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Sarcomeric cardiomyopathy

Natalie Weber, Kristin Schwanke, Stephan Greten, Meike Wendland, Bogdan Iorga, Martin Fischer, Cornelia Geers-Knörr, Jan Hegermann, Christoph Wrede, Jan Fiedler, Henning Kempf, Annika Franke, Birgit Piep, Angelika Pfanne, Thomas Thum, Ulrich Martin, Bernhard Brenner, Robert Zweigerdt, Theresia Kraft
Human pluripotent stem cell (hPSC)-derived cardiomyocytes hold great potential for in vitro modeling of diseases like cardiomyopathies. Yet, knowledge about expression and functional impact of sarcomeric protein isoforms like the myosin heavy chain (MyHC) in hPSC-cardiomyocytes is scarce. We hypothesized that ventricular β-MyHC expression alters contraction and calcium kinetics and drives morphological and electrophysiological differentiation towards ventricular-like cardiomyocytes. To address this, we (1) generated human embryonic stem cell-derived cardiomyocytes (hESC-CMs) that switched towards exclusive β-MyHC, and (2) functionally and morphologically characterized these hESC-CMs at the single-cell level...
November 2016: Basic Research in Cardiology
Beatriz Piva E Mattos, Fernando Luís Scolari, Marco Antonio Rodrigues Torres, Laura Simon, Valéria Centeno de Freitas, Roberto Giugliani, Úrsula Matte
Background: Mutations in sarcomeric genes are found in 60-70% of individuals with familial forms of hypertrophic cardiomyopathy (HCM). However, this estimate refers to northern hemisphere populations. The molecular-genetic profile of HCM has been subject of few investigations in Brazil, particularly in the south of the country. Objective: To investigate mutations in the sarcomeric genes MYH7, MYBPC3 and TNNT2 in a cohort of HCM patients living in the extreme south of Brazil, and to evaluate genotype-phenotype associations...
September 2016: Arquivos Brasileiros de Cardiologia
Alexandra Pérez-Serra, Rocio Toro, Georgia Sarquella-Brugada, David de Gonzalo-Calvo, Sergi Cesar, Esther Carro, Vicenta Llorente-Cortes, Anna Iglesias, Josep Brugada, Ramon Brugada, Oscar Campuzano
Dilated cardiomyopathy is a rare cardiac disease characterized by left ventricular dilatation and systolic dysfunction leading to heart failure and sudden cardiac death. Currently, despite several conditions have been reported as aetiologies of the disease, a large number of cases remain classified as idiopathic. Recent studies determine that nearly 60% of cases are inherited, therefore due to a genetic cause. Progressive technological advances in genetic analysis have identified over 60 genes associated with this entity, being TTN the main gene, so far...
September 21, 2016: International Journal of Cardiology
Iman A Mohamed, Navaneethakrishnan T Krishnamoorthy, Gheyath K Nasrallah, Sahar Da'as
Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant genetic cardiovascular disorder marked by genetic and phenotypic heterogeneity. Mutations in the gene encodes the cardiac myosin-binding protein C, cMYBPC3 is amongst the various sarcomeric genes that are associated with HCM. These mutations produce mutated mRNAs and truncated cMyBP-C proteins. In this review, we will discuss the implications and molecular mechanisms involved in MYBPC3 different mutations. Further, we will highlight the novel targets that can be developed into potential therapeutics for the treatment of HMC...
October 12, 2016: Journal of Cellular Physiology
Mayra de A Marques, Guilherme A P de Oliveira
Inherited myopathies affect both skeletal and cardiac muscle and are commonly associated with genetic dysfunctions, leading to the production of anomalous proteins. In cardiomyopathies, mutations frequently occur in sarcomeric genes, but the cause-effect scenario between genetic alterations and pathological processes remains elusive. Hypertrophic cardiomyopathy (HCM) was the first cardiac disease associated with a genetic background. Since the discovery of the first mutation in the β-myosin heavy chain, more than 1400 new mutations in 11 sarcomeric genes have been reported, awarding HCM the title of the "disease of the sarcomere...
2016: Frontiers in Physiology
Adam S Helms, Francisco J Alvarado, Jaime Yob, Vi T Tang, Francis Pagani, Mark W Russell, Héctor H Valdivia, Sharlene M Day
BACKGROUND: -Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: -We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: -Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban (PLN), calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM compared to controls...
