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HCM mutation carrier

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https://www.readbyqxmd.com/read/28624223/evaluation-of-mybpc3-trans-splicing-and-gene-replacement-as-therapeutic-options-in-human-ipsc-derived-cardiomyocytes
#1
Maksymilian Prondzynski, Elisabeth Krämer, Sandra D Laufer, Aya Shibamiya, Ole Pless, Frederik Flenner, Oliver J Müller, Julia Münch, Charles Redwood, Arne Hansen, Monica Patten, Thomas Eschenhagen, Giulia Mearini, Lucie Carrier
Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans-splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Here we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from an HCM patient carrying a heterozygous c.1358-1359insC MYBPC3 mutation and from a healthy donor. HCM hiPSC-CMs exhibited ∼50% lower MYBPC3 mRNA and cMyBP-C protein levels than control, no truncated cMyBP-C, larger cell size, and altered gene expression, thus reproducing human HCM features...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28538763/myosin-binding-protein-c-compound-heterozygous-variant-effect-on-the-phenotypic-expression-of-hypertrophic-cardiomyopathy
#2
Julianny Freitas Rafael, Fernando Eugênio Dos Santos Cruz, Antônio Carlos Campos de Carvalho, Ilan Gottlieb, José Guilherme Cazelli, Ana Paula Siciliano, Glauber Monteiro Dias
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disease caused by mutations in genes encoding sarcomere proteins. It is the major cause of sudden cardiac death in young high-level athletes. Studies have demonstrated a poorer prognosis when associated with specific mutations. The association between HCM genotype and phenotype has been the subject of several studies since the discovery of the genetic nature of the disease. This study shows the effect of a MYBPC3 compound variant on the phenotypic HCM expression...
April 2017: Arquivos Brasileiros de Cardiologia
https://www.readbyqxmd.com/read/28454798/the-design-of-the-valsartan-for-attenuating-disease-evolution-in-early-sarcomeric-hypertrophic-cardiomyopathy-vanish-trial
#3
Carolyn Y Ho, John J V McMurray, Allison L Cirino, Steven D Colan, Sharlene M Day, Akshay S Desai, Steven E Lipshultz, Calum A MacRae, Ling Shi, Scott D Solomon, E John Orav, Eugene Braunwald
Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease...
May 2017: American Heart Journal
https://www.readbyqxmd.com/read/28408782/assessment-of-regional-left-ventricular-systolic-function-by-strain-imaging-echocardiography-in-phenotypically-normal-and-abnormal-maine-coon-cats-tested-for-the-a31p-mutation-in-the-mybpc3-gene
#4
Arine Pellegrino, Alexandre G T Daniel, Guilherme G Pereira, Paula H Itikawa, Maria Helena M A Larsson
Myocardial dysfunction occurs in cats with hypertrophic cardiomyopathy (HCM), but little is known about the early stages of the disease. Strain imaging echocardiography is a method that enables the quantitative assessment of myocardial function and deformity, allowing the characterization of systolic dysfunction. The objective of this study was to assess systolic function using strain imaging echocardiography in Maine coon cats genetically tested for the A31P mutation in the MYBPC3 gene, with and without ventricular hypertrophy...
April 2017: Canadian Journal of Veterinary Research, Revue Canadienne de Recherche Vétérinaire
https://www.readbyqxmd.com/read/28393127/novel-junctophilin-2-mutation-a405s-is-associated-with-basal-septal-hypertrophy-and-diastolic-dysfunction
#5
Ann P Quick, Andrew P Landstrom, Qiongling Wang, David L Beavers, Julia O Reynolds, Giselle Barreto-Torres, Viet Tran, Jordan Showell, Leonne E Philippen, Shaine A Morris, Darlene Skapura, J Martijn Bos, Steen E Pedersen, Robia G Pautler, Michael J Ackerman, Xander H T Wehrens
BACKGROUND: Hypertrophic cardiomyopathy (HCM), defined as asymmetric left ventricular hypertrophy, is a leading cause of cardiac death in the young. Perturbations in calcium (Ca(2+)) handling proteins have been implicated in the pathogenesis of HCM. JPH2-encoded junctophilin 2 is a major component of the junctional membrane complex, the subcellular microdomain involved in excitation-contraction coupling. We hypothesized that a novel JPH2 mutation identified in patients with HCM is causally linked to HCM, and alters intracellular Ca(2+) signaling in a pro-hypertrophic manner...
