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Journal articles on the topic 'Fibers Disarray'
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1
Daliento, Luciano, Roldano Scognamiglio, Gaetano Thiene, Anita Hegerty, Siew Yen Ho, Francesca Caneve, and Robert H. Anderson. "Morphologic and functional analysis of myocardial status in pulmonary atresia with intact ventricular septum—an angiographic, histologic and morphometric study." Cardiology in the Young 2, no. 4 (October 1992): 361–66. http://dx.doi.org/10.1017/s1047951100007952.
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SummaryWe studied 11 patients with pulmonary atresia and intact ventricular septum who died at ages ranging from one day to three years. All but two neonates died after surgery. Pre-surgical catheterization with left and right cineventriculography was performed in nine patients, and quantitative parameters were calculated. By histologic examination of transverse transmural sections, the incidence and extent of myocardial ischemia or infarction were determined, as well as the percentage area per field occupied by vessels, myocytes orientated longitudinally or transversely, interstitial space, and disarrayed fibers. Comparable sections were obtained from six normal neonates to constitute a control group. Myocardial ischemia or infarction were frequent complications. Morphometric analysis demonstrated a significant difference between the control group and the patients with regard to the percentage of myocytes (longitudinal and transverse), the percentage of area occupied by myocardial disarray, and the presence of fibrosis. The highest values for the proportion of disarray were seen in those patients with small right ventricles. The percentage of myocytes varied, but the highest degree of disarray always correlated with the lowest percentage of myocytes. The highest percentage value of left ventricular disarray was associated with the lowest ratio of left ventricular mass to end diastolic volume (inadequate hypertrophy). The lowest indices of contractility and left ventricular pump function were associated with myocytes less than 55% of normal. A linear correlation was found between the percentage area of fibrosis and the ratio of systolic pressure to end systolic volume in the left ventricle, arid between fibrosis and ejection fraction. Values for fibrosis exceeding 15% were associated with decreased functional indices. Disarray, therefore, seems to express a primary inability of myocardium to respond to anomalous overload with adequate hypertrophy and/or hyperplasia.
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Kirschner, Sebastian E., Edgar Becker, Massimo Antognozzi, Hans-Peter Kubis, Antonio Francino, Francisco Navarro-López, Nana Bit-Avragim, et al. "Hypertrophic cardiomyopathy-related β-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 3 (March 2005): H1242—H1251. http://dx.doi.org/10.1152/ajpheart.00686.2004.
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Disease-causing mutations in cardiac myosin heavy chain (β-MHC) are identified in about one-third of families with hypertrophic cardiomyopathy (HCM). The effect of myosin mutations on calcium sensitivity of the myofilaments, however, is largely unknown. Because normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle, which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium sensitivity (pCa50) and the steepness of force-pCa relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations. Fibers with the Arg723Gly and Arg719Trp mutations showed a decrease in mean pCa50, whereas those with the Ile736Thr mutation showed slightly increased mean pCa50 with higher active forces at low calcium concentrations and residual active force even under relaxing conditions. In addition, there was a marked variability in pCa50 between individual fibers carrying the same mutation ranging from an almost normal response to highly significant differences that were not observed in controls. While changes in mean pCa50 may suggest specific pharmacological treatment (e.g., calcium antagonists), the observed large functional variability among individual muscle cells might negate such selective treatment. More importantly, the variability in pCa50 from fiber to fiber is likely to cause imbalances in force generation and be the primary cause for contractile dysfunction and development of disarray in the myocardium.
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Pierantozzi, Enrico, Péter Szentesi, Cecilia Paolini, Beatrix Dienes, János Fodor, Tamás Oláh, Barbara Colombini, et al. "Impaired Intracellular Ca2+ Dynamics, M-Band and Sarcomere Fragility in Skeletal Muscles of Obscurin KO Mice." International Journal of Molecular Sciences 23, no. 3 (January 24, 2022): 1319. http://dx.doi.org/10.3390/ijms23031319.
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Obscurin is a giant sarcomeric protein expressed in striated muscles known to establish several interactions with other proteins of the sarcomere, but also with proteins of the sarcoplasmic reticulum and costameres. Here, we report experiments aiming to better understand the contribution of obscurin to skeletal muscle fibers, starting with a detailed characterization of the diaphragm muscle function, which we previously reported to be the most affected muscle in obscurin (Obscn) KO mice. Twitch and tetanus tension were not significantly different in the diaphragm of WT and Obscn KO mice, while the time to peak (TTP) and half relaxation time (HRT) were prolonged. Differences in force-frequency and force-velocity relationships and an enhanced fatigability are observed in an Obscn KO diaphragm with respect to WT controls. Voltage clamp experiments show that a sarcoplasmic reticulum’s Ca2+ release and SERCA reuptake rates were decreased in muscle fibers from Obscn KO mice, suggesting that an impairment in intracellular Ca2+ dynamics could explain the observed differences in the TTP and HRT in the diaphragm. In partial contrast with previous observations, Obscn KO mice show a normal exercise tolerance, but fiber damage, the altered sarcomere ultrastructure and M-band disarray are still observed after intense exercise.
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Zimmerman, Scott D., William J. Karlon, Jeffrey W. Holmes, Jeffrey H. Omens, and James W. Covell. "Structural and mechanical factors influencing infarct scar collagen organization." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 1 (January 1, 2000): H194—H200. http://dx.doi.org/10.1152/ajpheart.2000.278.1.h194.
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Although large collagen fibers in myocardial infarct scar are highly organized, little is known about mechanisms controlling this organization. The preexisting extracellular matrix may act as a scaffold along which fibroblasts migrate. Conversely, deformation within the ischemic area could guide fibroblasts so new collagen is oriented to counteract the stretch. To investigate these potential mechanisms, we infarcted three groups of pigs. Group 1 served as infarct controls. Group 2 had the endocardium slit longitudinally to alter local systolic deformation. Group 3had a plug sectioned from ischemic tissue and rotated 90°. The slit altered systolic deformation in the infarcted tissue, changing circumferential strain from expansion to compression and increasing radial strain and shears and the variability of collagen fiber angles but not the mean angle. In the plug pigs, when deformation, matrix orientation, and continuity are altered in the infarct area, the result is complete disarray in the organization of collagen within the infarct scar.
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Andrade, Zilton A., and Ediriomar Peixoto. "Pathology of periportal fibrosis involution in human schistosomiasis." Revista do Instituto de Medicina Tropical de São Paulo 34, no. 4 (August 1992): 263–72. http://dx.doi.org/10.1590/s0036-46651992000400001.
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Optical and electron microscopical evidences of focal matrix degradation were frequently seen in liver sections of periportal fibrosis caused by schistosomiasis mansoni in man. The material came from 14 wedge hepatic biopsies taken from patients with chronic advanced hepatosplenic disease and undergoing operations for the relief of portal hypertension. Besides the presence of focal areas of rarefaction, fragmentation and dispersion of collagen fibers, the enlarged portal spaces also showed hyperplasia of elastic tissue and disarray of smooth muscle fibers following destruction of portal vein branches. Eggs were scanty in the tissue sections, and matrix degradation probably represented involuting changes related to the progressive diminution of parasite-related aggression, which occurs spontaneously with age or after cure by chemotherapy. The changes indicative of matrix degradation now described are probably the basic morphological counterpart of periportal fibrosis involution currently being documented by ultrasonography in hepatosplenic patients submitted to curative chemotherapy.
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Usyk, T. P., J. H. Omens, and A. D. McCulloch. "Regional septal dysfunction in a three-dimensional computational model of focal myofiber disarray." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 2 (August 1, 2001): H506—H514. http://dx.doi.org/10.1152/ajpheart.2001.281.2.h506.
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MLC2v/ ras transgenic mice display a phenotype characteristic of hypertrophic cardiomyopathy, with septal hypertrophy and focal myocyte disarray. Experimental measurements of septal wall mechanics in ras transgenic mice have previously shown that regions of myocyte disarray have reduced principal systolic shortening, torsional systolic shear, and sarcomere length. To investigate the mechanisms of this regional dysfunction, a three-dimensional prolate spheroidal finite-element model was used to simulate filling and ejection in the hypertrophied mouse left ventricle with septal disarray. Focally disarrayed septal myocardium was modeled by randomly distributed three-dimensional regions of altered material properties based on measured statistical distributions of muscle fiber angular dispersion. Material properties in disarrayed regions were modeled by decreased systolic anisotropy derived from increased fiber angle dispersion and decreased systolic tension development associated with reduced sarcomere lengths. Compared with measurements in ras transgenic mice, the model showed similar heterogeneity of septal systolic strain with the largest reductions in principal shortening and torsional shear in regions of greatest disarray. Average systolic principal shortening on the right ventricular septal surface of the model was −0.114 for normal regions and −0.065 for disarrayed regions; for torsional shear, these values were 0.047 and 0.019, respectively. These model results suggest that regional dysfunction in ras transgenic mice may be explained in part by the observed structural defects, including myofiber dispersion and reduced sarcomere length, which contributed about equally to predicted dysfunction in the disarrayed myocardium.
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Ritter, Paul, Stefanie Nübler, Andreas Buttgereit, Lucas R. Smith, Alexander Mühlberg, Julian Bauer, Mena Michael, et al. "Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah−/−) Model." International Journal of Molecular Sciences 23, no. 18 (September 16, 2022): 10841. http://dx.doi.org/10.3390/ijms231810841.
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Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the mdx mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the Cmah gene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of ‘structural weakness’, intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from extensor digitorum longus (EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness in mdx Cmah−/− diaphragm was similar to wt mice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced in mdx Cmah−/− diaphragm (15% in EDL). Myofibrillar architecture was severely compromised in mdx Cmah−/− single fibers of both muscle types, but more pronounced in diaphragm. Our results show that the mdx Cmah−/− genotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background.