September 29, 2016: Circulation
Janelle Geist, Aikaterini Kontrogianni-Konstantopoulos
Myosin Binding Protein-C (MyBP-C) comprises a family of accessory proteins that includes the cardiac, slow skeletal, and fast skeletal isoforms. The three isoforms share structural and sequence homology, and localize at the C-zone of the sarcomeric A-band where they interact with thick and thin filaments to regulate the cycling of actomyosin crossbridges. The cardiac isoform, encoded by MYBPC3, has been extensively studied over the last several decades due to its high mutational rate in congenital hypertrophic and dilated cardiomyopathy...
2016: Frontiers in Physiology
Margaret V Westfall
Secondary shifts develop in post-translational phosphorylation of sarcomeric proteins in multiple animal models of inherited cardiomyopathy. These signaling alterations together with the primary mutation are predicted to contribute to the overall cardiac phenotype. As a result, identification and integration of post-translational myofilament signaling responses are identified as priorities for gaining insights into sarcomeric cardiomyopathies. However, significant questions remain about the nature and contribution of post-translational phosphorylation to structural remodeling and cardiac dysfunction in animal models and human patients...
2016: Frontiers in Physiology
Julius Bogomolovas, Jennifer R Fleming, Brian R Anderson, Rhys Williams, Stephan Lange, Bernd Simon, Muzamil M Khan, Rüdiger Rudolf, Barbara Franke, Belinda Bullard, Daniel J Rigden, Henk Granzier, Siegfried Labeit, Olga Mayans
Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level...
September 2016: Open Biology
Anna Kostareva, Artem Kiselev, Alexandra Gudkova, Goar Frishman, Andreas Ruepp, Dmitrij Frishman, Natalia Smolina, Svetlana Tarnovskaya, Daniel Nilsson, Anna Zlotina, Tatiana Khodyuchenko, Tatiana Vershinina, Tatiana Pervunina, Alexandra Klyushina, Andrey Kozlenok, Gunnar Sjoberg, Irina Golovljova, Thomas Sejersen, Eugeniy Shlyakhto
BACKGROUND: Cardiomyopathies represent a rare group of disorders often of genetic origin. While approximately 50% of genetic causes are known for other types of cardiomyopathies, the genetic spectrum of restrictive cardiomyopathy (RCM) is largely unknown. The aim of the present study was to identify the genetic background of idiopathic RCM and to compile the obtained genetic variants to the novel signalling pathways using in silico protein network analysis. PATIENTS AND METHODS: We used Illumina MiSeq setup to screen for 108 cardiomyopathy and arrhythmia-associated genes in 24 patients with idiopathic RCM...
2016: PloS One
Rahul C Deo
BACKGROUND: -Truncating mutations in the giant sarcomeric gene Titin are the most common type of genetic alteration in dilated cardiomyopathy (DCM). Detailed studies have amassed a wealth of information regarding truncating variant position in cases and controls. Nonetheless, considerable confusion exists as to how to interpret the pathogenicity of these variants, hindering our ability to make useful recommendations to patients. METHODS AND RESULTS: -Building on our recent discovery of a conserved internal promoter within the Titin gene, we sought to develop an integrative statistical model to explain the observed pattern of TTN truncation variants in DCM patients and population controls...
September 13, 2016: Circulation. Cardiovascular Genetics
Pranoti Hiremath, Patrick R Lawler, Jennifer E Ho, Andrew W Correia, Siddique A Abbasi, Raymond Y Kwong, Michael Jerosch-Herold, Carolyn Y Ho, Susan Cheng
BACKGROUND: The noninvasive assessment of altered myocardium in patients with genetic mutations that are associated with hypertrophic cardiomyopathy (HCM) remains challenging. In this pilot study, we evaluated whether a novel echocardiography-based assessment of myocardial microstructure, the signal intensity coefficient (SIC), could detect tissue-level alterations in HCM sarcomere mutation carriers with and without left ventricular hypertrophy. METHODS AND RESULTS: We studied 3 groups of genotyped individuals: sarcomere mutation carriers with left ventricular hypertrophy (clinical HCM; n=36), mutation carriers with normal left ventricular wall thickness (subclinical HCM; n=28), and healthy controls (n=10)...
