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Sarcomeric cardiomyopathy

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https://www.readbyqxmd.com/read/29463717/sarcomeric-perturbations-of-myosin-motors-lead-to-dilated-cardiomyopathy-in-genetically-modified-myl2-mice
#1
Chen-Ching Yuan, Katarzyna Kazmierczak, Jingsheng Liang, Zhiqun Zhou, Sunil Yadav, Aldrin V Gomes, Thomas C Irving, Danuta Szczesna-Cordary
Dilated cardiomyopathy (DCM) is a devastating heart disease that affects about 1 million people in the United States, but the underlying mechanisms remain poorly understood. In this study, we aimed to determine the biomechanical and structural causes of DCM in transgenic mice carrying a novel mutation in the MYL2 gene, encoding the cardiac myosin regulatory light chain. Transgenic D94A (aspartic acid-to-alanine) mice were created and investigated by echocardiography and invasive hemodynamic and molecular structural and functional assessments...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29452157/hypertrophic-cardiomyopathy-mutation-r58q-in-the-myosin-regulatory-light-chain-perturbs-thick-filament-based-regulation-in-cardiac-muscle
#2
Thomas Kampourakis, Saraswathi Ponnam, Malcolm Irving
Hypertrophic cardiomyopathy (HCM) is frequently linked to mutations in the protein components of the myosin-containing thick filaments leading to contractile dysfunction and ultimately heart failure. However, the molecular structure-function relationships that underlie these pathological effects remain largely obscure. Here we chose an example mutation (R58Q) in the myosin regulatory light chain (RLC) that is associated with a severe HCM phenotype and combined the results from a wide range of in vitro and in situ structural and functional studies on isolated protein components, myofibrils and ventricular trabeculae to create an extensive map of structure-function relationships...
February 13, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29451820/the-hcm-linked-w792r-mutation-in-cardiac-myosin-binding-protein-c-reduces-c6-fniii-domain-stability
#3
Dan F Smelter, Willem J De Lange, Wenxuan Cai, Ying Ge, John C Ralphe
Cardiac myosin binding protein-C (cMyBP-C) is a functional sarcomeric protein that regulates contractility in response to contractile demand, and many mutations in cMyBP-C lead to hypertrophic cardiomyopathy (HCM). To gain insight into the effects of disease-causing cMyBP-C missense mutations on contractile function, we expressed the pathogenic W792R mutation in mouse cardiomyocytes lacking endogenous cMyBP-C and studied the functional effects using three-dimensional engineered cardiac tissue (mECT) constructs...
February 16, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29451818/overexpression-of-heart-specific-small-subunit-of-myosin-light-chain-phosphatase-results-in-heart-failure-and-conduction-disturbance
#4
Takuro Arimura, Antoine Muchir, Masayoshi Kuwahara, Sachio Morimoto, Taisuke Ishikawa, Cheng-Kun Du, Dong-Yun Zhan, Shu Nakao, Noboru Machida, Ryo Tanaka, Yoshihisa Yamane, Takeharu Hayashi, Akinori Kimura
Mutations in genes encoding components of sarcomere cause cardiomyopathy, which is often associated with abnormal Ca 2+ sensitivity of muscle contraction. We previously showed that a heart-specific myosin light chain phosphatase small subunit, hHS-M 21 , increases the Ca 2+ -sensitivity of muscle contraction. The aim of this study was to investigate the function of hHS-M 21 in vivo and the causative role of abnormal Ca 2+ sensitivity in cardiomyopathy. We generated transgenic (Tg) mice with cardiac-specific overexpression of hHS-M 21 ...
