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Sarcomeric cardiomyopathy

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https://www.readbyqxmd.com/read/29228435/review-of-recent-advances-in-the-management-of-hypertrophic-cardiomyopathy
#1
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
#2
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
#3
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
#4
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...
November 28, 2017: Biology Open
https://www.readbyqxmd.com/read/29177058/biomarkers-of-cardiovascular-stress-and-fibrosis-in-preclinical-hypertrophic-cardiomyopathy
#5
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
https://www.readbyqxmd.com/read/29167554/phenotypic-expression-of-a-novel-desmin-gene-mutation-hypertrophic-cardiomyopathy-followed-by-systemic-myopathy
#6
Haruhito Harada, Takeharu Hayashi, Hirofumi Nishi, Ken Kusaba, Yoshinori Koga, Yasutoshi Koga, Ikuya Nonaka, Akinori Kimura
Hypertrophic cardiomyopathy is a heterogeneous disease caused by gene mutations. Most of the disease-causing mutations were found in the genes for sarcomeric proteins, but there are several cases carrying mutations in genes for extra-sarcomeric cytoskeletons. Desmin is a member of extra-sarcomeric cytoskeletons and plays an important role in muscle contraction. Mutations in the desmin gene cause various type of general myopathy and/or cardiomyopathy, known as desmin-related myopathies. We identified a novel desmin missense mutation, Thr219Pro, in the homozygous state in a patient, who first manifested with hypertrophic cardiomyopathy and later progressed to general myopathy...
November 22, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29150126/hypertrophic-cardiomyopathy
#7
REVIEW
Juan José Santos Mateo, María Sabater Molina, Juan Ramón Gimeno Blanes
Hypertrophic cardiomyopathy is the most common inherited cardiovascular disease. It is characterized by increased ventricular wall thickness and is highly complex due to its heterogeneous clinical presentation, several phenotypes, large number of associated causal mutations and broad spectrum of complications. It is caused by mutations in sarcomeric proteins, which are identified in up to 60% of cases of the disease. Clinical manifestations of Hypertrophic Cardiomyopathy include shortness of breath, chest pain, palpitations and syncope, which are related to the onset of diastolic dysfunction, left ventricular outflow tract obstruction, ischemia, atrial fibrillation and abnormal vascular responses...
November 14, 2017: Medicina Clínica
https://www.readbyqxmd.com/read/29131758/titin-gene-and-protein-functions-in-passive-and-active-muscle
#8
Wolfgang A Linke
The thin and thick filaments of muscle sarcomeres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platform, and provider of passive tension and elasticity in myocytes. This review summarizes recent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and cardiac myocytes. A main theme is the evolving role of titin as a modulator of contraction. Topics include strain-sensing via titin in the sarcomeric A-band as the basis for length-dependent activation, titin elastic recoil and refolding of titin domains as an energy source, and Ca2+-dependent stiffening of titin stretched during eccentric muscle contractions...
November 13, 2017: Annual Review of Physiology
https://www.readbyqxmd.com/read/29109008/the-pathogenic-gene-screening-in-a-chinese-familial-dilated-cardiomyopathy-pedigree-from-hubei
#9
Yongnan Lyu, Jingjing Chen, Hongxin Xu
Dilated cardiomyopathy arises from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. In this study, we report a Chinese family with two members affected by TTN. Blood samples were collected from all family members. Genomic DNA was isolated from blood, and all coding exons and adjacent intronic sequences of the TTN gene were examined for mutation analysis using polymerase chain reaction (PCR)-based sequencing...
November 3, 2017: Gene
https://www.readbyqxmd.com/read/29108014/allosteric-modulation-of-cardiac-myosin-dynamics-by-omecamtiv-mecarbil
#10
Shaima Hashem, Matteo Tiberti, Arianna Fornili
New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear...