September 2016: Circulation. Heart Failure
Andre Monteiro da Rocha, Guadalupe Guerrero-Serna, Adam Helms, Carly Luzod, Sergey Mironov, Mark Russell, José Jalife, Sharlene M Day, Gary D Smith, Todd J Herron
AIMS: Mutations of cardiac sarcomere genes have been identified to cause HCM, but the molecular mechanisms that lead to cardiomyocyte hypertrophy and risk for sudden death are uncertain. The aim of this study was to examine HCM disease mechanisms at play during cardiac differentiation of human HCM specific pluripotent stem cells. METHODS AND RESULTS: We generated a human embryonic stem cell (hESC) line carrying a naturally occurring mutation of MYPBC3 (c.2905 +1 G >A) to study HCM pathogenesis during cardiac differentiation...
September 9, 2016: Journal of Molecular and Cellular Cardiology
Gabriella Captur, James C Moon
No abstract text is available yet for this article.
September 7, 2016: Heart: Official Journal of the British Cardiac Society
Eyal Reinstein, Ana Gutierrez-Fernandez, Shay Tzur, Concetta Bormans, Shai Marcu, Einav Tayeb-Fligelman, Chana Vinkler, Annick Raas-Rothschild, Dana Irge, Meytal Landau, Mordechai Shohat, Xose S Puente, Doron M Behar, Carlos Lopez-Otın
In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene...
September 7, 2016: European Journal of Human Genetics: EJHG
Krzysztof Jaworski, Olga Możeńska, Dariusz A Kosior
Hypertrophic cardiomyopathy (HCM) is characterized by a primarily increased ventricular wall thickness, usually caused by the mutations in genes encoding sarcomere proteins. Thanks to the growing awareness in the medical community as well as advances in diagnostic techniques HCM can be diagnosed at earlier stages than ever before. However, in some cases the first symptom of this disease is a sudden cardiac death (SCD) and diagnosis remains unknown until post-mortem examination. Implantation of a cardioverterdefibrillator (ICD) provides the most effective method of SCD prevention...
August 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Carolyn Y Ho, Allison L Cirino, Neal K Lakdawala, John Groarke, Anne Marie Valente, Christopher Semsarian, Steven D Colan, E John Orav
OBJECTIVE: The early natural history of sarcomere mutations and the evolution to hypertrophic cardiomyopathy (HCM) are poorly characterised. To describe phenotypic progression, we compared mutation carriers who developed HCM to those who did not during prospective longitudinal investigation. METHODS: Sarcomere mutation carriers without baseline left ventricular hypertrophy (LVH) were studied during participation in a pilot clinical trial testing diltiazem versus placebo...
September 2, 2016: Heart: Official Journal of the British Cardiac Society
Krzysztof Jaworski, Olga Możeńska, Dariusz A Kosior
Hypertrophic cardiomyopathy (HCM) is characterized by a primarily increased ventricular wall thickness, usually caused by the mutations in genes encoding sarcomere proteins. Thanks to the growing awareness in the medical community as well as advances in diagnostic techniques HCM can be diagnosed at earlier stages than ever before. However, in some cases the first symptom of this disease is a sudden cardiac death (SCD) and diagnosis remains unknown until post-mortem examination. Implantation of a cardioverterdefibrillator (ICD) provides the most effective method of SCD prevention...
July 2016: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
Elham Kayvanpour, Farbod Sedaghat-Hamedani, Ali Amr, Alan Lai, Jan Haas, Daniel B Holzer, Karen S Frese, Andreas Keller, Katrin Jensen, Hugo A Katus, Benjamin Meder
AIMS: Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM. METHODS AND RESULTS: We retrieved PubMed/Medline literature on genotype-phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3...
August 30, 2016: Clinical Research in Cardiology: Official Journal of the German Cardiac Society
Nawel Jaafar, Juan Gómez, Ikram Kammoun, Ihsen Zairi, Wael Ben Amara, Salem Kachboura, Sondes Kraiem, Mohamed Hammami, Sara Iglesias, Belén Alonso, Eliecer Coto
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder associated with heart failure and sudden death. Mutations in the cardiac sarcomere genes are found in approximately half of HCM patients and are more common among cases with a family history of the disease. Data about the mutational spectrum of the sarcomeric genes in HCM patients from Northern Africa are limited. The population of Tunisia is particularly interesting due to its Berber genetic background...
August 30, 2016: Genetic Testing and Molecular Biomarkers
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