Liao, Tang Dong. Henry Ford Hospital; Estados Unidos Fil: Chen, Xiaojuan. Henry Ford Hospital; Estados Unidos Fil: González, Germán Esteban. Henry Ford Hospital; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bobbitt, Kevin R.. Henry Ford Hospital; Estados Unidos Fil: Smolarek, Derek. Henry Ford Hospital; Estados Unidos Fil: Peterson, Ed L.. Henry Ford Hospital; Estados Unidos Fil: Kedl, Ross. University of Colorado; Estados Unidos Fil: Yang, Xiao Ping. Henry Ford Hospital; Estados Unidos Fil: Rhaleb, Nour Eddine. Henry Ford Hospital; Estados Unidos Fil: Carretero, Oscar A.. Henry Ford Hospital; Estados Unidos

IL-6 knockout (KO) mice were reported to spontaneously develop cardiac dysfunction and fibrosis. These KO mice also develop less hypertension when fed high salt and infused with angiotensin II (Ang II). We tested the hypothesis that in IL-6-KO mice the attenuated hypertension in response to Ang II-salt is due to the development of cardiac dysfunction. Male C57Bl/6J and IL-6-/- mice (B6.129S6- Il6 tm1Kopf ) were implanted with telemetry devices for blood pressure measurements, infused with vehicle (V) or Ang II (90 ng/min/mouse subcutaneously) and feed a high salt diet (4% salt diet, HS) for 8 weeks (W). We studied 4 experimental groups: 1) C57BL/6J + V (n=9); 2) IL6-KO + V (n=9); 3) C57BL/6J + Ang II (n=8) and 4) IL6-KO + Ang II (n=6). Blood pressure and echocardiography data were collected before starting the HS diet and Ang II infusion (baseline) and 8 weeks after HS alone or combined with Ang II. Results (Mean±SEM) Conclusion: Our results do not support our hypothesis and shows that the lack of IL-6 does not affect development of hypertension or cardiac hypertrophy but rather prevents cardiac dysfunction, LV dilation, myocardial inflammation and fibrosis in Ang II-salt-induced hypertension, suggesting that IL-6 plays an important role in cardiac dysfunction associated with hypertension.

The goal of this study was to evaluate the functional behavior of recruitable (mostly capillary) and nonrecruitable (mostly arterioles and venules) components of the intramyocardial microvasculature in the in situ heart of intact experimental animals. For this purpose fast X-ray computerized tomography (CT) scans were performed in a group of anesthetized pigs. Each scan was performed during an aortic root angiogram and was repeated after sequential injections of a suspension of nonradioactive microspheres into a selected coronary artery. Regional myocardial perfusion (F, ml.g-1.min-1) and intramyocardial blood volume (rho, ml/g) were estimated from the dynamic CT image sequences. For the intramyocardial microcirculation, rho = AF + B square root of F [where A = 0.016 min and B = 0.076 (ml.min/g)1/2] was shown to describe the rho-to-F relationship over the entire range of flows observed. With increasing embolization with 15-microns diameter microspheres, the coefficients A and B changed in a way consistent with A describing the transit time through the functionally recruitable component and B/ square root of F describing the transit time through the functionally nonrecruitable component of the microcirculation.

Controlled-source electromagnetic method can now survey along several profiles in a working area to span a 3D data set. However, these data are commonly interpreted by 2D models along each profile, and combined together to create a persudo-3D resistivity volume. Meanwhile, to obtain reasonable results, data collection must meet special requirements and undergo corrections, e.g., far-field and static correction (Zonge, 1989). Besides, other factors, like source effect and inhomogeneous between source and receiver, can distort the 2D inversion model seriously. In this case, 3D inversions are helpful.

BACKGROUND The goal of this study was to explore the role of several factors that affect intramyocardial blood volume by using minimally invasive computed tomography. Anesthetized dogs were scanned with the dynamic spatial reconstructor, a high-speed tomographic scanner, during injection of a bolus of iohexol into the aortic root. METHODS AND RESULTS In control dogs, it is indicated that the fraction of myocardium that is blood (FMB, %) relates to myocardial perfusion (F, milliliters per gram per minute) in that region as FMB congruent to a.F1/2, where a = 9.5 +/- 1.2% (milliliters times minute per gram)1/2 (mean +/- SD) in the subendocardium and a = 9.6 +/- 1.1% in the subepicardium. In another group of dogs, for the myocardium perfused by a stenosed epicardial artery, a increased to approximately 10 for a 25-43% stenosis (or pressure gradient of 9 mm Hg across narrowing) and to greater than 11 for a 50-55% stenosis (or pressure gradient of 40 mm Hg across narrowing). In these dogs, flow was not impaired under control hemodynamic conditions, but the usual increase of flow (i.e., flow reserve) observed under maximum vasodilation conditions was impaired. In another group of dogs, progressive embolization (using 15-microns-diameter microspheres) of the left ventricular myocardial microcirculation caused the value of a to remain at approximately 9.5 with embolization up to 50% of the fatal dose of microspheres, but it then decreased progressively with embolization to 4.6 at the fatal dose. CONCLUSIONS We conclude that the FMB/F relation reflects hemodynamic conductance at the microvascular level.

