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| Open AccessGenome-wide association analysis of left ventricular imaging-derived phenotypes identifies 72 risk loci and yields genetic insights into hypertrophic cardiomyopathy
Changes of left ventricular structure are used to predict morbidity and mortality in cardiovascular diseases. Here the authors conducted a study using advanced deep learning technology to analyze left ventricular regional wall thickness (LVRWT) in a large population, identifying 72 significant genetic loci linked to LVRWT traits.
- Caibo Ning
- , Linyun Fan
- & Xiaoping Miao
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Article
| Open AccessMYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)
Arrhythmogenic cardiomyopathy is an untreatable heart muscle disease and a common cause of sudden cardiac death in young athletes. The authors show a link between actomyosin dysregulation and cardiac dysfunction by studying nonsense PKP2 mutants classified as pathogenic to identify a potential treatment.
- Nieves García-Quintáns
- , Silvia Sacristán
- & Juan A. Bernal
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Article
| Open AccessLysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34
iPLA2β produces lipid mediators and induces nuclear shrinkage in caspase-independent cell death. Here, the authors show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death mediated through GPR34 in pressure-overloaded mouse hearts, leading to cardiac dysfunction.
- Ryuta Sugihara
- , Manabu Taneike
- & Kinya Otsu
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Article
| Open AccessMislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3
The authors show that loss-of-interaction with the nuclear importer, TNPO3, causes cytoplasmic mislocalization of RBM20 variants linked to severe cases of dilated cardiomyopathy. Restoring their nuclear localization alleviates the disease phenotype.
- Julia Kornienko
- , Marta Rodríguez-Martínez
- & Lars M. Steinmetz
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Article
| Open AccessStriated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy
Dilated cardiomyopathy is the second most common cause for heart failure. Here the authors combine CRISPR base editors with the muscle-targeting viral vector AAVMYO to repair patient mutations in the cardiac splice factor Rbm20 in two mouse models.
- Markus Grosch
- , Laura Schraft
- & Lars M. Steinmetz
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Article
| Open AccessIDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart
Protein targets that are affected by ROS and underly impaired inotropic effects in the heart are largely unknown. Here, the authors identify the γ-subunit of IDH3 as a redox switch linking oxidative stress to impaired metabolism and heart function.
- Maithily S. Nanadikar
- , Ana M. Vergel Leon
- & Dörthe M. Katschinski
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Article
| Open AccessRetinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice
The current challenges for diabetic cardiomyopathy (DCM) are unclear mechanisms and no effective therapy in clinics. Here, the authors found that the decrease of cardiac retinol dehydrogenase 10 in type 2 diabetes leads to retinol metabolism disorder, cardiac lipid toxicity and cardiomyopathy development, suggesting that correcting the imbalance of cardiac retinol metabolism may be an effective strategy for the treatment of DCM.
- Yandi Wu
- , Tongsheng Huang
- & Weibin Cai
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Article
| Open AccessVGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid–liquid phase separation
Heart fibrosis involves a feedback loop where stiffening increases fibrosis-related gene expression in myofibroblasts. Here authors reveal the mechanosensitive nuclear translocation of VGLL3, where it phase separates and promotes collagen production, and show that its knock-out is protective after myocardial infarction.
- Yuma Horii
- , Shoichi Matsuda
- & Michio Nakaya
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Article
| Open AccessActin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations
Lamin A/C gene mutations cause dilated cardiomyopathy associated with cofilin-1 phosphorylation and actin destabilization. Here, the authors show that phosphorylated cofilin-1 blunts the MRTF-A/SRF axis, leading to decreased tubulin acetylation and altered cardiac structure and function.
- Caroline Le Dour
- , Maria Chatzifrangkeskou
- & Antoine Muchir
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Article
| Open AccessTRPC channels blockade abolishes endotoxemic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage
TRPCs, nonselective cation channels, are involved in cardiac contraction and conduction. Here, the authors show that Trpc1/6 deficiency or pharmacological inhibition improves endotoxemic cardiac dysfunction and prolongs survival by prominently suppressing cardiac inflammation and ER Ca2+ release.
