keyword
https://read.qxmd.com/read/37830983/chronic-diastolic-stretch-unmasks-conduction-defects-in-an-in-vitro-model-of-arrhythmogenic-cardiomyopathy
#21
JOURNAL ARTICLE
Ronald Ng, Ilhan Gokhan, Paul Stankey, Fadi G Akar, Stuart G Campbell
We seek to elucidate the precise nature of mechanical loading that precipitates conduction deficits in a concealed-phase model of arrhythmogenic cardiomyopathy (ACM). ACM is a progressive disorder often resulting from mutations in desmosomal proteins. Exercise has been shown to worsen disease progression and unmask arrhythmia vulnerability, yet the underlying pathomechanisms may depend on the type and intensity of exercise. Because exercise causes myriad changes to multiple inter-dependent hemodynamic parameters, it is difficult to isolate its effects to specific changes in mechanical load...
October 13, 2023: American Journal of Physiology. Heart and Circulatory Physiology
https://read.qxmd.com/read/37771571/human-engineered-cardiac-tissue-model-of-hypertrophic-cardiomyopathy-recapitulates-key-hallmarks-of-the-disease-and-the-effect-of-chronic-mavacamten-treatment
#22
JOURNAL ARTICLE
Kai Wang, Brian J Schriver, Roozbeh Aschar-Sobbi, Alex Y Yi, Nicole T Feric, Michael P Graziano
Introduction: The development of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offers an opportunity to study genotype-phenotype correlation of hypertrophic cardiomyopathy (HCM), one of the most common inherited cardiac diseases. However, immaturity of the iPSC-CMs and the lack of a multicellular composition pose concerns over its faithfulness in disease modeling and its utility in developing mechanism-specific treatment. Methods: The Biowire platform was used to generate 3D engineered cardiac tissues (ECTs) using HCM patient-derived iPSC-CMs carrying a β-myosin mutation (MYH7-R403Q) and its isogenic control (WT), withal ECTs contained healthy human cardiac fibroblasts...
2023: Frontiers in Bioengineering and Biotechnology
https://read.qxmd.com/read/37651922/maturation-of-ipsc-derived-cardiomyocytes-in-a-heart-on-a-chip-device-enables-modeling-of-dilated-cardiomyopathy-caused-by-r222q-scn5a-mutation
#23
JOURNAL ARTICLE
Marianne Wauchop, Naimeh Rafatian, Yimu Zhao, Wenliang Chen, Mark Gagliardi, Stéphane Massé, Brian J Cox, Patrick Lai, Timothy Liang, Shira Landau, Stephanie Protze, Xiao Dong Gao, Erika Yan Wang, Kelvin Chan Tung, Zachary Laksman, Rick Xing Ze Lu, Gordon Keller, Kumaraswamy Nanthakumar, Milica Radisic, Peter H Backx
To better understand sodium channel (SCN5A)-related cardiomyopathies, we generated ventricular cardiomyocytes from induced pluripotent stem cells obtained from a dilated cardiomyopathy patient harbouring the R222Q mutation, which is only expressed in adult SCN5A isoforms. Because the adult SCN5A isoform was poorly expressed, without functional differences between R222Q and control in both embryoid bodies and cell sheet preparations (cultured for 29-35 days), we created heart-on-a-chip biowires which promote myocardial maturation...
October 2023: Biomaterials
https://read.qxmd.com/read/37643496/modelling-duchenne-muscular-dystrophy-in-vitro-with-newly-generated-blood-cell-derived-induced-pluripotent-stem-cell-line-orioni003-a
#24
JOURNAL ARTICLE
Dominika Hajduchova, Stanislava Suroviakova, Sandra Mersakova, Dusan Brany, Romana Zahumenska, Martin Rehak, Henrieta Skovierova, Slavomíra Nováková, Vladimir Nosal, Juraj Marcinek, Michal Kalman, Martin Jozef Pec, Mariana Brozmanova, Jana Melegova, Stefan Juhas, Jana Juhasova, Hana Studenovska, Barbora Mitruskova, Michal Pokusa, Marek Samec, Matej Samos, Andreas Nicodemou, Lubos Danisovic, Zuzana Dankova, Egon Kurca, Katarina Lexova Kolejakova, Jan Chandoga, Lukas Plank, Erika Halasova, Renata Pecova, Jan Strnadel
Here, we present newly derived in vitro model for modeling Duchenne muscular dystrophy. Our new cell line was derived by reprogramming of peripheral blood mononuclear cells (isolated from blood from pediatric patient) with Sendai virus encoding Yamanaka factors. Derived iPS cells are capable to differentiate in vitro into three germ layers as verified by immunocytochemistry. When differentiated in special medium, our iPSc formed spontaneously beating cardiomyocytes. As cardiomyopathy is the main clinical complication in patients with Duchenne muscular dystrophy, the cell line bearing the dystrophin gene mutation might be of interest to the research community...