November 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/29107503/abrogating-mitochondrial-dynamics-in-mouse-hearts-accelerates-mitochondrial-senescence
#11
Moshi Song, Antonietta Franco, Julie A Fleischer, Lihong Zhang, Gerald W Dorn
Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/Mfn2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/Mfn2/Drp1 cardiac triple-knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy...
October 21, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/29101517/intrinsic-myh7-expression-regulation-contributes-to-tissue-level-allelic-imbalance-in-hypertrophic-cardiomyopathy
#12
Judith Montag, Mandy Syring, Julia Rose, Anna-Lena Weber, Pia Ernstberger, Anne-Kathrin Mayer, Edgar Becker, Britta Keyser, Cristobal Dos Remedios, Andreas Perrot, Jolanda van der Velden, Antonio Francino, Francesco Navarro-Lopez, Carolyn Yung Ho, Bernhard Brenner, Theresia Kraft
HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue...
November 3, 2017: Journal of Muscle Research and Cell Motility
https://www.readbyqxmd.com/read/29093449/abnormal-contractility-in-human-heart-myofibrils-from-patients-with-dilated-cardiomyopathy-due-to-mutations-in-ttn-and-contractile-protein-genes
#13
Petr G Vikhorev, Natalia Smoktunowicz, Alex B Munster, O'Neal Copeland, Sawa Kostin, Cecile Montgiraud, Andrew E Messer, Mohammad R Toliat, Amy Li, Cristobal G Dos Remedios, Sean Lal, Cheavar A Blair, Kenneth S Campbell, Maya Guglin, Ralph Knoll, Steven B Marston
Dilated cardiomyopathy (DCM) is an important cause of heart failure. Single gene mutations in at least 50 genes have been proposed to account for 25-50% of DCM cases and up to 25% of inherited DCM has been attributed to truncating mutations in the sarcomeric structural protein titin (TTNtv). Whilst the primary molecular mechanism of some DCM-associated mutations in the contractile apparatus has been studied in vitro and in transgenic mice, the contractile defect in human heart muscle has not been studied. In this study we isolated cardiac myofibrils from 3 TTNtv mutants, and 3 with contractile protein mutations (TNNI3 K36Q, TNNC1 G159D and MYH7 E1426K) and measured their contractility and passive stiffness in comparison with donor heart muscle as a control...
November 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29091059/scanning-x-ray-diffraction-on-cardiac-tissue-automatized-data-analysis-and-processing
#14
Jan David Nicolas, Marten Bernhardt, Andrea Markus, Frauke Alves, Manfred Burghammer, Tim Salditt
A scanning X-ray diffraction study of cardiac tissue has been performed, covering the entire cross section of a mouse heart slice. To this end, moderate focusing by compound refractive lenses to micrometer spot size, continuous scanning, data acquisition by a fast single-photon-counting pixel detector, and fully automated analysis scripts have been combined. It was shown that a surprising amount of structural data can be harvested from such a scan, evaluating the local scattering intensity, interfilament spacing of the muscle tissue, the filament orientation, and the degree of anisotropy...
November 1, 2017: Journal of Synchrotron Radiation
https://www.readbyqxmd.com/read/29078393/hspb7-is-indispensable-for-heart-development-by-modulating-actin-filament-assembly
#15
Tongbin Wu, Yongxin Mu, Julius Bogomolovas, Xi Fang, Jennifer Veevers, Roberta B Nowak, Christopher T Pappas, Carol C Gregorio, Sylvia M Evans, Velia M Fowler, Ju Chen
Small heat shock protein HSPB7 is highly expressed in the heart. Several mutations within HSPB7 are associated with dilated cardiomyopathy and heart failure in human patients. However, the precise role of HSPB7 in the heart is still unclear. In this study, we generated global as well as cardiac-specific HSPB7 KO mouse models and found that loss of HSPB7 globally or specifically in cardiomyocytes resulted in embryonic lethality before embryonic day 12.5. Using biochemical and cell culture assays, we identified HSPB7 as an actin filament length regulator that repressed actin polymerization by binding to monomeric actin...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29021349/activation-of-autophagy-ameliorates-cardiomyopathy-in-mybpc3-targeted-knockin-mice
#16
Sonia R Singh, Antonia T L Zech, Birgit Geertz, Silke Reischmann-Düsener, Hanna Osinska, Maksymilian Prondzynski, Elisabeth Krämer, Qinghang Meng, Charles Redwood, Jolanda van der Velden, Jeffrey Robbins, Saskia Schlossarek, Lucie Carrier
BACKGROUND: Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome, or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cMyBP-C (cardiac myosin-binding protein C), is the most frequently mutated HCM gene. METHODS AND RESULTS: We evaluated autophagy in patients with HCM carrying MYBPC3 mutations and in a Mybpc3-targeted knockin HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in knockin mice...