February 16, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29416706/troponin-through-the-looking-glass-emerging-roles-beyond-regulation-of-striated-muscle-contraction
#5
REVIEW
Jamie R Johnston, P Bryant Chase, Jose Renato Pinto
Troponin is a heterotrimeric Ca2+-binding protein that has a well-established role in regulating striated muscle contraction. However, mounting evidence points to novel cellular functions of troponin, with profound implications in cancer, cardiomyopathy pathogenesis and skeletal muscle aging. Here, we highlight the non-canonical roles and aberrant expression patterns of troponin beyond the sarcomeric milieu. Utilizing bioinformatics tools and online databases, we also provide pathway, subcellular localization, and protein-protein/DNA interaction analyses that support a role for troponin in multiple subcellular compartments...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29414430/surgical-pathology-of-subaortic-septal-myectomy-histology-skips-over-clinical-diagnosis
#6
João Abecasis, Rosa Gouveia, Mariana Castro, Maria João Andrade, Regina Ribeiras, Sância Ramos, Miguel Abecasis, Nuno Cardim, Victor Gil
BACKGROUND: Subaortic septal myectomy is usually performed to mitigate obstruction in patients with the obstructive form of hypertrophic cardiomyopathy (HCM) or in those with congenital subaortic stenosis. Moreover, it is combined with aortic valve replacement in patients with severe aortic valve stenosis (SAS) and asymmetrical septal hypertrophy causing concomitant left ventricular outflow tract obstruction. When both conditions coexist, it is conceptually difficult to identify a cardiomyopathy beyond an adaptive myocardial hypertrophy, strictly related to pressure overload...
January 3, 2018: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
https://www.readbyqxmd.com/read/29398688/late-gadolinium-enhancement-for-prediction-of-mutation-positive-hypertrophic-cardiomyopathy-on-the-basis-of-panel-wide-sequencing
#7
Ryota Teramoto, Noboru Fujino, Tetsuo Konno, Akihiro Nomura, Yoji Nagata, Toyonobu Tsuda, Hayato Tada, Kenji Sakata, Masakazu Yamagishi, Kenshi Hayashi, Masa-Aki Kawashiri
BACKGROUND: Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) revealed a substantial variation in the extent of myocardial scarring, a pathological hallmark of hypertrophic cardiomyopathy (HCM). However, few data exist regarding the relationship between the presence of gene mutations and the extent of LGE. Therefore, we aimed to investigate whether variations in the extent of LGE in HCM patients can be explained by the presence or absence of disease-causing mutations...
February 3, 2018: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/29397107/platelet-function-analyzer-100-and-brain-natriuretic-peptide-as-biomarkers-in-obstructive-hypertrophic-cardiomyopathy
#8
Joseph L Blackshear, Robert E Safford, Colleen S Thomas, J Martijn Bos, Michael J Ackerman, Jeffrey B Geske, Steve R Ommen, Brian P Shapiro, Gretchen S Johns
To test dual blood biomarkers compared with electrocardiogram (ECG) for hypertrophic cardiomyopathy (HC) screening, we performed 3 analyses and cut-point assessments. First, we measured platelet function analyzer (PFA)-100 (n = 99) and normalized B-type natriuretic peptide (BNP) or NT-proBNP (BNP/upper limit of normal [ULN], n = 92) in 64 patients with HC and 29 normal controls (NCs). Second, from the regression equation between PFA and gradient (r = 0.77), we derived estimated PFA in a population of 189 patients with functional class I HC in whom measured BNP/ULN and ECG were available, and calculated single and dual biomarker sensitivity and specificity compared with ECG...
December 25, 2017: American Journal of Cardiology
https://www.readbyqxmd.com/read/29382361/trypanosoma-cruzi-activates-mouse-cardiac-fibroblasts-in-vitro-leading-to-fibroblast-myofibroblast-transition-and-increase-in-expression-of-extracellular-matrix-proteins
#9
Laura Lacerda Coelho, Isabela Resende Pereira, Mirian Claudia de Souza Pereira, Liliane Mesquita, Joseli Lannes-Vieira, Daniel Adesse, Luciana Ribeiro Garzoni
BACKGROUND: Cardiac fibrosis is a consequence of chronic chagasic cardiomyopathy (CCC). In other cardiovascular diseases, the protagonist role of fibroblasts in cardiac fibrosis is well established. However, the role of cardiac fibroblasts (CFs) in fibrosis during the CCC is not clear. Here, our aim was to investigate the effect of Trypanosoma cruzi, the etiological agent of Chagas disease on CFs activation. METHODS: Cardiac fibroblasts were purified from primary cultures of mouse embryo cardiac cells...