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Hara, Hironori, Sonoko Maemura, Takayuki Fujiwara, Norifumi Takeda, Satoshi Ishii, Hiroki Yagi, Takaaki Suzuki, et al. "Inhibition of transforming growth factor-β signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome." PLOS ONE 15, no. 11 (November 11, 2020): e0239908. http://dx.doi.org/10.1371/journal.pone.0239908.
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Increased transforming growth factor-β (TGF-β) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-β type II receptor gene Tgfbr2 in myeloid cells of Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) and evaluated macrophage infiltration and TGF-β signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO mice, both canonical and noncanonical TGF-β signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-β enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-β signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.
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Rybakova, Inna N., Jitandrakumar R. Patel, and James M. Ervasti. "The Dystrophin Complex Forms a Mechanically Strong Link between the Sarcolemma and Costameric Actin." Journal of Cell Biology 150, no. 5 (September 4, 2000): 1209–14. http://dx.doi.org/10.1083/jcb.150.5.1209.
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The absence of dystrophin complex leads to disorganization of the force-transmitting costameric cytoskeleton and disruption of sarcolemmal membrane integrity in skeletal muscle. However, it has not been determined whether the dystrophin complex can form a mechanically strong bond with any costameric protein. We performed confocal immunofluorescence analysis of isolated sarcolemma that were mechanically peeled from skeletal fibers of mouse hindlimb muscle. A population of γ-actin filaments was stably associated with sarcolemma isolated from normal muscle and displayed a costameric pattern that precisely overlapped with dystrophin. However, costameric actin was absent from all sarcolemma isolated from dystrophin-deficient mdx mouse muscle even though it was localized to costameres in situ. Vinculin, α-actinin, β-dystroglycan and utrophin were all retained on mdx sarcolemma, indicating that the loss of costameric actin was not due to generalized membrane instability. Our data demonstrate that the dystrophin complex forms a mechanically strong link between the sarcolemma and the costameric cytoskeleton through interaction with γ-actin filaments. Destabilization of costameric actin filaments may also be an important precursor to the costamere disarray observed in dystrophin-deficient muscle. Finally, these methods will be broadly useful in assessing the mechanical integrity of the membrane cytoskeleton in dystrophic animal models lacking other costameric proteins.
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Bambang, L. S., M. Moczar, L. Lecerf, and D. Loisance. "External Biodegradable Supporting Conduit Protects Endothelium in Vein Graft in Arterial Interposition." International Journal of Artificial Organs 20, no. 7 (July 1997): 397–406. http://dx.doi.org/10.1177/039139889702000708.
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The prevention of circumferential distension could reduce structural damage in arteriovenous grafts. We studied the effect of an external biodegradable supporting conduit on the endothelium and extracellular matrix in vein graft in a pig model. Cephalic vein control grafts (Group I) and jugular veins wrapped in a vicryl mesh tube (I.D. 4mm) (Group II) were implanted into autologous carotid arteries (n=14). The grafts were explanted after 1 and 24 hours and at 1 and 3 weeks and evaluated by ELISA for endothelial DNA synthesis and by immunohistoenzymic assays for cells and extracellular matrix. In group I an initial loss of endothelial and smooth muscle cells along with elastin breakdown was followed by an impaired endothelial regeneration and significant graft wall thickening. The elastic tissue was replaced by collagen type I and chondroitin sulfate accumulations, which included a disarray of α-smooth muscle actin positive cells. The endothelium was preserved in group II. After 3 weeks the circumferential elastin layers were densified, distended and separated from the endothelium by a neointimal growth of irregular thickness. Biodegradable perivenous conduit minimized endothelial injury and allowed the partial preservation of elastin fibers and smooth muscle cells in the arteriovenous graft. It did not however, prevent myofibroblastic cell proliferation and triggered a macrophagic reaction.
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Nascimento, Juliana Minardi, Gilberto Carlos Franchi, Alexandre Eduardo Nowill, Carla Beatriz Collares-Buzato, and Stephen Hyslop. "Cytoskeletal rearrangement and cell death induced by Bothrops alternatus snake venom in cultured Madin–Darby canine kidney cells." Biochemistry and Cell Biology 85, no. 5 (October 2007): 591–605. http://dx.doi.org/10.1139/o07-067.
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Bothrops snake venoms cause renal damage, with renal failure being the main cause of death in humans bitten by these snakes. In this work, we investigated the cytoskeletal rearrangement and cytotoxicity caused by Bothrops alternatus venom in cultured Madin–Darby canine kidney (MDCK) cells. Incubation with venom (10 and 100 µg/mL) significantly (p <0.05) decreased the cellular uptake of neutral red dye after 1 and 3 h. Venom (100 µg/mL) also markedly decreased the transepithelial electrical resistance (RT) across MDCK monolayers. Staining with rhodamine-conjugated phalloidin revealed disarray of the cytoskeleton that involved the stress fibers at the basal cell surface and focal adhesion-associated F-actin in the cell–matrix contact region. Feulgen staining showed a significant decrease in the number of cells undergoing mitosis and an increase in the frequency of altered nuclei. Scanning electron microscopy revealed a decrease in the number of microvilli and the presence of cells with a fusiform format. Flow cytometry with annexin V and propidium iodide showed that cell death occurred by necrosis, with little apoptosis, a conclusion supported by the lack of DNA fragmentation characteristic of apoptosis. Pretreating the cells with catalase significantly attenuated the venom-induced loss of viability, indicating a possible involvement of H2O2 in the cellular damage; less protection was observed with superoxide dismutase or Nω-nitro-l-arginine methyl ester. These results indicate that Bothrops alternatus venom is cytotoxic to cultured MDCK cells, possibly via the action of reactive oxygen species. This cytotoxicity could contribute to nephrotoxicity after envenoming by this species.
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Protasi, Feliciano, Laura Pietrangelo, and Simona Boncompagni. "Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing." International Journal of Molecular Sciences 22, no. 12 (June 8, 2021): 6195. http://dx.doi.org/10.3390/ijms22126195.
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Proper skeletal muscle function is controlled by intracellular Ca2+ concentration and by efficient production of energy (ATP), which, in turn, depend on: (a) the release and re-uptake of Ca2+ from sarcoplasmic-reticulum (SR) during excitation–contraction (EC) coupling, which controls the contraction and relaxation of sarcomeres; (b) the uptake of Ca2+ into the mitochondrial matrix, which stimulates aerobic ATP production; and finally (c) the entry of Ca2+ from the extracellular space via store-operated Ca2+ entry (SOCE), a mechanism that is important to limit/delay muscle fatigue. Abnormalities in Ca2+ handling underlie many physio-pathological conditions, including dysfunction in ageing. The specific focus of this review is to discuss the importance of the proper architecture of organelles and membrane systems involved in the mechanisms introduced above for the correct skeletal muscle function. We reviewed the existing literature about EC coupling, mitochondrial Ca2+ uptake, SOCE and about the structural membranes and organelles deputed to those functions and finally, we summarized the data collected in different, but complementary, projects studying changes caused by denervation and ageing to the structure and positioning of those organelles: a. denervation of muscle fibers—an event that contributes, to some degree, to muscle loss in ageing (known as sarcopenia)—causes misplacement and damage: (i) of membrane structures involved in EC coupling (calcium release units, CRUs) and (ii) of the mitochondrial network; b. sedentary ageing causes partial disarray/damage of CRUs and of calcium entry units (CEUs, structures involved in SOCE) and loss/misplacement of mitochondria; c. functional electrical stimulation (FES) and regular exercise promote the rescue/maintenance of the proper architecture of CRUs, CEUs, and of mitochondria in both denervation and ageing. All these structural changes were accompanied by related functional changes, i.e., loss/decay in function caused by denervation and ageing, and improved function following FES or exercise. These data suggest that the integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity); modifications in the architecture of these intracellular membrane systems may contribute to muscle dysfunction in ageing and sarcopenia.
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Larregina, Adriana, Ana R. Hernändez, Olga Pis Diez, Graciela Quijano, and Ricardo Drut. "Biventricular Hypoplasia with Myocardial Fiber Hypertrophy and Disarray." Pediatric Pathology 10, no. 6 (January 1990): 993–99. http://dx.doi.org/10.3109/15513819009064733.
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Milei, J., R. Migliore, F. Guerrero, C. Pedroza, and R. Storino. "Muscle Fiber Disarray in Patients without Hypertrophic Cardiomyopathy." Cardiology 72, no. 3 (1985): 105–12. http://dx.doi.org/10.1159/000173850.
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Chen, Junjie, Sheng-Kwei Song, Wei Liu, Mark McLean, J. Stacy Allen, Jie Tan, Samuel A. Wickline, and Xin Yu. "Remodeling of cardiac fiber structure after infarction in rats quantified with diffusion tensor MRI." American Journal of Physiology-Heart and Circulatory Physiology 285, no. 3 (September 2003): H946—H954. http://dx.doi.org/10.1152/ajpheart.00889.2002.
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Structural remodeling of myocardium after infarction plays a critical role in functional adaptation. Diffusion tensor magnetic resonance imaging (DTMRI) provides a means for rapid and nondestructive characterization of the three-dimensional fiber architecture of cardiac tissues. In this study, microscopic structural changes caused by MI were evaluated in Fischer 344 rats 4 wk after infarct surgery. DTMRI studies were performed on 15 excised, formalin-fixed rat hearts of both infarct (left anterior descending coronary artery occlusion, n = 8) and control (sham, n = 7) rats. Infarct myocardium exhibited increased water diffusivity (41% increase in trace values) and decreased diffusion anisotropy (37% decrease in relative anisotropy index). The reduced diffusion anisotropy correlated negatively with microscopic fiber disarray determined by histological analysis ( R = 0.81). Transmural courses of fiber orientation angles in infarct zones were similar to those of normal myocardium. However, regional angular deviation of the diffusion tensor increased significantly in the infarct myocardium and correlated strongly with microscopic fiber disarray ( R = 0.86). These results suggest that DTMRI may provide a valuable tool for defining structural remodeling in diseased myocardium at the cellular and tissue level.
