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| Open AccessSystematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database
Multiple drugs have been in the past associated with myocarditis. Here the authors perform a pharmacovigilance study and analyze 5108 reports of drug-induced myocarditis reporting temporal trends and overall mortality and identifying emerging drug classes among the treatments associated with myocarditis.
- Lee S. Nguyen
- , Leslie T. Cooper
- & Joe-Elie Salem
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Article
| Open AccessIstaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy
Arrhythmogenic cardiomyopathy is a genetically inherited disease caused by deletion of an arginine in Phospholamban (PLN), a small protein that regulates intracellular calcium levels. Here the authors show that zebrafish with the PLN p.Arg14del mutation develop severe cardiomyopathy which is preceded by contractile dysfunction and altered calcium dynamics and istaroxime is identified as a small molecule that can rescues some of these phenotypes.
- S. M. Kamel
- , C. J. M. van Opbergen
- & J. Bakkers
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Article
| Open AccessBiological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood
Idiopathic pulmonary arterial hypertension is a rare and fatal disease with a heterogeneous treatment response. Here the authors show that unsupervised machine learning of whole blood transcriptomes from 359 patients with idiopathic pulmonary arterial hypertension identifies 3 subgroups (endophenotypes) that improve risk stratification and provide new molecular insights.
- Sokratis Kariotis
- , Emmanuel Jammeh
- & Richard C. Trembath
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Article
| Open AccessPlasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis
ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.
- Ivana Slamova
- , Rozita Adib
- & J. Paul Simons
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Article
| Open AccessA tough nitric oxide-eluting hydrogel coating suppresses neointimal hyperplasia on vascular stent
Neointimal hyperplasia and stent thrombosis remain issues with vascular stents. Here, the authors report on the development of a nitric oxide releasing hydrogel which allows for endothelialisation of the stent surface and prevents smooth muscle cell growth reducing hyperplasia and thrombosis in in vivo models.
- Yin Chen
- , Peng Gao
- & Hongkai Wu
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Article
| Open AccessNeuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution
Ionizing radiation and chemotherapy deplete haematopoietic stem cells and damage the vascular niche. Here the authors show that irradiation induces SEMA3A secretion from bone marrow endothelial cells (ECs), inducing EC apoptosis via NRP1 and that NRP1 inhibition promotes vascular regeneration and R spondin 2 dependent hematopoietic regeneration.
- Christina M. Termini
- , Amara Pang
- & John P. Chute
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Article
| Open AccessDetrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure
In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel NaV1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model.
- Philipp Bengel
- , Nataliya Dybkova
- & Samuel Sossalla
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Article
| Open AccessThe history and geographic distribution of a KCNQ1 atrial fibrillation risk allele
Many rare high-impact variants have been associated with disease, but the origins and functional impact are not always explored. Here, the authors trace the ancestry of a rare high impact atrial fibrillation allele in KCNQ1, and use iPSC-derived cardiomyocytes to characterize the effect of the allele.
- Shannon Hateley
- , Angelica Lopez-Izquierdo
- & Martin Tristani-Firouzi
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Article
| Open AccessMulti-targeted 1H/19F MRI unmasks specific danger patterns for emerging cardiovascular disorders
The prediction of major cardiovascular events is still an unsolved problem. Here, the authors present a multi-color, multi-targeted non-invasive imaging technology that allows reliable in vivo identification of silent but prognostically highly relevant danger patterns prior to myocardial infarction in mice.
- Ulrich Flögel
- , Sebastian Temme
- & Bodo Levkau
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Article
| Open AccessCardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis
Noninvasive cardiac radiotherapy may effectively manage ventricular tachycardia in refractory patients, but its radiobiologic mechanisms of action are unclear. Here, the authors show that photon radiation durably and favourably reprograms cardiac conduction in the absence of transmural fibrosis suggesting this could be the mechanism through which cardiac radiotherapy to modulates arrhythmia susceptibility.
- David M. Zhang
- , Rachita Navara
- & Stacey L. Rentschler
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Article
| Open AccessActivation mechanism of human soluble guanylate cyclase by stimulators and activators
Soluble guanylate cyclase (sGC) is a validated drug target for cardiovascular diseases. Here, the authors report structures of human sGC in complex with NO and sGC stimulators or activator, providing insight into the mechanism of sGC activation by pharmacological compounds.
- Rui Liu
- , Yunlu Kang
- & Lei Chen
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Article
| Open AccessNrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
Following injury, cells in regenerative tissues can regrow, but how they adapt to injury conditions to regenerate the tissue is unclear. Here the authors identify a stress-responsive and cardioprotective factor Nrf1 that is critical for neonatal heart regeneration.