August 22, 2023: Stem Cell Research
https://read.qxmd.com/read/37609237/heart-on-a-chip-model-of-immune-induced-cardiac-dysfunction-reveals-the-role-of-free-mitochondrial-dna-and-therapeutic-effects-of-endothelial-exosomes
#25
Rick Xing Ze Lu, Naimeh Rafatian, Yimu Zhao, Karl T Wagner, Erika L Beroncal, Bo Li, Carol Lee, Jingan Chen, Eryn Churcher, Daniel Vosoughi, Ying Wang, Andrew Baker, Uriel Trahtemberg, Bowen Li, Agostino Pierro, Ana C Andreazza, Claudia C Dos Santos, Milica Radisic
Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip system with circulating immune cells to model SARS-CoV-2-induced acute myocarditis...
August 9, 2023: bioRxiv
https://read.qxmd.com/read/37595583/spatiotemporal-cell-junction-assembly-in-human-ipsc-cm-models-of-arrhythmogenic-cardiomyopathy
#26
JOURNAL ARTICLE
Sean L Kim, Michael A Trembley, Keel Yong Lee, Suji Choi, Luke A MacQueen, John F Zimmerman, Lousanne H C de Wit, Kevin Shani, Douglas E Henze, Daniel J Drennan, Shaila A Saifee, Li Jun Loh, Xujie Liu, Kevin Kit Parker, William T Pu
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in Plakophilin-2 (PKP2), a desmosome component within specialized cardiac cell junctions, cause the majority of ACM cases. However, the molecular mechanisms by which PKP2 variants induce disease phenotypes remain unclear. Here we built bioengineered platforms using genetically modified human induced pluripotent stem cell-derived cardiomyocytes to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro...
August 5, 2023: Stem Cell Reports
https://read.qxmd.com/read/37585285/nuclear-damage-in-lmna-mutant-ipsc-derived-cardiomyocytes-is-associated-with-impaired-lamin-localization-to-the-nuclear-envelope
#27
JOURNAL ARTICLE
Melanie Wallace, Hind Zahr, Shriya Perati, Chloé D Morsink, Lindsey E Johnson, Anthony M Gacita, Shuping Lai, Lori L Wallrath, Ivor J Benjamin, Elizabeth M McNally, Tyler J Kirby, Jan Lammerding
The LMNA gene encodes the nuclear envelope proteins Lamins A and C, which comprise a major part of the nuclear lamina, provide mechanical support to the nucleus, and participate in diverse intracellular signaling. LMNA mutations give rise to a collection of diseases called laminopathies, including dilated cardiomyopathy ( LMNA -DCM) and muscular dystrophies. Although nuclear deformities are a hallmark of LMNA -DCM, the role of nuclear abnormalities in the pathogenesis of LMNA -DCM remains incompletely understood...
August 16, 2023: Molecular Biology of the Cell
https://read.qxmd.com/read/37582912/bpifb4-and-its-longevity-associated-haplotype-protect-from-cardiac-ischemia-in-humans-and-mice
#28
JOURNAL ARTICLE
Monica Cattaneo, Aneta Aleksova, Alberto Malovini, Elisa Avolio, Anita Thomas, Valeria Vincenza Alvino, Michael Kilcooley, Marie Pieronne-Deperrois, Antoine Ouvrard-Pascaud, Anna Maciag, Gaia Spinetti, Sophie Kussauer, Heiko Lemcke, Anna Skorska, Praveen Vasudevan, Stefania Castiglione, Angela Raucci, Robert David, Vincent Richard, Antonio Paolo Beltrami, Paolo Madeddu, Annibale Alessandro Puca
Long-living individuals (LLIs) escape age-related cardiovascular complications until the very last stage of life. Previous studies have shown that a Longevity-Associated Variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene correlates with an extraordinarily prolonged life span. Moreover, delivery of the LAV-BPIFB4 gene exerted therapeutic action in murine models of atherosclerosis, limb ischemia, diabetic cardiomyopathy, and aging. We hypothesize that downregulation of BPIFB4 expression marks the severity of coronary artery disease (CAD) in human subjects, and supplementation of the LAV-BPIFB4 protects the heart from ischemia...