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Tseng, Wen-Yih I., Jiangang Dou, Timothy G. Reese, and Van J. Wedeen. "Imaging myocardial fiber disarray and intramural strain hypokinesis in hypertrophic cardiomyopathy with MRI." Journal of Magnetic Resonance Imaging 23, no. 1 (2005): 1–8. http://dx.doi.org/10.1002/jmri.20473.
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Reed, Umbertina Conti, Maria Bernardete Dutra Resende, Lúcio Gobbo Ferreira, Mary Souza Carvalho, Aron Diament, Milberto Scaff, and Suely Kazue Nagahashi Marie. "King-Denborough Syndrome: report of two Brazilian cases." Arquivos de Neuro-Psiquiatria 60, no. 3B (September 2002): 739–41. http://dx.doi.org/10.1590/s0004-282x2002000500011.
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We report on two boys aged 2 and 6 years-old respectively with dysmorphic face, ptosis, down-slanting palpebral fissures, hypertelorism, epicanthic folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, palmar simian line, pectus excavatum, winging of the scapulae, lumbar lordosis and mild thoracic scoliosis who present congenital hypotonia, slightly delayed motor development, diffuse joint hyperextensibility and mild proximal weakness. The muscle biopsy revealed minimal but identifiable changes represented by size fiber variability, type I fiber predominance and atrophy, perimysial fibrous infiltration and some disarray of the intermyofibrillary network. These cases correspond to the first Brazilian reports of the King-Denborough syndrome and our objective is increasing the awareness of this disorder as these patients are predisposed to developing malignant hyperthermia.
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Tezuka, Fumiaki, Ikuro Sato, Hiroki Mori, Masuko Nomura, and Waldemar Hort. "Quantitative Analysis of Fiber Disarray Developing in Papillary Muscles Unloaded after Mitral Valve Replacement." Pathology International 39, no. 12 (December 1989): 779–85. http://dx.doi.org/10.1111/j.1440-1827.1989.tb02430.x.
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Jain, Akshat, Jaiswal Vidyaagar, and Ravi Raghvan. "Sickle Cell Disease with Dermatomyositis - a Rare and Complex Comorbidity." Blood 138, Supplement 1 (November 5, 2021): 4174. http://dx.doi.org/10.1182/blood-2021-148878.
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Abstract Introduction and Case Presentation - A 4 yrs old female with sickle cell disease (SCD) and intermittent asthma presented with polyarthralgia predominantly involving bilateral hip and knee joints and became non-ambulatory over a course of 2 months. She developed chronic facial swelling, and a pruritic erythematous rash involving face, extensor surface of the hand and the right knee with significant weight loss. Physical examination was significant for heliotropic rash on the eyelids, Also present were Gottron's papules and macules on both hands and right knee along with right leg tenderness, muscle weakness, wasting and decreased range of motion at bilateral hip joints along with inguinal lymphadenopathy. Investigations were significant for severe anemia with hyperactive bone marrow, metabolic acidosis, normonatremic dehydration with absence of any evidence of an ongoing infectious process. Her Anti Nucleic acid antibody (ANA) panel, Aldolase, Rheumatoid factor and Angiotensin-1-Converting Enzyme levels were unremarkable. Creatine kinase levels were near normal. Her Neopterin and LDH levels were significantly elevated. Imaging with MRI scan with multiplanar multisequence of bilateral lower extremities and Pelvis showed significant diffuse myositis and soft tissue swelling. The diagnostic criterion for Juvenile Dermatomyositis include: (1) the typical pathognomonic rashes, (2) elevated muscle enzymes, (3) symmetric proximal muscle weakness and neck flexors, (4) muscle biopsy characteristic of juvenile dermatomyositis, and (5) EMG findings characteristic of juvenile dermatomyositis. Having ruled out an infectious process a muscle biopsy was performed, which also was subjected to Electron Microscopic (EM) analysis as the patient did not have extremely high muscle enzymes, necessitating a muscle biopsy . Hematoxylin & eosin stained sections were compatible with inflammatory myopathy. Ultrastructural examination demonstrated myofiber size variability, frequent rounded atrophic fibers with myofibrillar disarray, internalized nuclei, and increased interstitial collagen deposition. Endomysial capillaries were decreased in number, but showed reactive endothelial changes. Some showed prominent endothelial tubuloreticular inclusions (Figure),characteristic of JD. In summary, absence of serologic and tissue evidence of any other inflammatory myopathy, offending pharmacotherapy, infectious disease and presence of imaging and tissue evidence (vascular injury and tubuloreticular inclusions) comprised the work up of a child with SCD with Dermatomyositis. Management- Prompt treatment with prednisone (2 mg/kg/day), methotrexate (10 mg) weekly and monthly IVIG (2gm/kg/dose) infusions was started, once diagnosis was confirmed showing a dramatic clinical response. Prednisone was slowly tapered after 1 month of treatment. She showed gradual improvement in her symptoms, the strength in proximal muscle in both upper and lower limbs improved eventually to a point where the contractures in the elbows and knees improved and she started ambulating without support. Patient's Hydroxyurea was restarted at a low dose of 15mg/kg/day and increased to 20 mg/kg/day slowly, as her systemic symptoms of Dermatomyositis subsided. Discussion- Working up a child with SCD who presents with sudden onset non weight bearing can be complicated. Vaso-occlusive bony pain crisis , Osteomyelitis , septic arthritis are common clinical scenarios, but an underlying rheumatologic illness in pediatric SCD patient mimicking a sickle cell pain crisis presents a unique diagnostic challenge one which, albeit has been reported in literature, but rarely includes electron microscopic ultrastructural examination as part of evidence and work up. This patient's relatively mild muscle enzyme elevation and Hydroxyurea therapy made the initial diagnosis more challenging. We present the first pediatric SCD patient with clinically and pathologically proven case of Dermatomyositis with EM evidence, highlighting a unique clinical scenario ,diagnostic challenges and management strategies. Figure 1 Figure 1. Disclosures Jain: Octapharma: Consultancy; CSL Behring: Consultancy, Speakers Bureau; GBT: Consultancy; Blue Bird Bio: Consultancy; Takeda: Consultancy, Speakers Bureau.
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Wang, Y., K. Zhang, N. B. Wasala, D. Duan, and G. Yao. "Optical polarization tractography revealed significant fiber disarray in skeletal muscles of a mouse model for Duchenne muscular dystrophy." Biomedical Optics Express 6, no. 2 (January 7, 2015): 347. http://dx.doi.org/10.1364/boe.6.000347.
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Raghunathan, Suchi, Pratik Tank, Shraddha Bhadada, and Bhoomika Patel. "Evaluation of Buspirone on Streptozotocin Induced Type 1 Diabetes and Its Associated Complications." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/948427.
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We have evaluated the effect of buspirone (1.5 mg/kg/day, p.o.) type 1 diabetes induced cardiovascular complications induced by streptozotocin (STZ, 45 mg/kg, i.v.) in Wistar rats. Various biochemical, cardiovascular, and hemodynamic parameters were measured at the end of 8 weeks of treatment. STZ produced significant hyperglycaemia, hypoinsulinemia, and dyslipidemia, which was prevented by buspirone treatment. STZ produced increase in serum creatinine, urea, lactate dehydrogenase, creatinine kinase, and C-reactive protein levels and treatment with buspirone produced reduction in these levels. STZ produced increase in cardiac and LV hypertrophy index, LV/RV ratio, and LV collagen, which were decreased by buspirone treatment. Buspirone also prevented STZ induced hemodynamic alterations and oxidative stress. These results were further supported by histopathological studies in which buspirone showed marked reduction in fibrosis and cardiac fiber disarray. In conclusion, our data suggests that buspirone is beneficial as an antidiabetic agent in type 1 diabetes mellitus and also prevents its cardiac complications.
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Warmke, J., M. Yamakawa, J. Molloy, S. Falkenthal, and D. Maughan. "Myosin light chain-2 mutation affects flight, wing beat frequency, and indirect flight muscle contraction kinetics in Drosophila." Journal of Cell Biology 119, no. 6 (December 15, 1992): 1523–39. http://dx.doi.org/10.1083/jcb.119.6.1523.
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We have used a combination of classical genetic, molecular genetic, histological, biochemical, and biophysical techniques to identify and characterize a null mutation of the myosin light chain-2 (MLC-2) locus of Drosophila melanogaster. Mlc2E38 is a null mutation of the MLC-2 gene resulting from a nonsense mutation at the tenth codon position. Mlc2E38 confers dominant flightless behavior that is associated with reduced wing beat frequency. Mlc2E38 heterozygotes exhibit a 50% reduction of MLC-2 mRNA concentration in adult thoracic musculature, which results in a commensurate reduction of MLC-2 protein in the indirect flight muscles. Indirect flight muscle myofibrils from Mlc2E38 heterozygotes are aberrant, exhibiting myofilaments in disarray at the periphery. Calcium-activated Triton X-100-treated single fiber segments exhibit slower contraction kinetics than wild type. Introduction of a transformed copy of the wild type MLC-2 gene rescues the dominant flightless behavior of Mlc2E38 heterozygotes. Wing beat frequency and single fiber contraction kinetics of a representative rescued line are not significantly different from those of wild type. Together, these results indicate that wild type MLC-2 stoichiometry is required for normal indirect flight muscle assembly and function. Furthermore, these results suggest that the reduced wing beat frequency and possibly the flightless behavior conferred by Mlc2E38 is due in part to slower contraction kinetics of sarcomeric regions devoid or partly deficient in MLC-2.
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TANAKA, MASARU, HISAYOSHI FUJIWARA, TOMOYA ONODERA, DER-JINN WU, MITSUO MATSUDA, YOSHIHIRO HAMASHIMA, and CHUICHI KAWAI. "Pathogenetic role of myocardial fiber disarray in the progression of cardiac fibrosis in normal hearts, hypertensive hearts and hearts with hypertrophic cardiomyopathy." Japanese Circulation Journal 51, no. 6 (1987): 624–30. http://dx.doi.org/10.1253/jcj.51.624.