- Na Tang
- , Wen Tian
- & Wei Cao
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Article
| Open AccessThe E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis
Non-ischemic cardiomyopathy is a severe disease, characterized by interstitial fibrosis in the left ventricle of the heart. Here authors show that the E3 ubiquitin ligase WWP2 plays a pathogenic role in heart fibrosis via regulating a distinct monocyte population that initiates the process.
- Huimei Chen
- , Gabriel Chew
- & Enrico Petretto
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Article
| Open AccessGenome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure
Heart failure is a major cause of cardiovascular morbidity and mortality. Here, the authors report results of a genome-wide association study meta-analysis, characterizing the role of common genetic variants in heart failure, finding overlap with common cardiovascular risk factors and imaging measures of cardiac structure/function.
- Michael G. Levin
- , Noah L. Tsao
- & Scott M. Damrauer
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Article
| Open AccessTmem65 is critical for the structure and function of the intercalated discs in mouse hearts
The intercalated disc (ICD) is a membrane structure of the cardiac muscle involved in normal heart function. Here the authors report that knockdown of the ICD-bound transmembrane protein 65 results in impaired ICD structure, abnormal cardiac electrophysiology and cardiomyopathy in mice.
- Allen C. T. Teng
- , Liyang Gu
- & Anthony O. Gramolini
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Article
| Open AccessMitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment
Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.
- Enrique Balderas
- , David R. Eberhardt
- & Dipayan Chaudhuri
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Article
| Open AccessCMYA5 establishes cardiac dyad architecture and positioning
Heart muscle cells exhibit exquisitely organized subcellular features that enable efficient and coordinated heart muscle contraction, but little is known about how it is achieved. Here the authors show that CMYA5 organizes cardiomyocyte calcium release units and aligns them to sarcomeres, leading to abnormal calcium release, cardiac dysfunction, and inability to tolerate pressure overload, when absent.
- Fujian Lu
- , Qing Ma
- & William T. Pu
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Article
| Open AccessHeterogeneous repolarization creates ventricular tachycardia circuits in healed myocardial infarction scar
Ventricular arrhythmias after heart attack are a leading cause of death. Here the authors show, in a porcine model, that KCNE3 and KCNE4 upregulation and a unique pattern of repolarization heterogeneity in the scar facilitate reentrant ventricular tachycardia.
- Kamilla Kelemen
- , Ian D. Greener
- & J. Kevin Donahue
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Article
| Open AccessPhospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy
Heart failure is a major cause of morbidity and mortality worldwide. Here the authors show that subcutaneous administration of antisense oligonucleotides targeting PLN is an effective strategy in preclinical models of genetic cardiomyopathy and ischemia-driven heart failure.
- Niels Grote Beverborg
- , Daniela Später
- & Peter van der Meer
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Article
| Open AccessCardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis
The authors found that VDAC2 plays a crucial role in influencing mitochondrial calcium dynamics and cellular calcium signalling. A VDAC2 agonist, efsevin, rescued the heart failure phenotype, identifying a new potential therapeutic target for heart failure.
- Thirupura S. Shankar
- , Dinesh K. A. Ramadurai
- & Stavros G. Drakos
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Article
| Open AccessSingle-molecule, full-length transcript isoform sequencing reveals disease-associated RNA isoforms in cardiomyocytes
Alternative splicing generates RNA isoforms that contribute to phenotypic diversity. Here the authors perform single-molecule full-length RNA sequencing to identify disease-associated variant transcript isoforms.
- Chenchen Zhu
- , Jingyan Wu
- & Lars M. Steinmetz
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Article
| Open AccessOverexpression of human BAG3P209L in mice causes restrictive cardiomyopathy
An amino acid exchange (P209L) in the human co-chaperone BAG3 gives rise to severe childhood restrictive cardiomyopathy. Here the authors describe humanized transgenic mouse models which phenocopy the disease and provide insight into the pathogenic mechanisms.
- Kenichi Kimura
- , Astrid Ooms
- & Michael Hesse
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Article
| Open AccessA machine learning model for identifying patients at risk for wild-type transthyretin amyloid cardiomyopathy
Transthyretin amyloid cardiomyopathy is a treatable but often unrecognized cause of heart failure. We derived and validated a machine learning model based on medical diagnostic codes that identifies heart failure patients at risk for wild-type transthyretin amyloid cardiomyopathy.