February 2017: JACC. Basic to Translational Science
https://www.readbyqxmd.com/read/28381408/rare-genetic-variants-in-gata-transcription-factors-in-patients-with-hypertrophic-cardiomyopathy
#6
Cristina Alonso-Montes, Julián Rodríguez-Reguero, María Martín, Juan Gómez, Eliecer Coto, Manuel Naves-Díaz, César Morís, Jorge B Cannata-Andía, Isabel Rodríguez
Hypertrophic cardiomyopathy (HCM) is a very heterogeneous disease. Although primarily caused by mutations in genes encoding sarcomeric proteins, other genes might explain that heterogeneity. Potential candidate genes are GATA transcription factors that regulate the expression of proteins associated with HCM. Exons of GATA2, GATA4, and GATA6 genes were sequenced in 212 patients with unrelated HCM previously analyzed for genes encoding the most frequently mutated sarcomeric proteins. Functional effects of variants were predicted by in silico analyses...
April 5, 2017: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
https://www.readbyqxmd.com/read/28323875/the-clinical-features-outcomes-and-genetic-characteristics-of-hypertrophic-cardiomyopathy-patients-with-severe-right-ventricular-hypertrophy
#7
Xiying Guo, Chaomei Fan, Lei Tian, Yanling Liu, Hongyue Wang, Shihua Zhao, Fujian Duan, Xiuling Zhang, Xing Zhao, Fengqi Wang, Hongguang Zhu, Aiqing Lin, Xia Wu, Yishi Li
INTRODUCTION: Severe right ventricular hypertrophy (SRVH) is a rare phenotype in hypertrophic cardiomyopathy (HCM) for which limited information is available. This study was undertaken to investigate the clinical, prognostic and genetic characteristics of HCM patients with SRVH. METHODS: HCM with SRVH was defined as HCM with a maximum right ventricular wall thickness ≥10 mm. Whole-genome sequencing (WGS) was performed in HCM patients with SRVH. Multivariate Cox proportional hazards regression models were used to identify risk factors for cardiac death and events in HCM with SRVH...
2017: PloS One
https://www.readbyqxmd.com/read/28255011/ranolazine-prevents-phenotype-development-in-a-mouse-model-of-hypertrophic-cardiomyopathy
#8
Raffaele Coppini, Luca Mazzoni, Cecilia Ferrantini, Francesca Gentile, Josè Manuel Pioner, Annunziatina Laurino, Lorenzo Santini, Valentina Bargelli, Matteo Rotellini, Gianluca Bartolucci, Claudia Crocini, Leonardo Sacconi, Chiara Tesi, Luiz Belardinelli, Jil Tardiff, Alessandro Mugelli, Iacopo Olivotto, Elisabetta Cerbai, Corrado Poggesi
BACKGROUND: Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na(+) current blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro. METHODS AND RESULTS: To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals...
March 2017: Circulation. Heart Failure
https://www.readbyqxmd.com/read/28241245/the-burden-of-early-phenotypes-and-the-influence-of-wall-thickness-in-hypertrophic-cardiomyopathy-mutation-carriers-findings-from-the-hcmnet-study
#9
Carolyn Y Ho, Sharlene M Day, Steven D Colan, Mark W Russell, Jeffrey A Towbin, Mark V Sherrid, Charles E Canter, John L Jefferies, Anne M Murphy, Allison L Cirino, Theodore P Abraham, Matthew Taylor, Luisa Mestroni, David A Bluemke, Petr Jarolim, Ling Shi, Lynn A Sleeper, Christine E Seidman, E John Orav
Importance: Sarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression. Objectives: (1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers...