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Zhang, Qinghai, Xiao He, Shihao Yao, Tianxiang Lin, Luwen Zhang, Danni Chen, Chao Chen, et al. "Ablation of Mto1 in zebrafish exhibited hypertrophic cardiomyopathy manifested by mitochondrion RNA maturation deficiency." Nucleic Acids Research 49, no. 8 (April 9, 2021): 4689–704. http://dx.doi.org/10.1093/nar/gkab228.
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Abstract Deficient maturations of mitochondrial transcripts are linked to clinical abnormalities but their pathophysiology remains elusive. Previous investigations showed that pathogenic variants in MTO1 for the biosynthesis of τm5U of tRNAGlu, tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR) were associated with hypertrophic cardiomyopathy (HCM). Using mto1 knock-out(KO) zebrafish generated by CRISPR/Cas9 system, we demonstrated the pleiotropic effects of Mto1 deficiency on mitochondrial RNA maturations. The perturbed structure and stability of tRNAs caused by mto1 deletion were evidenced by conformation changes and sensitivity to S1-mediated digestion of tRNAGln, tRNALys, tRNATrp and tRNALeu(UUR). Notably, mto1KO zebrafish exhibited the global decreases in the aminoacylation of mitochondrial tRNAs with the taurine modification. Strikingly, ablated mto1 mediated the expression of MTPAP and caused the altered polyadenylation of cox1, cox3, and nd1 mRNAs. Immunoprecipitation assay indicated the interaction of MTO1 with MTPAP related to mRNA polyadenylation. These alterations impaired mitochondrial translation and reduced activities of oxidative phosphorylation complexes. These mitochondria dysfunctions caused heart development defects and hypertrophy of cardiomyocytes and myocardial fiber disarray in ventricles. These cardiac defects in the mto1KO zebrafish recapitulated the clinical phenotypes in HCM patients carrying the MTO1 mutation(s). Our findings highlighted the critical role of MTO1 in mitochondrial transcript maturation and their pathological consequences in hypertrophic cardiomyopathy.
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Takayama, Yoshihisa, Yumi Okazaki, Tadashi Aruga, and Kashiko Kodate. "Hologram multiplexing with distorted wavefront and disarrayed polarization by use of a fiber bundle in rotary movement." Optics Communications 242, no. 4-6 (December 2004): 411–15. http://dx.doi.org/10.1016/j.optcom.2004.09.015.
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Russell, Noirin E., Peter Holloway, Stephen Quinn, Michael Foley, Peter Kelehan, and Fionnuala M. McAuliffe. "Cardiomyopathy and Cardiomegaly in Stillborn Infants of Diabetic Mothers." Pediatric and Developmental Pathology 11, no. 1 (January 2008): 10–14. http://dx.doi.org/10.2350/07-05-0277.1.
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To report the incidence of cardiomegaly in stillborn normally formed infants of mothers with diabetes mellitus. This is a retrospective study with institutional ethics approval. The presence of cardiomegaly was recorded in stillborn infants of diabetic mothers ( N = 27) and compared with that recorded in stillborn large-for–gestational age (LGA > 90th percentile, n = 18) and stillborn appropriately grown (10th to 90th percentiles, n = 107) nondiabetic infants. Blinded to the clinical details, the histology slides were reviewed to measure cardiac wall thickness and to record the presence or absence of myocardial fiber disarray. Stillborn infants of mothers with diabetes mellitus, when compared with appropriately grown stillborn nondiabetic infants and when adjusted for birth weight, had heavier hearts, thicker ventricular free wall measurements, and lighter brains. While cardiomegaly was reported in 22% of stillborn LGA infants, comparison with stillborn appropriately grown infants revealed no difference in heart weights corrected for birth weight. Comparison of LGA nondiabetic infants with stillborn diabetes mellitus infants revealed greater actual heart weight/expected for birth weight ( P < 0.05) and lighter brains (actual brain weight/expected for birth weight, P < 0.05) in the diabetes mellitus group. Cardiomegaly is a common finding in stillborn infants of mothers with diabetes mellitus and may contribute to the risk of fetal death in these pregnancies.
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Valberg, Stephanie J., Sudeep Perumbakkam, Erica C. McKenzie, and Carrie J. Finno. "Proteome and transcriptome profiling of equine myofibrillar myopathy identifies diminished peroxiredoxin 6 and altered cysteine metabolic pathways." Physiological Genomics 50, no. 12 (December 1, 2018): 1036–50. http://dx.doi.org/10.1152/physiolgenomics.00044.2018.
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Equine myofibrillar myopathy (MFM) causes exertional muscle pain and is characterized by myofibrillar disarray and ectopic desmin aggregates of unknown origin. To investigate the pathophysiology of MFM, we compared resting and 3 h postexercise transcriptomes of gluteal muscle and the resting skeletal muscle proteome of MFM and control Arabian horses with RNA sequencing and isobaric tags for relative and absolute quantitation analyses. Three hours after exercise, 191 genes were identified as differentially expressed (DE) in MFM vs. control muscle with >1 log2 fold change (FC) in genes involved in sulfur compound/cysteine metabolism such as cystathionine-beta-synthase ( CBS, ↓4.51), a cysteine and neutral amino acid membrane transporter ( SLC7A10, ↓1.80 MFM), and a cationic transporter (SLC24A1, ↓1.11 MFM). In MFM vs. control at rest, 284 genes were DE with >1 log2 FC in pathways for structure morphogenesis, fiber organization, tissue development, and cell differentiation including > 1 log2 FC in cardiac alpha actin ( ACTC1 ↑2.5 MFM), cytoskeletal desmoplakin ( DSP ↑2.4 MFM), and basement membrane usherin ( USH2A ↓2.9 MFM). Proteome analysis revealed significantly lower antioxidant peroxiredoxin 6 content (PRDX6, ↓4.14 log2 FC MFM), higher fatty acid transport enzyme carnitine palmitoyl transferase (CPT1B, ↑3.49 MFM), and lower sarcomere protein tropomyosin (TPM2, ↓3.24 MFM) in MFM vs. control muscle at rest. We propose that in MFM horses, altered cysteine metabolism and a deficiency of cysteine-containing antioxidants combined with a high capacity to oxidize fatty acids and generate ROS during aerobic exercise causes chronic oxidation and aggregation of key proteins such as desmin.
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Benoist, David, Rachel Stones, Mark J. Drinkhill, Alan P. Benson, Zhaokang Yang, Cecile Cassan, Stephen H. Gilbert, et al. "Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 11 (June 1, 2012): H2381—H2395. http://dx.doi.org/10.1152/ajpheart.01084.2011.
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Pulmonary hypertension provokes right heart failure and arrhythmias. Better understanding of the mechanisms underlying these arrhythmias is needed to facilitate new therapeutic approaches for the hypertensive, failing right ventricle (RV). The aim of our study was to identify the mechanisms generating arrhythmias in a model of RV failure induced by pulmonary hypertension. Rats were injected with monocrotaline to induce either RV hypertrophy or failure or with saline (control). ECGs were measured in conscious, unrestrained animals by telemetry. In isolated hearts, electrical activity was measured by optical mapping and myofiber orientation by diffusion tensor-MRI. Sarcoplasmic reticular Ca2+ handling was studied in single myocytes. Compared with control animals, the T-wave of the ECG was prolonged and in three of seven heart failure animals, prominent T-wave alternans occurred. Discordant action potential (AP) alternans occurred in isolated failing hearts and Ca2+ transient alternans in failing myocytes. In failing hearts, AP duration and dispersion were increased; conduction velocity and AP restitution were steeper. The latter was intrinsic to failing single myocytes. Failing hearts had greater fiber angle disarray; this correlated with AP duration. Failing myocytes had reduced sarco(endo)plasmic reticular Ca2+-ATPase activity, increased sarcoplasmic reticular Ca2+-release fraction, and increased Ca2+ spark leak. In hypertrophied hearts and myocytes, dysfunctional adaptation had begun, but alternans did not develop. We conclude that increased electrical and structural heterogeneity and dysfunctional sarcoplasmic reticular Ca2+ handling increased the probability of alternans, a proarrhythmic predictor of sudden cardiac death. These mechanisms are potential therapeutic targets for the correction of arrhythmias in hypertensive, failing RVs.
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Ibrahim, D., and A. Gohara. "Unusual Death; Light Microscopy Solves The Mystery With An Archetypal Depiction Of An Unexpected Rare Cause." American Journal of Clinical Pathology 154, Supplement_1 (October 2020): S81. http://dx.doi.org/10.1093/ajcp/aqaa161.177.
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Abstract Casestudy: Hypertrophic cardiomyopathy is a heterogeneous disease with a number of phenotypes. We present the rarest phenotype, 1% of all cases, the midventricular obstructive type. It is characterized by hypertrophy in the mid portion of the left ventricle involving the papillary muscles, resulting in systolic intraluminal obstruction of the mid-ventricle. An unusual case of a 41-year-old male who died suddenly while hiking. He had no past medical history except for hyperlipidemia. He had no history of hypertension, with documented repeated normal blood pressures. No family history of cardiac problems, sudden death, or death at young age. On autopsy examination, his heart weighed 540 grams. The left ventricle was concentrically hypertrophied, 1.8 cm in thickness, with prominent papillary muscles and small lumen. The interventricular septum measured 1.8 cm in thickness, with increase sub-aortic wall thickness. Microscopic examination revealed myocyte hypertrophy with boxcar-like nuclear enlargement and interstitial fibrosis. There was myocardial fiber disarray. Intramural vessels showed dysplastic changes with medial thickening and narrowing of the lumen. Genetic cardiomyopathy panel testing on paraffin-embedded sections was negative; testing-on whole blood is preferred but body was embalmed before autopsy. The immediate cause of death was hypertrophic cardiomyopathy leading to pulmonary edema with potential complications as arrhythmias and low cardiac output. This case highlights the importance of light microscopy in the diagnostic process despite negative genetics. It also underscores the crucially of adopting better strategies to identify the disease since sudden death occurs frequently in those where diagnosis is missed during life.