August 15, 2023: Cell Death & Disease
https://read.qxmd.com/read/37572165/hutchinson-gilford-progeria-patient-derived-cardiomyocyte-model-of-carrying-lmna-gene-variant-c-1824-c%C3%A2-%C3%A2-t
#29
JOURNAL ARTICLE
Selene Perales, Vinoth Sigamani, Sheeja Rajasingh, Andras Czirok, Johnson Rajasingh
Cardiovascular diseases, atherosclerosis, and strokes are the most common causes of death in patients with Hutchinson-Gilford progeria syndrome (HGPS). The LMNA variant c.1824C > T accounts for ~ 90% of HGPS cases. The detailed molecular mechanisms of Lamin A in the heart remain elusive due to the lack of appropriate in vitro models. We hypothesize that HGPS patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMCs) will provide a model platform to study the cardio-pathologic mechanisms associated with HGPS...
August 12, 2023: Cell and Tissue Research
https://read.qxmd.com/read/37533404/metabolic-switch-from-fatty-acid-oxidation-to%C3%A2-glycolysis-in-knock-in-mouse-model-of-barth%C3%A2-syndrome
#30
JOURNAL ARTICLE
Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling
Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation...
August 3, 2023: EMBO Molecular Medicine
https://read.qxmd.com/read/37503283/mechanisms-of-innate-immune-injury-in-arrhythmogenic-cardiomyopathy
#31
Stephen P Chelko, Vinay Penna, Morgan Engel, Maicon Landim-Vieira, Elisa N Cannon, Kory Lavine, Jeffrey E Saffitz
UNLABELLED: Inhibition of nuclear factor kappa-B (NFκB) signaling prevents disease in Dsg2 mut/mut mice, a model of arrhythmogenic cardiomyopathy (ACM). Moreover, NFκB is activated in ACM patient-derived iPSC-cardiac myocytes under basal conditions in vitro . Here, we used genetic approaches and sequencing studies to define the relative pathogenic roles of immune signaling in cardiac myocytes vs. inflammatory cells in Dsg2 mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2 mut/mut mice...
July 13, 2023: bioRxiv
https://read.qxmd.com/read/37371654/the-junctophilin-2-mutation-p-thr161lys-is-associated-with-hypertrophic-cardiomyopathy-using-patient-specific-ips-cardiomyocytes-and-demonstrates-prolonged-action-potential-and-increased-arrhythmogenicity
#32
JOURNAL ARTICLE
Joona Valtonen, Chandra Prajapati, Reeja Maria Cherian, Sari Vanninen, Marisa Ojala, Krista Leivo, Tiina Heliö, Juha Koskenvuo, Katriina Aalto-Setälä
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases; it is primarily caused by mutations in sarcomeric genes. However, HCM is also associated with mutations in non-sarcomeric proteins and a Finnish founder mutation for HCM in non-sarcomeric protein junctophilin-2 (JPH2) has been identified. This study aimed at assessing the issue of modelling the rare Finnish founder mutation in cardiomyocytes (CMs) differentiated from iPSCs; therefore, presenting the same cardiac abnormalities observed in the patients...
May 27, 2023: Biomedicines
https://read.qxmd.com/read/37349842/functional-defects-in-hipscs-derived-cardiomyocytes-from-patients-with-a-plekhm2-mutation-associated-with-dilated-cardiomyopathy-and-left-ventricular-non-compaction
#33
JOURNAL ARTICLE
Nataly Korover, Sharon Etzion, Alexander Cherniak, Tatiana Rabinski, Aviva Levitas, Yoram Etzion, Rivka Ofir, Ruti Parvari, Smadar Cohen
Dilated cardiomyopathy (DCM) is a primary myocardial disease, leading to heart failure and excessive risk of sudden cardiac death with rather poorly understood pathophysiology. In 2015, Parvari's group identified a recessive mutation in the autophagy regulator, PLEKHM2 gene, in a family with severe recessive DCM and left ventricular non-compaction (LVNC). Fibroblasts isolated from these patients exhibited abnormal subcellular distribution of endosomes, Golgi apparatus, lysosomes and had impaired autophagy flux...