Galectin-3 (Gal-3) is secreted by activated macrophages. In hypertension, Gal-3 is a marker for hypertrophic hearts prone to develop heart failure. Gal-3 infused in pericardial sac leads to cardiac inflammation, remodeling, and dysfunction. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a naturally occurring tetrapeptide, prevents and reverses inflammation and collagen deposition in the heart in hypertension and heart failure postmyocardial infarction. In the present study, we hypothesize that Ac-SDKP prevents Gal-3-induced cardiac inflammation, remodeling, and dysfunction, and these effects are mediated by the transforming growth factor (TGF)-β/Smad3 signaling pathway. Adult male rats were divided into four groups and received the following intrapericardial infusion for 4 wk: 1) vehicle (saline, n = 8); 2) Ac-SDKP (800 μg·kg−1·day−1, n = 8); 3) Gal-3 (12 μg/day, n = 7); and 4) Ac-SDKP + Gal-3 ( n = 7). Left ventricular ejection fraction, cardiac output, and transmitral velocity were measured by echocardiography; inflammatory cell infiltration, cardiomyocyte hypertrophy, and collagen deposition in the heart by histological and immunohistochemical staining; and TGF-β expression and Smad3 phosphorylation by Western blot. We found that, in the left ventricle, Gal-3 1) enhanced macrophage and mast cell infiltration, increased cardiac interstitial and perivascular fibrosis, and causes cardiac hypertrophy; 2) increased TGF-β expression and Smad3 phosphorylation; and 3) decreased negative change in pressure over time response to isoproterenol challenge, ratio of early left ventricular filling phase to atrial contraction phase, and left ventricular ejection fraction. Ac-SDKP partially or completely prevented these effects. We conclude that Ac-SDKP prevents Gal-3-induced cardiac inflammation, fibrosis, hypertrophy, and dysfunction, possibly via inhibition of the TGF-β/Smad3 signaling pathway.

The hypothesis that inflammation plays a role in the pathogenesis of hypertension is supported by epidemiological studies indicating that inflammatory markers are associated with hypertension.1,2 However, association does not necessarily indicate cause and effect. Evidence that inflammation may participate in the pathogenesis of various models of experimental hypertension is provided by the use of immunosuppressive drugs. As indicated in the letter by Rodriguez-Iturbe et al,3 these compounds prevent inflammatory cell infiltration and decrease blood pressure. There are many other anti-inflammatory drugs, such as nonsteroidal anti-inflammatory agents or glucocorticoids, that do not ameliorate hypertension. On the contrary, they tend to antagonize the …

Angiotensin II (Ang II)–induced hypertension is associated with an inflammatory response that may contribute to the development of target organ damage. We tested the hypothesis that, in Ang II–induced hypertension, CC chemokine receptor 2 (CCR2) activation plays an important role in the development of renal fibrosis, damage, and dysfunction by causing oxidative stress, macrophage infiltration, and cell proliferation. To test this hypothesis, we used CCR2 knockout mice (CCR2 −/− ). The natural ligand of CCR2 is monocyte chemoattractant protein-1, a chemokine important for macrophage recruitment and activation. CCR2 −/− and age-matched wild-type (CCR2 +/+ ) C57BL/6J mice were infused continuously with either Ang II (5.2 ng/10 g per minute) or vehicle via osmotic minipumps for 2 or 4 weeks. Ang II infusion caused similar increases in systolic blood pressure and left ventricular hypertrophy in both strains of mice. However, in CCR2 −/− mice with Ang II–induced hypertension, oxidative stress, macrophage infiltration, albuminuria, and renal damage were significantly decreased, and glomerular filtration rate was significantly higher than in CCR2 +/+ mice. We concluded that, in Ang II–induced hypertension, CCR2 activation plays an important role in the development of hypertensive nephropathy via increased oxidative stress and inflammation.