April 1, 2017: JAMA Cardiology
https://www.readbyqxmd.com/read/28214152/clinical-and-genetic-diagnosis-of-familial-hypertrophic-cardiomyopathy-results-in-pediatric-cardiology
#10
Bárbara Cardoso, Inês Gomes, Petra Loureiro, Conceição Trigo, Fátima Ferreira Pinto
INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is most often of autosomal dominant inheritance with incomplete penetrance and variable expression. The main purpose of family screening is to identify relatives with unrecognized HCM and to monitor those at risk for disease, in order to minimize complications and to assess risk of sudden cardiac death. The ESC and ACCF/AHA guidelines on the diagnosis and management of HCM recommend the screening of child relatives from the age of 10-12 years...
March 2017: Portuguese Journal of Cardiology: An Official Journal of the Portuguese Society of Cardiology
https://www.readbyqxmd.com/read/28090637/diltiazem-prevents-stress-induced-contractile-deficits-in-cardiomyocytes-but-does-not-reverse-the-cardiomyopathy-phenotype-in-mybpc3-knock-in-mice
#11
Frederik Flenner, Birgit Geertz, Silke Reischmann-Düsener, Florian Weinberger, Thomas Eschenhagen, Lucie Carrier, Felix W Friedrich
KEY POINTS: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac illness and can lead to diastolic dysfunction, sudden cardiac death and heart failure. Treatment of HCM patients is empirical and current pharmacological treatments are unable to stop disease progression or reverse hypertrophy. In this study, we tested if the non-dihydropyridine Ca(2+) channel blocker diltiazem, which previously showed potential to stop disease progression, can improve the phenotype of a HCM mouse model (Mybpc3-targeted knock-in), which is based on a mutation commonly found in patients...
June 15, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28029522/a-novel-founder-mutation-in-mybpc3-phenotypic-comparison-with-the-most-prevalent-mybpc3-mutation-in-spain
#12
COMPARATIVE STUDY
María Sabater-Molina, Daniel Saura, Esperanza García-Molina Sáez, Josefa González-Carrillo, Luis Polo, Inmaculada Pérez-Sánchez, María Del Carmen Olmo, María José Oliva-Sandoval, Roberto Barriales-Villa, Pablo Carbonell, Domigo Pascual-Figal, Juan R Gimeno
INTRODUCTION AND OBJECTIVES: Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A). METHODS: We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p...
February 2017: Revista Española de Cardiología
https://www.readbyqxmd.com/read/28013283/delayed-and-decreased-lv-untwist-and-unstrain-rate-in-mutation-carriers-for-hypertrophic-cardiomyopathy
#13
Floris Kauer, Bas M van Dalen, Michelle Michels, Arend F L Schinkel, Wim B Vletter, Marjon van Slegtenhorst, Osama I I Soliman, Marcel L Geleijnse
Background: The echocardiographic focus to detect abnormalities in genetically hypertrophic cardiomyopathy (HCM) affected subjects without left ventricular (LV) hypertrophy (G+/LVH-) has been on diastolic abnormalities in transmitral flow and longitudinal myocardial function with tissue Doppler imaging. The aim of this study was to assess diastolic LV unstrain and untwist. Methods and results: Forty-one consecutive genotyped family members of HCM patients (mean age 37 ± 11 years, 16 men) and 41 age- and gender-matched healthy volunteers underwent speckle-tracking echocardiography to measure untwist and unstrain...