January 30, 2018: Parasites & Vectors
https://www.readbyqxmd.com/read/29331499/hspb7-is-a-cardioprotective-chaperone-facilitating-sarcomeric-proteostasis
#10
Emily J Mercer, Yi-Fan Lin, Leona Cohen-Gould, Todd Evans
Small heat shock proteins are chaperones with variable mechanisms of action. The function of cardiac family member Hspb7 is unknown, despite being identified through GWAS as a potential cardiomyopathy risk gene. We discovered that zebrafish hspb7 mutants display mild focal cardiac fibrosis and sarcomeric abnormalities. Significant mortality was observed in adult hspb7 mutants subjected to exercise stress, demonstrating a genetic and environmental interaction that determines disease outcome. We identified large sarcomeric proteins FilaminC and Titin as Hspb7 binding partners in cardiac cells...
January 10, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29316444/force-generation-via-%C3%AE-cardiac-myosin-titin-and-%C3%AE-actinin-drives-cardiac-sarcomere-assembly-from-cell-matrix-adhesions
#11
Anant Chopra, Matthew L Kutys, Kehan Zhang, William J Polacheck, Calvin C Sheng, Rebeccah J Luu, Jeroen Eyckmans, J Travis Hinson, Jonathan G Seidman, Christine E Seidman, Christopher S Chen
Truncating mutations in the sarcomere protein titin cause dilated cardiomyopathy due to sarcomere insufficiency. However, it remains mechanistically unclear how these mutations decrease sarcomere content in cardiomyocytes. Utilizing human induced pluripotent stem cell-derived cardiomyocytes, CRISPR/Cas9, and live microscopy, we characterize the fundamental mechanisms of human cardiac sarcomere formation. We observe that sarcomerogenesis initiates at protocostameres, sites of cell-extracellular matrix adhesion, where nucleation and centripetal assembly of α-actinin-2-containing fibers provide a template for the fusion of Z-disk precursors, Z bodies, and subsequent striation...
January 8, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29284499/left-atrial-structure-and-function-in-hypertrophic-cardiomyopathy-sarcomere-mutation-carriers-with-and-without-left-ventricular-hypertrophy
#12
Hoshang Farhad, Sara B Seidelmann, Davis Vigneault, Siddique A Abbasi, Eunice Yang, Sharlene M Day, Steven D Colan, Mark W Russell, Jeffrey Towbin, Mark V Sherrid, Charles E Canter, Ling Shi, Michael Jerosch-Herold, David A Bluemke, Carolyn Ho, Tomas G Neilan
BACKGROUND: Impaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH). METHOD: Seventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15)...
December 28, 2017: Journal of Cardiovascular Magnetic Resonance
https://www.readbyqxmd.com/read/29275006/altered-myofilament-structure-and-function-in-dogs-with-duchenne-muscular-dystrophy-cardiomyopathy
#13
Younss Ait Mou, Alain Lacampagne, Thomas Irving, Valérie Scheuermann, Stéphane Blot, Bijan Ghaleh, Pieter P de Tombe, Olivier Cazorla
AIM: Duchenne Muscular Dystrophy (DMD) is associated with progressive depressed left ventricular (LV) function. However, DMD effects on myofilament structure and function are poorly understood. Golden Retriever Muscular Dystrophy (GRMD) is a dog model of DMD recapitulating the human form of DMD. OBJECTIVE: The objective of this study is to evaluate myofilament structure and function alterations in GRMD model with spontaneous cardiac failure. METHODS AND RESULTS: We have employed synchrotron X-rays diffraction to evaluate myofilament lattice spacing at various sarcomere lengths (SL) on permeabilized LV myocardium...
December 21, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29238064/role-of-titin-in-cardiomyopathy-from-dna-variants-to-patient-stratification
#14
REVIEW
James S Ware, Stuart A Cook
Dilated cardiomyopathy (DCM) affects approximately 1 in 250 individuals and is the leading indication for heart transplantation. DCM is often familial, and the most common genetic predisposition is a truncating variation in the giant sarcomeric protein, titin, which occurs in up to 15% of ambulant patients with DCM and 25% of end-stage or familial cases. In this article, we review the evidence for the role of titin truncation in the pathogenesis of DCM and our understanding of the molecular mechanisms and pathophysiological consequences of variation in the gene encoding titin (TTN)...