October 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/29018006/%C3%AE-galactosidase-a-genotype-n215s-induces-a-specific-cardiac-variant-of-fabry-disease
#17
Daniel Oder, Dan Liu, Kai Hu, Nurcan Üçeyler, Tim Salinger, Jonas Müntze, Kristina Lorenz, Reinhard Kandolf, Hermann-Josef Gröne, Claudia Sommer, Georg Ertl, Christoph Wanner, Peter Nordbeck
BACKGROUND: Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific α-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement. METHODS AND RESULTS: All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14-74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c...
October 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/28986452/care-in-specialized-centers-and-data-sharing-increase-agreement-in-hypertrophic-cardiomyopathy-genetic-test-interpretation
#18
Aisha Furqan, Patricia Arscott, Francesca Girolami, Allison L Cirino, Michelle Michels, Sharlene M Day, Iacopo Olivotto, Carolyn Y Ho, Euan Ashley, Eric M Green, Colleen Caleshu
BACKGROUND: Clinically impactful differences in the interpretation of genetic test results occur between laboratories and clinicians. To improve the classification of variants, a better understanding of why discrepancies occur and how they can be reduced is needed. METHODS AND RESULTS: We examined the frequency, causes, and resolution of discordant variant classifications in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), a consortium of international centers with expertise in the clinical management and genetic architecture of hypertrophic cardiomyopathy...
October 2017: Circulation. Cardiovascular Genetics
https://www.readbyqxmd.com/read/28973951/molecular-mechanisms-and-structural-features-of-cardiomyopathy-causing-troponin-t-mutants-in-the-tropomyosin-overlap-region
#19
Binnu Gangadharan, Margaret S Sunitha, Souhrid Mukherjee, Ritu Roy Chowdhury, Farah Haque, Narendrakumar Sekar, Ramanathan Sowdhamini, James A Spudich, John A Mercer
Point mutations in genes encoding sarcomeric proteins are the leading cause of inherited primary cardiomyopathies. Among them are mutations in the TNNT2 gene that encodes cardiac troponin T (TnT). These mutations are clustered in the tropomyosin (Tm) binding region of TnT, TNT1 (residues 80-180). To understand the mechanistic changes caused by pathogenic mutations in the TNT1 region, six hypertrophic cardiomyopathy (HCM) and two dilated cardiomyopathy (DCM) mutants were studied by biochemical approaches. Binding assays in the absence and presence of actin revealed changes in the affinity of some, but not all, TnT mutants for Tm relative to WT TnT...
October 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28972856/cardiac-actin-changes-in-the-actomyosin-interface-have-different-effects-on-myosin-duty-ratio
#20
Haidun Liu, Mary Evelyn Henein, Maria Anillo, John F Dawson
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disease (CD) that commonly causes an increased size of cardiomyocytes in the left ventricle. The proteins myosin and actin interact in the myocardium to produce contraction through the actomyosin ATPase cycle. The duty ratio (<i>r</i>) of myosin is the proportion of the actomyosin ATPase cycle that myosin is bound to actin and does work. A common hypothesis is that HCM mutations increase contraction in cardiac sarcomeres; however, the available data is not clear on this connection...
October 3, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
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