We have shown previously that cyclooxygenase-2 inhibition reduces cardiac hypertrophy and fibrosis postmyocardial infarction (MI) in a mouse model and that prostaglandin E 2 stimulates cardiomyocyte hypertrophy in vitro through its EP 4 receptor. Because the role of cardiac myocyte EP 4 in cardiac function and hypertrophy in vivo is unknown, we generated mice lacking EP 4 only in cardiomyocytes (CM- EP 4 knockout [KO]). Twelve- to 14-week–old mice were evaluated using echocardiography and histology. There were no differences in ejection fraction, myocyte cross-sectional area, and interstitial collagen fraction between KO mice and littermate controls. To test the hypothesis that EP 4 is involved in cardiac remodeling after MI, we induced MI by ligating the left anterior descending coronary artery. Two weeks later, the mice were subjected to echocardiography, and hearts were removed for histology and Western blot. There was no difference in infarct size between KO mice and controls; however, KO mice showed less myocyte cross-sectional area and interstitial collagen fraction than controls. Also, CM-EP4 KO mice had reduced ejection fraction. Because the transcription factor Stat-3 is involved in hypertrophy and protection from ischemic injury, we tested whether it was activated in control and KO mouse hearts after MI. Western blot indicated that Stat-3 was activated in control hearts after MI but not in KO hearts. Thus, CM-EP4 deletion decreased hypertrophy, fibrosis, and activation of Stat-3. However, cardiac function was unexpectedly worsened in these mice. We conclude that cardiac myocyte EP 4 plays a role in hypertrophy via activation of Stat-3, a process that seems to be cardioprotective.

A novel method for self adapting morphological top-hat operator was presented. The structural elements of opening top-hat are trained by utilizing the support vector machine from a mass of sample sets. Once the machine is trained by the samples of structural elements, it can implement background suppressing in the following frames. Practical infrared image sequence background suppressing shows that the proposed method based on support vector machine was fit for lower signal noise ratio image. Experimental results of the actual measurement show that using the improved top-hat operator, the detection probability of image with sbr (sbrap0.9 dB) is higher than 96%, compared with fixed top-hat filter, the detection probability is improved by nearly 7%.

Background Mitogen-activated protein kinases (MAPKs) have emerged as an important pathophysiologic regulator during the development of heart failure (HF). p38 MAPK activity is elevated in cardiac hypertrophy and HF. We used a mouse model of myocardial infarction (MI) to test the hypotheses that (1) inhibition of p38 MAPK activity may improve cardiac function and remodeling after myocardial infarction (MI) and (2) coadministration of a p38 inhibitor (p38i) and an angiotensin-converting enzyme inhibitor (ACEI) may provide only limited further cardioprotection in this model. Methods and results MI was induced in C57BL/6J mice by ligating the left anterior descending coronary artery and then either left untreated or treated with a p38i (SC-409, 30 mg/kg/day in chow), ACEI (enalapril, 20 mg/kg in drinking water), or p38i plus ACEI for 12 weeks. Echocardiography was performed and systolic blood pressure measured before MI and weekly thereafter. At the end of the study, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA) were examined histologically. We found that p38i significantly increased left ventricular ejection fraction and cardiac output and decreased left ventricular area at diastole, ICF, and MCSA. ACEi and p38i each had similar beneficial effects in this mouse model of HF produced by a large MI. Coadministration of p38i and ACEi did not provide any additional benefit. Conclusion Our data suggest that inhibition of p38 MAPK provides significant cardioprotection in mice with HF post-MI.

Kinins exert cardioprotective effects via 2 G-protein-coupled receptors, B 1 and B 2. Using B 1 kinin receptor gene knockout mice (B 1 −/− ), we tested the hypotheses that the B 1 receptor plays an important role in preservation of cardiac function, whereas lack of B 1 may accelerate cardiac remodeling and dysfunction after myocardial infarction, and that B 2 receptors may compensate for lack of B 1 , whereas blockade of B 2 receptors in B 1 −/− mice may cause further deterioration of cardiac function and remodeling. Female B 1 −/− mice and wild-type controls (C57BL/6J, B 1 +/+ ) underwent sham surgery or myocardial infarction and were treated with either vehicle or B 2 -antagonist (icatibant, 500 μg/kg per day, subcutaneous) for 8 weeks. We found that in sham myocardial infarction, B 1 −/− mice had a larger left ventricular diastolic chamber dimension both initially and at 4 to 8 weeks compared with B 1 +/+ . Left ventricular mass and myocyte size were also larger in B 1 −/− with sham operation than in B 1 +/+ , although cardiac function did not differ between strains. After myocardial infarction, cardiac remodeling and function were similar in both strains, although B 1 −/− mice tended to have lower blood pressure. Blockade of B 2 receptors tended to worsen cardiac remodeling and dysfunction in B 1 −/− but not in B 1 +/+ . These results may suggest that B 2 receptors play an important role in compensating for lack of B 1 receptors in mice with myocardial infarction. Dual blockade of both B 1 and B 2 eliminates this compensation, leading to further deterioration of cardiac dysfunction and remodeling after myocardial infarction.