April 1, 2017: European Heart Journal Cardiovascular Imaging
https://www.readbyqxmd.com/read/27994558/epigallocatechin-3-gallate-accelerates-relaxation-and-ca-2-transient-decay-and-desensitizes-myofilaments-in-healthy-and-mybpc3-targeted-knock-in-cardiomyopathic-mice
#14
Felix W Friedrich, Frederik Flenner, Mahtab Nasib, Thomas Eschenhagen, Lucie Carrier
Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disease with left ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction. Increased myofilament Ca(2+) sensitivity could be the underlying cause of diastolic dysfunction. Epigallocatechin-3-gallate (EGCg), a catechin found in green tea, has been reported to decrease myofilament Ca(2+) sensitivity in HCM models with troponin mutations. However, whether this is also the case for HCM-associated thick filament mutations is not known...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27885498/prognostic-predictive-value-of-gene-mutations-in-japanese-patients-with-hypertrophic-cardiomyopathy
#15
Ayako Chida, Kei Inai, Hiroki Sato, Eriko Shimada, Tsutomu Nishizawa, Mitsuyo Shimada, Michiko Furutani, Yoshiyuki Furutani, Yoichi Kawamura, Masaya Sugimoto, Jun Ishihara, Masako Fujiwara, Takashi Soga, Masatoshi Kawana, Shinya Fuji, Shigeru Tateno, Kenji Kuraishi, Shigetoyo Kogaki, Mitsuhiro Nishimura, Mamoru Ayusawa, Fukiko Ichida, Hirokuni Yamazawa, Rumiko Matsuoka, Shigeaki Nonoyama, Toshio Nakanishi
Although some studies have attempted to find useful prognostic factors in hypertrophic cardiomyopathy (HCM), those results are not fully helpful for use in actual clinical practice. Furthermore, several genetic abnormalities associated with HCM have been identified. However, the genotype-phenotype correlation in HCM remains to be elucidated. Here, we attempted to assess patients with different types of gene mutations causing HCM and investigate the prognosis. A total of 140 patients with HCM underwent a screening test for myofilament gene mutations by direct sequencing of eight sarcomeric genes...
June 2017: Heart and Vessels
https://www.readbyqxmd.com/read/27623770/ultrasonic-assessment-of-myocardial-microstructure-in-hypertrophic-cardiomyopathy-sarcomere-mutation-carriers-with-and-without-left-ventricular-hypertrophy
#16
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
https://www.readbyqxmd.com/read/27590665/evolution-of-hypertrophic-cardiomyopathy-in-sarcomere-mutation-carriers
#17
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
https://www.readbyqxmd.com/read/27574918/spectrum-of-mutations-in-hypertrophic-cardiomyopathy-genes-among-tunisian-patients
#18
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 cardiac genetic 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...
November 2016: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/27373729/a-long-term-follow-up-study-of-carriers-of-hypertrophic-cardiomyopathy-mutations
#19
Don R McTaggart, Kathryn J Ogden, Jessica A Marathe
BACKGROUND: Adults who test positive for a mutation associated with the development of hypertrophic cardiomyopathy (HCM) but who have not manifested left ventricular hypertrophy (LVH) at the time of that diagnosis are now commonly identified in the era of genetic testing. There are little published data, however, on the long-term outlook for these phenotypically normal gene carriers. METHODS: Fifteen genotype positive/LVH negative patients with HCM were identified, seven of which were children when first diagnosed as gene carriers...
January 2017: Heart, Lung & Circulation
https://www.readbyqxmd.com/read/27348999/spectrum-of-mybpc3-gene-mutations-in-patients-with-hypertrophic-cardiomyopathy-reporting-two-novel-mutations-from-north-west-of-iran
#20
Leila Emrahi, Mehrnoush Toufan Tabrizi, Jalal Gharehsouran, Seyyed Mojtaba Mohaddes Ardebili, Mehrdad Asghari Estiar
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death (SCD) in children and young adults and is the most frequent genetically determined cardiovascular disease following autosomal dominant pattern of inheritance. A number of genes have been shown to be responsible for HCM including MYBPC3. Cmybc, the protein encoded by MYBPC3 is a sarcomeric thick filament protein that interacts with titin, myosin, and actin to control sarcomeric gathering. Mutations in the MYBPC3 gene have been found to be associated with a history of sudden cardiac death in HCM patients...
2016: Clinical Laboratory
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