December 14, 2017: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/29230178/human-cardiac-31p-mr-spectroscopy-at-3-tesla-cannot-detect-failing-myocardial-energy-homeostasis-during-exercise
#15
Adrianus J Bakermans, Jason N Bazil, Aart J Nederveen, Gustav J Strijkers, S Matthijs Boekholdt, Daniel A Beard, Jeroen A L Jeneson
Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29228435/review-of-recent-advances-in-the-management-of-hypertrophic-cardiomyopathy
#16
Y Cao, P-Y Zhang
Hypertrophic cardiomyopathy (HCM) is a complex but common monogenic cardiovascular disorder characterized by unexplained non dilated left ventricular (LV) thickening in the absence of another cardiac or systemic disease. The condition is associated with sudden and unexpected death in young individuals including trained athletes. HCM represents a genetic disorder caused by mutations in genes encoding sarcomeric proteins of the cardiac myocyte. This review article discusses the genetics behind HCM, its clinical presentation, and diagnosis and the present-day pharmacological management of HCM...
November 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29217433/hypertrophic-cardiomyopathy-linked-mutation-in-troponin-t-causes-myofibrillar-disarray-and-pro-arrhythmic-action-potential-changes-in-human-ipsc-cardiomyocytes
#17
Lili Wang, Kyungsoo Kim, Shan Parikh, Adrian Gabriel Cadar, Kevin R Bersell, Huan He, Jose R Pinto, Dmytro O Kryshtal, Bjorn C Knollmann
BACKGROUND: Mutations in cardiac troponin T (TnT) are linked to increased risk of ventricular arrhythmia and sudden death despite causing little to no cardiac hypertrophy. Studies in mice suggest that the hypertrophic cardiomyopathy (HCM)-associated TnT-I79N mutation increases myofilament Ca sensitivity and is arrhythmogenic, but whether findings from mice translate to human cardiomyocyte electrophysiology is not known. OBJECTIVES: To study the effects of the TnT-I79N mutation in human cardiomyocytes...
December 4, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29206857/z-disc-protein-chapb-induces-cardiomyopathy-and-contractile-dysfunction-in-the-postnatal-heart
#18
Willemijn van Eldik, Brigit den Adel, Jantine Monshouwer-Kloots, Daniela Salvatori, Saskia Maas, Ingeborg van der Made, Esther E Creemers, Derk Frank, Norbert Frey, Nicky Boontje, Jolanda van der Velden, Paul Steendijk, Christine Mummery, Robert Passier, Abdelaziz Beqqali
AIMS: The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease...
2017: PloS One
https://www.readbyqxmd.com/read/29183906/cardiac-enriched-baf-chromatin-remodeling-complex-subunit-baf60c-regulates-gene-expression-programs-essential-for-heart-development-and-function
#19
Xin Sun, Swetansu K Hota, Yu-Qing Zhou, Stefanie Novak, Dario Miguel-Perez, Danos Christodoulou, Christine E Seidman, J G Seidman, Carol C Gregorio, R Mark Henkelman, Janet Rossant, Benoit G Bruneau
How chromatin-remodeling complexes modulate gene networks to control organ-specific properties is not well understood. For example, Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex, but its role in heart development is not fully understood. We found that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes resulted in postnatal dilated cardiomyopathy with impaired contractile function...
January 5, 2018: Biology Open
https://www.readbyqxmd.com/read/29177058/biomarkers-of-cardiovascular-stress-and-fibrosis-in-preclinical-hypertrophic-cardiomyopathy
#20
Jennifer E Ho, Ling Shi, Sharlene M Day, Steven D Colan, Mark W Russell, Jeffrey A Towbin, Mark V Sherrid, Charles E Canter, John Lynn Jefferies, Anne Murphy, Matthew Taylor, Luisa Mestroni, Allison L Cirino, Lynn A Sleeper, Peter Jarolim, Begoña Lopez, Arantxa Gonzalez, Javier Diez, E John Orav, Carolyn Y Ho
Objective: Sarcomeric gene mutation carriers without overt left ventricular hypertrophy (G+/LVH-) can harbour subclinical changes in cardiovascular structure and function that precede the development of hypertrophic cardiomyopathy (HCM). We sought to investigate if circulating biomarkers of cardiovascular stress and collagen metabolism among G+/LVH- individuals, measured at rest and following exercise provocation, yield further insights into the underlying biology of HCM. Methods: We studied 76 individuals with overt HCM, 50 G+/LVH- individuals and 41 genotype-negative related controls enrolled in a cross-sectional, multicentre observational study (HCMNet)...
2017: Open Heart
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