June 23, 2023: Biological Research
https://read.qxmd.com/read/37344639/molecular-and-cellular-evidence-for-the-impact-of-a-hypertrophic-cardiomyopathy-associated-raf1-variant-on-the-structure-and-function-of-contractile-machinery-in-bioartificial-cardiac-tissues
#34
JOURNAL ARTICLE
Saeideh Nakhaei-Rad, Fereshteh Haghighi, Farhad Bazgir, Julia Dahlmann, Alexandra Viktoria Busley, Marcel Buchholzer, Karolin Kleemann, Anne Schänzer, Andrea Borchardt, Andreas Hahn, Sebastian Kötter, Denny Schanze, Ruchika Anand, Florian Funk, Annette Vera Kronenbitter, Jürgen Scheller, Roland P Piekorz, Andreas S Reichert, Marianne Volleth, Matthew J Wolf, Ion Cristian Cirstea, Bruce D Gelb, Marco Tartaglia, Joachim P Schmitt, Martina Krüger, Ingo Kutschka, Lukas Cyganek, Martin Zenker, George Kensah, Mohammad R Ahmadian
Noonan syndrome (NS), the most common among RASopathies, is caused by germline variants in genes encoding components of the RAS-MAPK pathway. Distinct variants, including the recurrent Ser257Leu substitution in RAF1, are associated with severe hypertrophic cardiomyopathy (HCM). Here, we investigated the elusive mechanistic link between NS-associated RAF1S257L and HCM using three-dimensional cardiac bodies and bioartificial cardiac tissues generated from patient-derived induced pluripotent stem cells (iPSCs) harboring the pathogenic RAF1 c...
June 21, 2023: Communications Biology
https://read.qxmd.com/read/37313752/an-alternative-mechanism-of-subcellular-iron-uptake-deficiency-in-cardiomyocytes
#35
JOURNAL ARTICLE
Yuanyuan Dai, Nadezda Ignatyeva, Hang Xu, Ruheen Wali, Karl Toischer, Sören Brandenburg, Christof Lenz, Julius Pronto, Funsho E Fakuade, Samuel Sossalla, Elisabeth M Zeisberg, Andreas Janshoff, Ingo Kutschka, Niels Voigt, Henning Urlaub, Torsten Bloch Rasmussen, Jens Mogensen, Stephan E Lehnart, Gerd Hasenfuss, Antje Ebert
BACKGROUND: Systemic defects in intestinal iron absorption, circulation, and retention cause iron deficiency in 50% of patients with heart failure. Defective subcellular iron uptake mechanisms that are independent of systemic absorption are incompletely understood. The main intracellular route for iron uptake in cardiomyocytes is clathrin-mediated endocytosis. METHODS: We investigated subcellular iron uptake mechanisms in patient-derived and CRISPR/Cas-edited induced pluripotent stem cell-derived cardiomyocytes as well as patient-derived heart tissue...
June 14, 2023: Circulation Research
https://read.qxmd.com/read/37292763/reducing-microtubule-detyrosination-improves-heart-function-in-hcm-mice-and-human-ipsc-engineered-heart-tissues
#36
Niels Pietsch, Christina Yingxian Chen, Svenja Kupsch, Lucas Bacmeister, Birgit Geertz, Marisol Herera-Rivero, Hanna Voß, Elisabeth Krämer, Ingke Braren, Dirk Westermann, Hartmut Schlüter, Giulia Mearini, Saskia Schlossarek, Jolanda van der Velden, Matthew A Caporizzo, Diana Lindner, Benjamin L Prosser, Lucie Carrier
RATIONALE: Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular (LV) hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that α-tubulin detyrosination (dTyr-tub) is markedly elevated in heart failure. Reduction of dTyr-tub by inhibition of the detyrosinase (VASH/SVBP complex) or activation of the tyrosinase (tubulin tyrosine ligase, TTL) markedly improved contractility and reduced stiffness in human failing cardiomyocytes, and thus poses a new perspective for HCM treatment...