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Yuan, Ma, Zhang, and Jing. "Transforming growth factor-beta signaling pathway in Marfans syndrome: a preliminary histopathological study." Vasa 40, no. 5 (September 1, 2011): 369–74. http://dx.doi.org/10.1024/0301-1526/a000133.
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Background: Marfans syndrome is an inherited disorder that affects the connective tissue. It has been proposed that mutations of FBN1 gene or of transforming growth factor (TGF)-beta type II receptor may be responsible for its pathogenesis. However, the role of TGF-beta signaling pathway in the development of Marfans syndrome has not been comprehensively investigated. Materials and methods: Surgical specimens of the aorta were obtained from two female Marfan patients, and the control aortic tissue was taken from an autopsy of a healthy individual. The aortic specimens were examined with hematoxylin-eosin, Massons trichrome, von Gieson/victoria blue-van Gieson bichrome, and immunohistochemical stainings of TGF-beta1, TGF-beta type I receptor, Smad2/3, Smad4 and Smad7. Results: Hematoxylin-eosin staining demonstrated severe elastic lamellar disruption and patchy vascular smooth muscle dissolution in the aortic media of the Marfan patients. Collagen deposition, interlamilar elastic fiber fragmentation, loss or proliferation, and acid mucopolysaccharide accumulation were observed in the disarrayed aortic wall structures of Marfan patients by Massons trichrome, victoria blue-van Gieson bichrome, and Alcian blue and periodic schiffs (AB-PAS) stainings, respectively. By immunohistochemistry, structural disruptions with enhanced TGF-beta;1 in the cytoplasm, Smad2/3 in the interstices, Smad4 in the cytoplasm, nuclei or interstices, and OOO Smad7, in the nucleus along with attenuated TGF-beta type I receptor in the aortic tissues of Marfan patients in comparison to the healthy control. Conclusions: Marfan patients may have aberrant TGF-beta signaling pathway associated with increased collagen deposition, interlamilar elastic fiber degenerative changes, and acid mucopolysaccharide accumulation. The signaling dysregulation may play an important role in the pathogenesis of this genetic disorder.
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Civitarese, Robert A., Ilana Talior-Volodarsky, Melissa Mitchell, Jean-François Desjardins, Golam Kabir, Donald Gullberg, Christopher A. McCulloch, and Kim A. Connelly. "Abstract 17939: Lack of the Alpha-11 Integrin in the Heart is Associated With Progressive Diastolic Dysfunction, Myofibrillar Disarray and Impaired Cardiomyocyte Growth." Circulation 130, suppl_2 (November 25, 2014). http://dx.doi.org/10.1161/circ.130.suppl_2.17939.
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BACKGROUND: Integrins, transmembrane receptors, play crucial roles in diverse cellular and developmental processes due to critical interactions with the extracellular matrix (ECM). During fetal development and towards adulthood, heart growth and function is suggested to depend on forming and remodeling the ECM and its connection to the myocyte. Currently however, the role of integrins in cardiovascular development (CVD) is poorly defined. Thus, we hypothesized that the α11 integrin (α11), which is expressed by fibroblasts and binds preferentially to type I collagen fibers, plays a vital role in CVD. METHODS: α11 KO and wildtype littermate mice (both n = 8) were examined at 4 weeks and 8 weeks of age. Animals underwent function assessments, including echocardiography and invasive pressure volume (PV) loop analysis, and structural examination via histological and electron microscopy (EM) analysis. RESULTS: At 4 weeks, heart weight (HW) and HW indexed to tibial length were decreased in α11 KO mice (P < 0.05), which were normalized at 8 weeks. Echocardiography revealed reduced end-diastolic area (EDA) at 4 weeks (P < 0.05). Despite normalization of EDA at 8 weeks, PV loop revealed impaired diastolic function as evidence by increased EDP, prolonged Tau and steeper EDPVR (all P < 0.05). No differences in HR or systolic parameters were evident. α11 KO mice also demonstrated structural changes. WGA staining revealed evidence of myofibrillar disarray. Connexin 43 and desmin staining showed increased Z-disk and intermediate filament clustering, respectively. LV myocyte size was also reduced (P < 0.05). Similarly, EM analysis showed reduced cardiomyocyte thickness and distance between end plates (both P < 0.05). CONCLUSION: Loss of α11 resulted in progressively worsening diastolic function that was associated with myofibrillar disarray and impaired cardiomyocyte growth. These findings suggest that α11 is required for the development of normal heart structure and function.
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Green, Eric M., Robert M. Weiss, Abhay Divekar, Sadie R. Bartholomew Ingle, Marcus Henze, Raja Kawas, Lindsey Gifford, et al. "Abstract 16: A Minipig Genetic Model of Hypertrophic Cardiomyopathy." Circulation Research 121, suppl_1 (July 21, 2017). http://dx.doi.org/10.1161/res.121.suppl_1.16.
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Introduction: Hypertrophic cardiomyopathy (HCM) is a heritable disease of heart muscle associated with increased risk of heart failure and sudden death. Mutations in genes encoding sarcomere proteins are commonly associated with HCM. However, the mechanisms by which these mutations lead to molecular, cellular and organ-level pathophysiology are uncertain, partly because of the lack of model systems amenable to integrated translational studies. Methods: Using homologous recombination and somatic cell nuclear transfer, we generated Yucatan minipigs with a heterozygous knock-in of the R403Q mutation in MYH7 , a well-characterized human HCM mutation. We conducted deep phenotyping with biomechanical studies of myocardial tissue samples, circulating biomarker analysis, cardiac imaging and histologic and multi-omic analysis of LV biopsy samples. Results: We followed a cohort of 22 R403Q pigs and 6 WT herdmates. Juvenile animals (3 months) showed early signs of HCM with elevated serum troponin I, increased myocardial contractility in muscle fibers and hearts and interstitial fibrosis and myocyte disarray. At late adolescence (9 months), disarray and fibrosis had progressed, but contractility had normalized with some pigs progressing to systolic dysfunction. Across the cohort, end-diastolic pressure was increased with evidence of diastolic dysfunction and elevation in B-type natriuretic peptide. Transcriptomic analysis at both 3 and 9 months showed dysregulation of metabolic modules and an upregulation of pro-fibrotic pathways. By one year of age, 11 of 22 R403Q pigs had suffered sudden cardiac death, whereas all wildtype pigs survived. Conclusions: We have developed the first large-animal genetic model of HCM. Young pigs with the MYH7 R403Q mutation show functional and histologic features of the preclinical human phenotype, and late adolescent animals have signs of advanced disease with an increased rate of sudden cardiac death. These data suggest that our minipig model may yield insights throughout the natural history of HCM from preclinical to end-stage disease. This model will thus be invaluable for advancing understanding of HCM and for the development of novel therapeutics.
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Chen, Peng, Bo Yu, Zongzhe Li, Yanghui Chen, Yang Sun, and Dao Wen Wang. "COL5A1 Variants Cause Aortic Dissection by Activating TGF‐β‐Signaling Pathway." Journal of the American Heart Association 10, no. 11 (June 2021). http://dx.doi.org/10.1161/jaha.120.019276.
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Background Aortic dissection (AD) is one of the most life‐threatening cardiovascular diseases that exhibit high genetic heterogeneity. However, it is unclear whether variants within the COL5A1 gene can cause AD. Therefore, we intend to determine whether COL5A1 is a causative gene of AD. Methods and Results We performed targeted sequencing in 702 patients with unrelated sporadic AD and 163 matched healthy controls using a predesigned panel with 152 vessel matrix‐related genes. As a result, we identified that 11 variants in COL5A1 caused AD in 11 out of the 702 patients with AD. Furthermore, Col5a1 knockout ( Col5a1 +/− ) rats were generated through the CRISPR/Cas9 system. Although there was no spontaneous AD, electron microscopy revealed a fracture of elastic fibers and disarray of collagenous fibers in 6‐week‐old Col5a1 +/− rats, but not in WT rats (93.3% versus 0.0%, P <0.001). Three‐week‐old rats were used to induce the AD phenotype with β‐aminopropionitrile monofumarate for 4 weeks followed by angiotensin II for 72 hours. The β‐aminopropionitrile monofumarate and angiotensin II‐treated rat model confirmed that Col5a1 +/− rats had considerably higher AD incidence than WT rats. Subsequent mechanism analyses demonstrated that the transforming growth factor‐β‐signaling pathway was significantly activated in Col5a1 +/− rats. Conclusions Our findings, for the first time, revealed a relationship between variants in COL5A1 and AD via targeted sequencing in 1.57% patients with sporadic aortic dissection. The Col5a1 knockout rats exhibited AD after an intervention, indicating that COL5A1 is a causative gene of AD. Activation of the transforming growth factor‐β‐signaling pathway may be implicated in the pathogenesis of this kind of AD.
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Chen, Jiyuan, Callie Kwartler, Christina L. Papke, Andrew Peters, Lea-Jeanne Ringuette, Jiumei Cao, Shanzhi Wang, et al. "Abstract 458: Loss of Smooth Muscle α-actin in Mice Results in Thoracic Aortic Aneurysms via Increased Reactive Oxygen Species, Increased Nox4,and Increased Angiotensin II type 1 Receptor-Mediated Signaling." Arteriosclerosis, Thrombosis, and Vascular Biology 35, suppl_1 (May 2015). http://dx.doi.org/10.1161/atvb.35.suppl_1.458.