- Ahsan Huda
- , Adam Castaño
- & Sanjiv J. Shah
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Article
| Open AccessIndividualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes
Understanding patient-specific pathobiological pathways is a critical step for advancing precision medicine. Here the authors show that individualized protein-protein interaction networks provide key insight on patient-level pathobiology and clinically relevant pathophenotypic characteristics in a complex disease.
- Bradley A. Maron
- , Rui-Sheng Wang
- & Joseph Loscalzo
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Article
| Open AccessAnalysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy
Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM.
- James P. Pirruccello
- , Alexander Bick
- & Krishna G. Aragam
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Article
| Open AccessA PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis
Molecular mechanisms linking myocardial insulin resistance to diabetic cardiomyopathy are incompletely understood. Here the authors show that myocardial insulin resistance impairs a PKB-SPEG-SERCA2a signaling axis, which contributes to the development of diabetic cardiomyopathy.
- Chao Quan
- , Qian Du
- & Shuai Chen
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Article
| Open AccessMD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy
The mechanisms underlying cardiac inflammation in diabetic cardiomyopathy are incompletely understood. Here the authors show that advanced glycation end products bind to the TLR4 co-receptor MD2 initiating pro-inflammatory pathways.
- Yi Wang
- , Wu Luo
- & Guang Liang
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Article
| Open AccessElimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure
Mutations in Ftkn cause Fukuyama muscular dystrophy, and heart failure is the main cause of death in thes patients. Here the authors show that acute elimination of Fktn in adult mice causes early mortality, and this is associated with myocyte dysfunction, with disorganised Golg-microtubule networks, and that the pathology can be ameliorated with colchicine treatment.
- Yoshihiro Ujihara
- , Motoi Kanagawa
- & Yuki Katanosaka
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Article
| Open AccessWWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.
- Huimei Chen
- , Aida Moreno-Moral
- & Enrico Petretto
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Article
| Open Accessβ-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity
Hypertrophic cardiomyopathy (HCM) leads to hyper-contractility of the heart and is often caused by mutations in human β-cardiac myosin. Here authors show that four separate β-cardiac myosin mutations can modulate myosin activity by disrupting intramolecular interactions.
- Arjun S. Adhikari
- , Darshan V. Trivedi
- & Kathleen M. Ruppel
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Article
| Open AccessThe K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy
Mutation of LMNA, encoding Lamin A/C nuclear proteins, cause dilated cardiomyopathy and conduction disorders. Here, the authors show that patient-specific iPSC-derived CMs carrying the K219T LMNA mutation have downregulated Nav1.5 channels due to dynamic cooperation of Lamin A/C and Polycomb repressor complex 2 at the SCN5A promoter.
- Nicolò Salvarani
- , Silvia Crasto
- & Elisa Di Pasquale
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Article
| Open AccessPI3Kα-regulated gelsolin activity is a critical determinant of cardiac cytoskeletal remodeling and heart disease
Gelsolin is an actin severing and capping protein that regulates cytoskeletal remodeling. Here the authors show that gelsolin is negatively regulated in the heart by PI3Kα‐ generated PIP3, and that loss of gelsolin activity prevents adverse cytoskeletal remodeling and heart failure.
- Vaibhav B. Patel
- , Pavel Zhabyeyev
- & Gavin Y. Oudit
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Article
| Open AccessPathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder
Mitochondrial protein synthesis requires charging a mitochondrial tRNA with its amino acid. Here, the authors describe pathogenic variants in the GatCAB protein complex genes required for the generation of glutaminyl-mt-tRNAGln, that impairs mitochondrial translation and presents with cardiomyopathy.
- Marisa W. Friederich
- , Sharita Timal
- & Johan L. K. Van Hove
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| Open AccessHypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition
Hypertrophic cardiomyopathy (HCM) is caused by point mutations in sarcomeric proteins. Here the authors develop an optimized model of the sequestered state of cardiac myosin and define the features affecting the lever arm compliance, allowing them to group mutations in classes and to elucidate the molecular mechanisms leading to cardiac dysfunction in HCM.
- Julien Robert-Paganin
- , Daniel Auguin
- & Anne Houdusse
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Article
| Open AccessNF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model
The molecular mechanisms leading to heart failure in patients with Duchenne muscular dystrophy are unclear. Here the authors show that NF-κB is activated in the heart of dystrophin-deficient mice and that its ablation rescues cardiac function through chromatin remodeling and activation of gene expression.