May 26, 2023: bioRxiv
https://read.qxmd.com/read/37205556/lactate-and-immunomagnetic-purified-ipsc-derived-cardiomyocytes-generate-comparable-engineered-cardiac-tissue-constructs
#37
Kalina J Rossler, Willem J de Lange, Morgan W Mann, Timothy J Aballo, Jake A Melby, Jianhua Zhang, Gina Kim, Elizabeth F Bayne, Yanlong Zhu, Emily T Farrell, Timothy J Kamp, J Carter Ralphe, Ying Ge
Three-dimensional engineered cardiac tissue (ECT) using purified human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has emerged as an appealing model system for the study of human cardiac biology and disease. A recent study reported widely-used metabolic (lactate) purification of monolayer hiPSC-CM cultures results in an ischemic cardiomyopathy-like phenotype compared to magnetic antibody-based cell sorting (MACS) purification, complicating the interpretation of studies using lactate-purified hiPSC-CMs...
May 6, 2023: bioRxiv
https://read.qxmd.com/read/37200096/1-deoxynojirimycin-promotes-cardiac-function-and-rescues-mitochondrial-cristae-in-mitochondrial-hypertrophic-cardiomyopathy
#38
JOURNAL ARTICLE
Qianqian Zhuang, Fengfeng Guo, Lei Fu, Yufei Dong, Shaofang Xie, Xue Ding, Shuangyi Hu, Xuanhao D Zhou, Yangwei Jiang, Hui Zhou, Yue Qiu, Zhaoying Lei, Mengyao Li, Huajian Cai, Mingjie Fan, Lingjie Sang, Yong Fu, Dong Zhang, Aifu Lin, Xu Li, Tilo Kunath, Ruhong Zhou, Ping Liang, Zhong Liu, Qingfeng Yan
Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young individuals. Due to heterogeneity in the clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction...
May 18, 2023: Journal of Clinical Investigation
https://read.qxmd.com/read/37164047/multicenter-clinical-and-functional-evidence-reclassifies-a-recurrent-noncanonical-filamin-c-splice-altering-variant
#39
JOURNAL ARTICLE
Matthew J O'Neill, Suet Nee Chen, Lynne Rumping, Renee Johnson, Marjon van Slegtenhorst, Andrew M Glazer, Tao Yang, Joseph F Solus, Julie Laudeman, Devyn W Mitchell, Loren R Vanags, Brett M Kroncke, Katherine Anderson, Shanshan Gao, Job A J Verdonschot, Han Brunner, Debby Hellebrekers, Matthew R G Taylor, Dan M Roden, Marja W Wessels, Ronald H Lekanne Dit Deprez, Diane Fatkin, Luisa Mestroni, M Benjamin Shoemaker
BACKGROUND: Truncating variants in filamin C (FLNC) can cause arrhythmogenic cardiomyopathy (ACM) through haploinsufficiency. Noncanonical splice-altering variants may contribute to this phenotype. OBJECTIVE: The purpose of this study was to investigate the clinical and functional consequences of a recurrent FLNC intronic variant of uncertain significance (VUS), c.970-4A>G. METHODS: Clinical data in 9 variant heterozygotes from 4 kindreds were obtained from 5 tertiary health care centers...
May 9, 2023: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://read.qxmd.com/read/37047128/med25-limits-master-regulators-that-govern-adipogenesis
#40
JOURNAL ARTICLE
Jasmine Saunders, Kunal Sikder, Elizabeth Phillips, Anurag Ishwar, David Mothy, Kenneth B Margulies, Jason C Choi
Mediator 25 (Med25) is a member of the mediator complex that relays signals from transcription factors to the RNA polymerase II machinery. Multiple transcription factors, particularly those involved in lipid metabolism, utilize the mediator complex, but how Med25 is involved in this context is unclear. We previously identified Med25 in a translatome screen of adult cardiomyocytes (CMs) in a novel cell type-specific model of LMNA cardiomyopathy. In this study, we show that Med25 upregulation is coincident with myocardial lipid accumulation...
March 24, 2023: International Journal of Molecular Sciences
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