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Objective: ACTA2 mutations cause 10-14% of familial thoracic aortic aneurysms and dissections. Mice deficient in smooth muscle α-actin (Acta2-/-) develop root and ascending thoracic aortic enlargement associated with thickening of the aortic media and fragmentation and disarray of elastic fibers. We hypothesized that blocking AT1 activation would block the aortic pathology and prevent aortic enlargement in Acta2-/- mice. Methods and Results: Beginning at 4 weeks of age, Acta2-/- mice were treated with losartan or placebo (n≥10) for 6 months and echocardiograms were performed at baseline and every other month. The aortic root in Acta2-/- mice was found to undergo progressive dilatation. After 6 months of treatment, there was no difference in the diameter of the aortic root between wild-type (WT) mice and the losartan treated mice (p=0.44). Histologic analysis of Acta2-/- aortas demonstrated medial thickening and fragmentation of elastic fibers which was normalized by treatment with losartan. Gene expression of matrix metalloproteinase-2 and -9 (Mmp2, Mmp9), along with lumican and decorin, interleukin-6 (Il6) and phosphorylation of RelA (a subunit of nuclear factor κB, NF-κB) was increased in Acta2-/- aortas, and was corrected by treatment with losartan. NADPH oxidase 4 and AT1a mRNA was increased in Acta2-/- aortic smooth muscle cells (SMCs) and aortas. Increase of AT1a was blocked by lowering reactive oxygen species (ROS) with N-actetyl cysteine (NAC). Angiotensin II (AngII) dose response studies suggested Acta2-/- aortic SMCs had increased sensitivity to Ang II. Additionally, Acta2-/- SMCs had increased ROS compared to WT by flow cytometry (P<0.05). Increased ROS was also observed in aortic samples derived from Acta2-/- mice. Blocking ROS using NAC attenuated aneurysm formation by reducing the expression of Mmps and IL6 and reducing signaling through AT1 in Acta2-/- mice. Genetic deletion of AT1a attenuated ROS and expression of Mmps and IL6 levels in the Acta2-/-aortas but not to WT levels. Conclusions: Our results demonstrate that complete loss of α-SMA leads to aortic dilation and pathologic changes by increasing SMC ROS levels, thus increasing sensitivity to AngII, which results in NF-κB activation and increased expression of Mmps and IL6.
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Williams, Zoë J., Deborah Velez-Irizarry, Keri Gardner, and Stephanie J. Valberg. "Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy." BMC Genomics 22, no. 1 (June 11, 2021). http://dx.doi.org/10.1186/s12864-021-07758-0.
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Abstract Background Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy. Results We identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy. Conclusions A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM.
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Phan, Noel M., Arick Park, Ting Zhou, David Scott, Qiwei Wang, Paul Tang, Daniel S. Greenspan, and Bo Liu. "Abstract 183: Collagen Type V (Col V) Contributes to the Development of Aortic Dissections and Aneurysms." Arteriosclerosis, Thrombosis, and Vascular Biology 36, suppl_1 (May 2016). http://dx.doi.org/10.1161/atvb.36.suppl_1.183.
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Background: Negative remodeling of extracellular matrix (ECM) is a key pathological feature associated with aortic dissections and aneurysms. Col V is a minor fibrillar collagen that incorporates into growing fibrils with Col I, and is involved in regulating the geometry and tensile strength of ECM. Col V normally exists as α 1 (V) 2 α 2 (V) 1 heterotrimers but may present as α 1 (V) 3 homotrimers in pathological tissues. To experimentally increase the existence of α 1 (V) 3 homotrimer, we deleted the Col5a2 gene, which encodes the α2(V) chain. Col5a2 +/- mice showed increased compliance and reduced tensile strength in the skin and aorta. In the present study, we tested whether Col5a2 deficiency affects the pathogenesis of aortic dissections and aneurysms. Methods and Results: Six-month-old male Col5a2 +/- and Col5a2 +/+ mice on an Ldlr null background were infused with Angiontensin II (AngII). Mortality for Col5 a2 +/- mice within the first 7 days was 45% vs 0% for WT ( P <0.045, n=9), with 60% due to aortic arch rupture and 40% due to dissection. Among those that survived the 28 day treatment, 7/ 7 Col5a2 +/ - mice developed abdominal aortic aneurysm, defined as greater than or equal to 50% increase in the maximal external suprarenal diameter over infrarenal aorta, whereas 5/9 WT showed aneurysm dilatation. Compared to WT, aneurysm dilatations were significantly increased in Col5a2 +/ - mice (132.1 ± 8.5% vs 90.12 ± 9.6%, P <0.017). Histological analyses revealed marked disarray and loss of elastic fibers in Col5a2 +/- aortas and no difference in levels of fragmentation. Moreover, medial layer integrity was deteriorated in Col5a2 +/- mice and was associated with increased infiltration of macrophages. Conclusions: Collectively, our data suggest that haploinsufficiency for the α2(V) chain leads to media layer changes and increased susceptibility to aortic arch ruptures, dissections, and larger aortic aneurysms. The α2(V) chain may thus represent a novel candidate marker/target for the identification and treatment of aortic dissection and aneurysm.
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Geng, Yong-Jian, Dongchun Guo, Dianna M. Milewicz, L. Maximillian Buja, Jinjie Wang, and Shuping Ge. "Abstract 2677: Reduction In Tie-2+/flk-1+ Vascular Stem Cells In Thoracic Aortic Aneurysm With Dissections: A Novel Contributor To Acellular Lesion Development." Circulation 116, suppl_16 (October 16, 2007). http://dx.doi.org/10.1161/circ.116.suppl_16.ii_593-c.
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Background. Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) are a life-threatening disease triggered by a complex interactions between environmental and genetic factors. Pathologically, this disease is characterized by a progressive loss of vascular smooth muscle cells (SMCs) and extracellular elastic fibers in the aortic media. Apoptosis, a form of programmed cell death, has been shown to contribute to the loss of medial SMCs. However, little is known about the role of vascular progenitor or stem cells in the pathogenesis of aortic aneurysms. Methods and Results. In this study we examined expression of Tie-2 (receptor for angiopoietin) and Flk-1 (receptor for vascular endothelial cell growth factor), two receptors critical for regulation of vascular stem cell survival and growth in the aortic lesions of patients with TAAD. Immunohistochemistry with specific antibodies against Tie-2 and Flk-1 showed a marked reduction in the numbers of Tie+/Flk+ cells in TAAD when compared to control aortas. There was also a change in the distribution pattern of vascular progenitor cells positive for both Tie-2 and Flk-1 in TAAD patients’ aortic tissues. Compared to normal control aortas, the Tie-2 and Flk-1 immunostained cells were much lower in intensity and scattered. In the regions with paucity of Tie-2+/Flk-1+ cells, there was an increased number of apoptotic cells as determined by in situ DNA end-labeling (TUNEL). Many of the Tie-2 and Flk-1 positive cells in TAAD showed poor morphology with nuclear degeneration and cytoplasmic fragmentation and disarray. Conclusion . These results indicate a paucity of Tie-2+/Flk-1+ vascular stem cells in the aortic wall of patients with TAAD, implying that the stem cell capacity to regenerate SMCs is exhausted. Similar loss of stem cells is observed with Duchenne muscular dystrophy, where the regenerated capacity is significantly compromised. Stem cells loss may similarly impair the capacity of SMCs in aortic tissue in repair and regeneration, and ultimately lead to TAAD formation.
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Riehle, Christian, Benjamin Wayment, Karla M. Pires, Annie B. Moreira, Heather Theobald, Xiaocheng Dong, Morris F. White, Sheldon E. Litwin, and E. Dale Abel. "Abstract 3559: Insulin Receptor Substrates (IRS) Signaling are Essential Regulators of Mitochondrial Function and Cardiomyocyte Survival." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_444-b.
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It has recently been reported that impaired PI3K signaling leads to cardiac mitochondrial dysfunction and that cardiac insulin receptor deficiency impairs cardiac growth. Signaling from insulin and insulin-like growth factor 1 receptors to PI3K is mediated by insulin receptor substrates (IRS) 1 and 2. Our objective was to determine the contribution of IRS isoforms on cardiac structure, mitochondrial and contractile function. For this purpose we generated mice with cardiomyocyte-specific deletion of IRS1 (CIRS1KO) or IRS2 (CIRS2KO) or IRS1 + IRS2 (CIRS12KO). While the single KOs had normal survival, CIRS12KO mice died from heart failure within the first eleven weeks of life. At the age of 8 weeks, heart weight-to-tibia length ratios, HW/TL were reduced by 11% (p<0.05) in CIRS1KO versus WT. ADP-stimulated mitochondrial oxygen consumption (V-ADP) was decreased by 22% (p<0.05) and ATP synthesis by 16% (p<0.05) in saponin-permeabilized cardiac fibers using pyruvate as substrate but not with palmitoyl carnitine (PC) or glutamate. In contrast, HW/TL was unchanged in CIRS2KO at the age of 8 weeks and was increased at the age of 14 weeks (+7%, p<0.05). Similarly, ADP-stimulated respirations were reduced in CIRS2KO at both ages by −21% and −16% respectively, (p < 0.05) only with pyruvate as substrate. In contrast, CIRS12KO developed dilated cardiomyopathy at the age of 4 weeks (LVDs + 18.9%, LVPWd −12.7%, LVPWs −21.4%, FS −36.7%, EF −26.3%, p<0.05). Histology revealed myofibrillar loss and disarray and increased fibrosis. Using stereology, cardiomyocyte nuclei per area was reduced by 27% and cardiomyocyte cross-sectional area was increased by 33% (both, p<0.05). Using pyruvate, PC or glutamate as substrates, V-ADP and ATP-synthesis rates were reduced by 33– 41%. Transcriptional analysis revealed a coordinate downregulation (by 40 – 60%) of PDK4 and PDH subunits, FAO and OXPHOS genes that were associated with a 35% reduction in expression of PGC-1β. At the protein level, expression of the complex II subunit, succinate-ubiquinol oxidoreductase was reduced by −51% (p<0.01). These data identify a critical role for IRS-mediated signaling in the regulation mitochondrial gene and protein expression, mitochondrial function and cardiomyocyte survival.