- Jennifer M. Peterson
- , David J. Wang
- & Denis C. Guttridge
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| Open AccessIntegrated omics dissection of proteome dynamics during cardiac remodeling
Transcriptome data provide only a partial picture of disease states. Here, via integration of transcript-, protein abundance and protein turnover data for a mouse model of cardiac hypertrophy, the authors uncover additional disease gene signatures, and show that turnover data sheds unique light on posttranslational regulation.
- Edward Lau
- , Quan Cao
- & Peipei Ping
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Article
| Open AccessMLP and CARP are linked to chronic PKCα signalling in dilated cardiomyopathy
Altered function of the muscle LIM protein (MLP) causes dilated cardiomyopathy in mice and humans. Lange et al. explain the molecular role of MLP in the heart by showing that it affects the signalling complex at the intercalated discs of failing hearts that consists of PKCα, PLCβ1 and CARP by inhibiting PKCα auto-phosphorylation and function.
- Stephan Lange
- , Katja Gehmlich
- & Elisabeth Ehler
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Article
| Open AccessSuppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy
Identifying pathways that cause pathological cardiac hypertrophy holds great therapeutic potential. Here the authors discover one such pathway and show that SIKE, an inhibitor of interferon signalling, prevents pathological but not physiological cardiac hypertrophy by interacting with TBK1 and modulating the TBK1/AKT signalling in rodents and monkeys.
- Ke-Qiong Deng
- , Aibing Wang
- & Hongliang Li
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Article
| Open AccessIncreased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure
Transcription factor COUP-TFII is elevated in the hearts of non-ischaemic cardiomyopathy patients, but the nature of this correlation is unknown. Here the authors show that forced cardiac expression of COUP-TFII in mice causes dilated cardiomyopathy because of altered mitochondrial function and impaired metabolic remodelling.
- San-Pin Wu
- , Chung-Yang Kao
- & Sophia Y. Tsai
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Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence
The epigenetic factor Bmi1 regulates self-renewal of many adult stem cells, but its role in heart function is unknown. Here the authors show that Bmi1 prevents cardiac senescence by inhibiting the tumor suppressor protein p16INK4ain adult mice, protecting them from dilated cardiomyopathy and heart failure.
- I. Gonzalez-Valdes
- , I. Hidalgo
- & S. Gonzalez
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Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice
Hereditary hypertrophic cardiomyopathy (HCM) is caused by mutations in cardiomyocyte genes, such as MYBPC3. Here, the authors use virus-mediated gene therapy to correct Mycbpc3mutations in 1-day-old mice and, by administering just a single dose, prevent development of HCM over a period of 34 weeks.
- Giulia Mearini
- , Doreen Stimpel
- & Lucie Carrier
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Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in young adults. Here, the authors show that mutations in a sarcomeric protein filamin C contribute to the development of familial HCM and are associated with an increased incidence of sudden cardiac death.
- Rafael Valdés-Mas
- , Ana Gutiérrez-Fernández
- & Carlos López-Otín
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Article |
Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function
The transduction of mechanical forces into signals that alter cardiac contractility is important for heart function. Here the authors show that integrin-linked kinase acts as a mechanosensor in cardiomyocytes, and affects cardiac contractility by regulating SERCA-2a and phospholamban.
- Alexandra Traister
- , Mark Li
- & John G. Coles
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Article |
Rag GTPases are cardioprotective by regulating lysosomal function
Rag family proteins control activation of the mTORC1 complex at the lysosome. Here the authors show that loss of RagA/B causes cardiac hypertrophy in mice, revealing an mTORC-independent function of Rag GTPAses as regulators of lysosome function and autophagic flux in cardiomyocytes.
- Young Chul Kim
- , Hyun Woo Park
- & Kun-Liang Guan
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Article |
Mutations in Alström protein impair terminal differentiation of cardiomyocytes
Cardiomyocyte cell cycle arrest is important for mammalian heart maturation, but the process is poorly understood. Here, the authors use exome sequencing to identify compound heterozygous ALMS1mutations associated with cardiomyocyte replication and provide evidence that Alström protein deficiency impairs postnatal cardiomyocyte cell cycle arrest.
- Lincoln T. Shenje
- , Peter Andersen
- & Daniel P. Judge