Background Spironolactone, a nonselective aldosterone blocker, has a cardioprotective effect; however, significant endocrine side effects limit its use. Eplerenone is a new selective aldosterone blocker. We investigated whether eplerenone attenuates cardiac remodeling and improves function in a mouse model of heart failure and whether coadministration of eplerenone and an angiotensin-converting enzyme inhibitor (ACEi) provides better cardioprotection than either agent alone. Methods and results C57BL/6J mice were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. Two weeks later, the mice were either left untreated or treated with (1) eplerenone, (2) ACEi, or (3) eplerenone plus ACEi for 12 weeks. Systolic blood pressure (SBP) was measured and echocardiography performed before MI and weekly thereafter. At the end of the study, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA) were examined histologically. We found that (1) eplerenone significantly improved ejection fraction and cardiac output and decreased left ventricular (LV) systolic area, LV weight, ICF, and MCSA independently of changes in SBP compared with untreated animals; (2) ACEi had similar beneficial effects, accompanied by a significant reduction in SBP; and (3) combined treatment offered limited additional benefit beyond monotherapy. Conclusions In mice with MI, eplerenone attenuates progression of heart failure comparably to ACEi, and its effect is independent of BP lowering.

Background Vasopeptidase inhibitors (VPi) may provide a new means of treating hypertension and congestive heart failure, because they simultaneously block angiotensin-converting enzyme (ACE) and neutral endopeptidase-24.11 (NEP-24.11), thereby inhibiting the renin-angiotensin system and enhancing vasodilator and natriuretic substances such as kinins and natriuretic peptides. Methods Using B2 kinin receptor gene knockout mice (B2−/−), we tested the hypotheses that (1) VPi may provide better cardioprotection than ACE or NEP inhibitors alone (ACEi and NEPi) and (2) the effects of these inhibitors are partially mediated by kinins. Four weeks after myocardial infarction, B2−/− mice and B2+/+ mice were started on vehicle, ACEi (ramipril, 2.5 mg/kg/d), NEPi (candoxatril, 20 mg/kg/d) or VPi (omapatrilat, 50 mg/kg/d), which was continued for 20 weeks. Systolic blood pressure was measured weekly and cardiac function evaluated monthly by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were measured histopathologically. Results We found that ACEi or NEPi improved cardiac function and remodeling and that these effects were more obvious in mice receiving VPi. Furthermore, the beneficial cardiac effects of ACEi, NEPi, and VPi were significantly attenuated in B2−/− mice. We concluded that dual inhibition of ACE and NEP with VPi provides better cardioprotection than ACEi or NEPi alone in mice with congestive heart failure induced by myocardial infarction, and these effects are mediated at least in part via kinins.

Angiotensin II (Ang II) acts mainly on two receptor subtypes: AT 1 and AT 2 . Most of the known biological actions of Ang II are mediated by AT 1 receptors; however, the role of AT 2 receptors remains unclear. We tested the hypothesis that the cardioprotective effects of AT 1 receptor antagonists (AT 1 -ant) after myocardial infarction (MI) are partially mediated by activation of AT 2 receptors; thus in AT 2 receptor gene knockout mice (AT 2 −/Y), the effect of AT 1 -ant will be diminished or absent. MI was induced by ligating the left anterior descending coronary artery. Four weeks later, AT 2 −/Y and their wild-type littermates (AT 2 +/Y) were started on vehicle, AT 1 -ant (valsartan, 50 mg/kg per day), or ACE inhibitor (enalapril, 20 mg/kg per day) for 20 weeks. Basal blood pressure and cardiac function as well as remodeling after MI did not differ between AT 2 +/Y and AT 2 −/Y. AT 1 -ant increased ejection fraction and cardiac output and decreased left ventricular diastolic dimension, myocyte cross-sectional area, and interstitial collagen deposition in AT 2 +/Y, and these effects were significantly diminished in AT 2 −/Y. ACE inhibitors improved cardiac function and remodeling similarly in both strains. We concluded that (1) activation of AT 2 during AT 1 blockade plays an important role in the therapeutic effect of AT 1 -ant and (2) the AT 2 receptor may not play an important role in regulation of cardiac function, either under basal conditions after MI remodeling or in the therapeutic effect of ACE inhibitors.

Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B2 receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B2 kinin receptor antagonist in BN rats.