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Bowman, Marion Hofmann, Jeannine Wilk, Gene Kim, Yanmin Zhang, Jalees Rehman, and Elizabeth McNally. "Abstract 424: Vascular Smooth Muscle Cell Expression of S100a12 in Vivo Induces Enhanced Oxidative Stress & Vascular Remodeling." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_302-d.
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S100A12 is a small calcium binding protein that is a signal transduction ligand of the receptor for advance glycation endproducts (RAGE). S100A12, like RAGE, is expressed in the vessel wall of atherosclerotic vasculature, particularly in smooth muscle cells (SMC). While RAGE has been extensively implicated in inflammatory states such as atherosclerosis, the role of S100A12 is less clear. We tested the hypothesis that expression of human S100A12 directly exacerbates vascular inflammation. Several lines of Bl6/J transgenic mice (tg) expressing human S100A12 in SMC under control of the SM22a promoter were generated. Primary aortic SMC from tg and wild type (wt) littermates were isolated and analyzed for (i) proliferation using MTS/Formazan Assay and BrdU incorporation, (ii) oxidative stress using using flow cytometry with MitoSOX antibody, oxidative DNA damage using immunofluorescence microscopy with anti-8-oxo-dG antibody, and NF-kB activation measured by EMSA and (iii) cytokine expression measured by IL-6 ELISA. Furthermore, the aortas from tg and wt mice were examined. Results: Tg but not wt SMC expressed S100A12 protein. Tg SMC had a significant 1.9 to 2.7 fold increase in conversion of MTS into Formazan at 24–96 hours likely reflective of increased metabolic activity since BrdU incorporation into DNA was less in tg compared to wt SMC (4% vs 21% positive BrdU nuclei, p <0.05). Tg SMC showed significantly higher levels of mitochondrial generated ROS, nuclear staining for oxidative DNA damage which was not detected in the nuclei of wt SMC’s, and a 2.5 fold increase in NFkB activity. IL-6 production at baseline was higher in tg SMC’s (615 vs 213 pg/ml, p< 0.05) and increased dramatically after LPS treatment (10 ng/ml) in tg SMC’s (2130 vs 415 pg/ml). Histologic examination of the thoracic aorta at 10 weeks of age revealed increased collagen deposition in the aortic media with fragmentation and disarray of elastic fibers. In vivo ultrasound revealed a progressive dilation of the aortic arch from age 10 weeks to 16 weeks of age (1.27 to 1.60 mm, p<0.05) in tg but not in wt littermate mice (1.30 to 1.33 mm, p=0.1). These data reveal the novel finding that targeted expression of human S100A12 in SMC modulates oxidative stress, inflammation and vascular remodeling.
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Andrade, Ana Cláudia De Souza, Laisa Marina Rosa Rey, Isabela Carvalho dos Santos, Sarah Gabriella Delallo Charnovski, Diogo Czornobai, Lariane Souza Silva, Jéssica Crespi Sabadin, and Daniela Dib Gonçalves. "Cutaneous Asthenia in a Domestic Cat (Felis silvestris catus)." Acta Scientiae Veterinariae 49 (January 18, 2021). http://dx.doi.org/10.22456/1679-9216.110142.
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Background: Cutaneous asthenia or Ehlers-Danlos syndrome is an inherited and rare disease. This infirmity is from an autosomal mutation that influences the collagen synthesis of the carrier. Thus, its skeleton, formed of fibers, is structurally defective. The disease is characterized by hyperelasticity and skin fragility, leading to lesions throughout the skin. The lesions may manifest in specific places or in a generalized way, being more frequent in the limbs, neck, and back. This disease does not have a specific treatment, only management care to avoid new traumas.Case: A 3-year-old male castrated, no defined race cat, was attended at one veterinary clinic with a history of intense itching. The rapid tests for feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) were negative. On physical examination, infestation by fleas, lesions all over the body, and skin hyperelasticity were observed. Topical treatment for ectoparasites as well as for body wounds was established. After the treatment, he returned without itching, but with the complaints of new lesions that did not heal. The patient underwent a total shearing to facilitate the treatment of the skin, and then he underwent blood tests, biochemistry, hormonal tests, and ultrasound, which showed no suggestive changes for hyperadrenocorticism and diabetes mellitus. His clinical signs, besides not matching with these diseases, also did not indicate skin fragility due to his history of age and balanced diet. The confirmation of the cutaneous asthenia syndrome was acquired through biopsy of skin fragment, in which it was observed disarray of collagen fibers, hypertrophy, and fibroblast hyperplasia, together with the rate of extensibility of the skin where the value reached the mark of 27.5%. Throughout the hospitalization, it was noted the progression of the disease with the appearance of new lesions, where there was no bleeding and they appeared even with the patient wearing padded clothes. Its progression lasted one year until the patient's euthanasia.Discussion: For the disposal of diabetes mellitus and hyperadrenocorticism as causes of the appearance of lesions by the body in the patient, he was submitted to the suppression tests with dexamethasone, in which he presented normality, in the biochemical examination it was dosed with fructosamine and glucose. The fructosamine was in the reference value, but the glucose was slightly altered, this increase may have been a result of stress at the time of blood collection. In addition to the patient not showing specific clinical signs such as polyphagia, polyuria, polydipsia, and weight loss, these are characteristic clinical signs of the disease. For the diagnosis of Ehlers-Danlos syndrome, histological examination, and calculation of the skin extensibility index were used, where the results obtained confirmed the suspicion. This genetic anomaly has no treatment, being progressive, so only environmental management is done to mitigate the appearance of the lesions and provide animal welfare. This case report contributes to aggregating the scientific literature in the area of veterinary medicine since skin asthenia is a rare disease and when its extent is total it becomes even more atypical. The availability of this article will provide a vision of palliative treatment for other cases, demonstrating the progressive nature of the lesions and the methods of diagnosis. Keywords: cat, collagen deficiency, ehlers-danlos syndrome, hyperelastic, skin.
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Kovacheva, Ekaterina, Tobias Gerach, Steffen Schuler, Marco Ochs, Olaf Dössel, and Axel Loewe. "Causes of altered ventricular mechanics in hypertrophic cardiomyopathy: an in-silico study." BioMedical Engineering OnLine 20, no. 1 (July 22, 2021). http://dx.doi.org/10.1186/s12938-021-00900-9.
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Abstract Background Hypertrophic cardiomyopathy (HCM) is typically caused by mutations in sarcomeric genes leading to cardiomyocyte disarray, replacement fibrosis, impaired contractility, and elevated filling pressures. These varying tissue properties are associated with certain strain patterns that may allow to establish a diagnosis by means of non-invasive imaging without the necessity of harmful myocardial biopsies or contrast agent application. With a numerical study, we aim to answer: how the variability in each of these mechanisms contributes to altered mechanics of the left ventricle (LV) and if the deformation obtained in in-silico experiments is comparable to values reported from clinical measurements. Methods We conducted an in-silico sensitivity study on physiological and pathological mechanisms potentially underlying the clinical HCM phenotype. The deformation of the four-chamber heart models was simulated using a finite-element mechanical solver with a sliding boundary condition to mimic the tissue surrounding the heart. Furthermore, a closed-loop circulatory model delivered the pressure values acting on the endocardium. Deformation measures and mechanical behavior of the heart models were evaluated globally and regionally. Results Hypertrophy of the LV affected the course of strain, strain rate, and wall thickening—the root-mean-squared difference of the wall thickening between control (mean thickness 10 mm) and hypertrophic geometries (17 mm) was >10%. A reduction of active force development by 40% led to less overall deformation: maximal radial strain reduced from 26 to 21%. A fivefold increase in tissue stiffness caused a more homogeneous distribution of the strain values among 17 heart segments. Fiber disarray led to minor changes in the circumferential and radial strain. A combination of pathological mechanisms led to reduced and slower deformation of the LV and halved the longitudinal shortening of the LA. Conclusions This study uses a computer model to determine the changes in LV deformation caused by pathological mechanisms that are presumed to underlay HCM. This knowledge can complement imaging-derived information to obtain a more accurate diagnosis of HCM.
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Shati, Ayed A., Mohamed Samir A. Zaki, Youssef A. Alqahtani, Mohamed A. Haidara, Mohammed A. Alshehri, Amal F. Dawood, and Refaat A. Eid. "Intermittent Short-Duration Re-oxygenation Attenuates Cardiac Changes in Response to Hypoxia: Histological, Ultrastructural and Oxidant/Antioxidant Parameters." British Journal of Biomedical Science 79 (March 18, 2022). http://dx.doi.org/10.3389/bjbs.2022.10150.
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Context: Intermittent short-duration re-oxygenation attenuates cardiac changes in response to hypoxia.Objective: To see if intermittent short-duration re-oxygenation may protect the heart muscle from hypoxia damage.Materials and Methods: Eighteen albino rats were used to carry out the study. Rats divided into: (normoxia); rats exposed to room air as a control, second (hypoxic) group; rats subjected to a pressure of 405 mmHg in a hypobaric chamber to simulate hypoxia at 5,000 m, and third (intermittent short-duration re-oxygenation); rats exposed to room air three times per day. Experiments were all 14 days long.Results: Hypoxia enhanced the oxidative stress biomarker malondialdehyde while lowering the antioxidant superoxide dismutase . The levels of tumour necrosis factor (TNF-α) and interleukin-6 (IL-6) in the myocardium were elevated in hypoxic hearts. The hypoxic rats’ cardiac myofibrils showed disarray of muscle fibres, vacuolation of the sarcoplasm, pyknosis of the nucleus, and expansion of intercellular gaps on histological examination. In addition, cardiomyocytes showed degenerative defects in ventricular myocardial cells on ultrastructural analysis. Myofibril thinning and degenerative mitochondrial changes affected intercalated discs with fascia adherent, desmosomes, and gap junction. Intermittent short-duration re-oxygenation improve cardiac histological, ultrastructural and oxidant/antioxidant parameters changes during hypoxia.Conclusion: Hypoxia showed a substantial impact on myocardial architecture, as well as increased oxidative stress and pro-inflammatory cytokines. Intermittent short-duration re-oxygenation significantly decreases hypoxia-induced cardiac changes.
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Sonnenschein, Kristina, Adriana Luisa Wilczek, David de Gonzalo-Calvo, Angelika Pfanne, Anselm Arthur Derda, Carolin Zwadlo, Udo Bavendiek, Johann Bauersachs, Jan Fiedler, and Thomas Thum. "Serum circular RNAs act as blood-based biomarkers for hypertrophic obstructive cardiomyopathy." Scientific Reports 9, no. 1 (December 2019). http://dx.doi.org/10.1038/s41598-019-56617-2.
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AbstractHypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and is associated with a high risk of sudden cardiac death. HCM is characterized by pronounced hypertrophy of cardiomyocytes, fiber disarray and development of fibrosis and can be divided into a non-obstructive (HNCM) and obstructive form (HOCM) therefore requiring personalized therapeutic therapies. In the present study, we investigated the expression patterns of several circulating circular RNAs (circRNAs) as potential biomarkers in patients with HCM. We included 64 patients with HCM and 53 healthy controls to the study and quantitatively measured the expression of a set of circRNAs already known to be associated with cardiac diseases (circDNAJC6) and/or being highly abundant in blood (circTMEM56 and circMBOAT2). Abundancy of circRNAs was then correlated to relevant clinical parameters. Serum expression levels of circRNAs DNAJC6, TMEM56 and MBOAT2 were downregulated in patients with HCM. The inverse association between circRNA levels and HCM remained unchanged even after adjusting for confounding factors. All circRNAs, evaluated separately or in combination, showed a robust discrimination capacity when comparing control subjects with HCM, HNCM or HOCM patients (AUC from 0.722 to 0.949). Two circRNAs, circTMEM56 and circDNAJC6, significantly negatively correlated with echocardiographic parameters for HOCM. Collectively, circulating circRNAs DNAJC6, TMEM56 and MBOAT2 can distinguish between healthy and HCM patients. In addition, circTMEM56 and circDNAJC6 could serve as indicators of disease severity in patients with HOCM. Thus, circRNAs emerge as novel biomarkers for HCM facilitating the clinical decision making in a personalized manner.
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Lee, Hyoung-Gon, Brian D. Hoit, Anna Liner, Sandra Richardson, Qun Chen, Edward J. Lesnefsky, and Mark A. Smith. "Abstract 1587: Conditional Overexpression of the Oncogene c-Myc Produces Hypertrophic Cardiomyopathy and Results in Mitochondrial Dysfunction at Complex I." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_352-a.
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c-Myc is transiently expressed early during cardiac pressure overload, but its pathological role is unclear. To address the contribution of c-myc in the genesis of cardiomyopathy, we established a tetracycline-inducible, cardiomyocyte-specific, c-myc-overexpressing bitrans-genic mouse. Doxycyline treatment (DOX) for 2 weeks (Myc-ON, n=5) increased cardiac mass two-fold with myocyte disarray, and increased fiber width and fibrosis compared to control mice (Myc-OFF, n=8); LV fractional shortening (15MHz, Sequoia, Siemens) was less (0.28±0.03(SEM) vs.0.53±0.04) and myocardial performance index was greater (0.91±0.15 vs. 0.36±0.03, both p<0.05) indicating ventricular dysfunction in Myc-ON vs. Myc-OFF. Death resulted from irreversible heart failure. The cell cycle markers PCNA, Ki-67 and cyclin D1 were strongly induced and BrdU incorporation confirmed cell cycle progression to S-phase. To determine if mitochondrial dysfunction contributed to the cardiomyopathy of c-Myc-overexpression, oxidative phosphorylation (OXPHOS) was studied with glutamate/malate (complex I), succinate (complex II) and TMPD-ascorbate (complex IV) as substrates. OXPHOS decreased with glutamate/malate (213±40 vs.329±25 nAO/min/mg, p<0.05) after two weeks of Myc-ON (n=4) vs. control (n=4), but was unaltered with other substrates, localizing a defect to complex I of the electron transport chain. The complex I defect was confirmed by a decrease in NADH:decylubiquinone oxidoreductase activity (561±49 vs.752±38 mU/mg). PGC-1a (a major regulatory mechanism of mitochondrial proliferation) was increased in Myc-ON, and ultrastructural analysis revealed a 2.5-fold increase in mitochondrial number, possibly in response to the OXPHOS defect. Taken together, these findings suggest: cardiac restricted temporally-defined Myc overexpression turns on cell cycle machinery in cardiomyocytes and produces decompensated hypertrophic cardiomyopathy; and activation of c-Myc leads to an OXPHOS defect at complex I. Since complex I defects impair energy production and increase the production of reactive oxygen species, we speculate that mitochondrial dysfunction contributes to the cardiomyopathy that develops when adult cardiomyocytes overexpress c-Myc.
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Matt, Peter, Jennifer Habashi, Florian Schoenhoff, James Black, Martin Grapow, Friedrich Eckstein, Thierry Carrel, David Huso, Jennifer E. Van Eyk, and Harry C. Dietz. "Abstract 2607: TGF-beta 1 as a Diagnostic Biomarker for Acute Aortic Dissection Type A in a Mouse Model of Marfan Syndrome." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_752-a.
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Objectives: Acute aortic dissection type A is the main cause of mortality in patients with Marfan Syndrome (MFS). The aim of this study was to develop a procedure to surgically induce an acute aortic dissection type A in a mouse model of MFS, and to discover a diagnostic biomarker of the aortic lesion. Methods: Ten fibrillin-1 deficient (Fbn1C1039G/+) and ten wild-type (WT) mice at 8 months of age were intubated, ventilated and the aorta exposed via hemisternotomy. We hypothesized that an aortic dissection type A could be induced by performing an aortic clamp injury. Serum samples were collected before and after induction (30 min) of the aortic lesion from the right femoral vein. Total (acid activated) TGF-beta 1 concentrations were measured by ELISA. Echo measurements of the aortic root were obtained from a parasternal long axis view in all mice. Results: Transthoracic echocardiography of the aortic root performed prior to surgery showed significantly larger diameters in Fbn1C1039G/+ mice compared to WT (p<0.0001). Aortic clamp injury led in Fbn1C1039G/+ and WT mice to a reproducible aortic wall hematoma, and intimal tears. Hematoxylin-eosin stained histological sections revealed aortic dissection of the medial layer in Fbn1C1039G/+ mice but not in WT (p<0.001). Elastin-stained sections revealed a significantly higher elastic fiber fragmentation and disarray in Fbn1C1039G/+ aortas compared to WT (p<0.001). Aortic dissection in Fbn1C1039G/+ mice was limited to the ascending aorta. Mean TGF-beta 1 serum concentrations significantly increased after inducing the aortic lesion in Fbn1C1039G/+ mice (p=0.01; 130 ng/ml vs 412.9 ng/ml) but not in WT mice (p=0.2). Sham operated Fbn1C1039G/+ and WT mice showed no difference in TGF-beta 1 serum concentrations before and after surgery (p=0.7; n=4). Conclusions: We present a reproducible and in the short-term non-lethal mouse model of a surgically induced acute aortic dissection type A in MFS. TGF-beta 1 serum concentrations after inducing the aortic lesion significantly increased in Fbn1C1039G/+ mice but not in WT and Sham operated mice. TGF-beta 1 is a promising diagnostic biomarker for an acute aortic dissection type A in MFS.
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Nakaboh, Ayumi, Akiko Goda, Shinji Nakao, Katsumi Oka, Takeshi Tsujino, Masao Yuba, Misato Otsuka, et al. "Abstract 5734: Left Ventricular Torsion Reflects Degree of Myocardial Fibrosis in Hypertrophic Cardiomyopathy." Circulation 118, suppl_18 (October 28, 2008). http://dx.doi.org/10.1161/circ.118.suppl_18.s_992-a.
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Background : LV torsion (LVtor) is reduced in patients with impaired LV systolic function, e.g., dilated cardiomyophaty. It used to be thought that LVtor is reduced in patients with hypertrophic caridiomyopathy (HCM) because of the myocardial disarray; however, recent observation showed that LVtor assessed with tagged magnetic resonance imaging (MRI) even increased in patients with HCM. Recently LVtor is assessable with novel ultrasound speckle tracking imaging (STI) method. This technique may be used to assess intra-ventricular torsion in the LV muscle (intra-LVtor) that occurs due to the different fiber directions between the endocardium and epicardium. In this study, we analyzed LVtor and intra-LVtor in light of LV fibrosis in patients with HCM. Methods : MRI and echo studies were performed in 10 patients with HCM in whom any medication had not been given to HCM. MRI was used to determine LV mass index. In addition, %DEmass was determined as an MRI index of the extent of myocardial fibrosis by dividing the extent of late gadolinium enhancement by LV mass. We acquired basal and apical short-axis LV images with 2D echocardiography for off-line STI analysis to determine LVtor and intra-LVtor. We traced 18 points of the endcardium and epicardium, respectively, and averaged all regional rotation at the basal and apical plane, respectively. LVtor was defined as the difference of LV rotation between the basal and apical plane. Intra-LVtor was defined as the difference in the rotation between the endcardium and epicardium. Results : There was a significant correlation between %DEmass and LVtor(r=−0.72, p<0.05, indicating that LVtor is reduced in HCM patients with larger extent of LV myocardial fibrosis. There was no significant correlation between LVtor and LV mass index (r=−0.15, p=n.s.). %DEmass also correlated with intra-LVtor (r=−0.67, p<0.05, indicating that intra-LVtor is reduced in HCM patients with larger extent of LV myocardial fibrosis. Conclusions : Both LV torsion and intra-LV torsion are reduced in HCM patients with extended LV fibrosis. In other words, the extent of myocardial fibrosis may be assessed with LVtor and intra-LVtor by use of speckle tracking imaging in patients with HCM.