- Miao Cui
- , Ayhan Atmanli
- & Eric N. Olson
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Article
| Open AccessPredicting post-operative right ventricular failure using video-based deep learning
The echocardiogram allows for a comprehensive assessment of the cardiac musculature and valves, but its rich temporally resolved data remain underutilized. Here, the authors develop a video AI system trained to predict post-operative right ventricular failure.
- Rohan Shad
- , Nicolas Quach
- & William Hiesinger
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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 AccessSelf-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.
- Yonatan R. Lewis-Israeli
- , Aaron H. Wasserman
- & Aitor Aguirre
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Article
| Open AccessDeep neural network-estimated electrocardiographic age as a mortality predictor
The electrocardiogram (ECG) is the most commonly used exam for the screening and evaluation of cardiovascular diseases. Here, the authors propose that the age predicted by artificial intelligence from the raw ECG tracing can be a measure of cardiovascular health and provide prognostic information.
- Emilly M. Lima
- , Antônio H. Ribeiro
- & Antonio Luiz P. Ribeiro
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Article
| Open AccessHuman iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro
The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.
- Jun Jie Tan
- , Jacques P. Guyette
- & Harald C. Ott
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Article
| Open AccessElectrophysiological engineering of heart-derived cells with calcium-dependent potassium channels improves cell therapy efficacy for cardioprotection
Strategies to improve the function of damaged hearts with progenitor cells have stalled. Here, the authors show that gene transfer of a calcium-dependent potassium channel enhances the functional properties and ability of explant-derived cells to improve heart function after a heart attack.
- Patrick Vigneault
- , Sandrine Parent
- & Stanley Nattel
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Article
| Open AccessA microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration
Myocardial regeneration and proliferation of heart muscle cells is limited to a short period after birth early postnatal life, after which heart muscle cells can only grow in size and not in number. Here, the authors identified that the expression level of an endogenous microRNA cluster in heart muscle promotes the passage of the proliferative state to adult heart growth, and modulating the expression of this cluster can stimulate heart regeneration after myocardial infarction.
- Andrea Raso
- , Ellen Dirkx
- & Leon J. De Windt
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Article
| Open AccessDisrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy
Mutations in the LaminA gene are the second most common inherited cause of Dilated Cardiomyopathy, a major form of heart failure. Here the authors show that disruption of the nuclear protein SUN1 in cardiomyocytes, by AAV mediated transduction of a SUN1 inhibitor, significantly suppress cardiomyopathy progression, providing a potential therapeutic route to treat this disease.
- Ruth Jinfen Chai
- , Hendrikje Werner
- & Colin L. Stewart
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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 AccessNitrate-functionalized patch confers cardioprotection and improves heart repair after myocardial infarction via local nitric oxide delivery
Nitric oxide (NO) is an important gaseous signaling molecule with multiple physiological roles in cardiovascular system. Here the authors develop a cardiac patch with NO releasing function that favors heart repair after myocardial infarction.
- Dashuai Zhu
- , Jingli Hou
- & Qiang Zhao
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Article
| Open AccessMassively parallel in vivo CRISPR screening identifies RNF20/40 as epigenetic regulators of cardiomyocyte maturation
Throughput of in vivo genetic screens is a barrier to efficient application. Here the authors use a high-throughput CRISPR-based in vivo forward genetic screen in mice to identify transcriptional regulators of cardiomyocyte maturation, including the epigenetic modifiers RNF20 and RNF40.
- Nathan J. VanDusen
- , Julianna Y. Lee
- & William T. Pu
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Article
| Open AccessRole of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels
Diverse macrophage subsets are found in adipose tissue where they regulate its physiology. Here, the authors used single-cell RNA sequencing to analyse the effect of post-prandial lipids on adipose tissue macrophages and identify Tim4 as a regulator of ABCA1+ macrophage function and post-prandial cholesterol transport.
- M. S. Magalhaes
- , P. Smith
- & C. Bénézech
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Article
| Open AccessSelf-healing polyurethane-elastomer with mechanical tunability for multiple biomedical applications in vivo
The unique properties of self-healing materials hold great potential in the field of biomedical engineering. Here, the authors designed a series of biodegradable and biocompatible self-healing elastomers with tunable mechanical properties, and apply them to various disease models in vivo, including aortic aneurism, bone fracture and nerve amputation.
- Chenyu Jiang
- , Luzhi Zhang
- & Xiaofeng Ye
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Article
| Open AccessSelf-rechargeable cardiac pacemaker system with triboelectric nanogenerators
Self-powered implantable devices have the potential to extend device operation, though current energy harvesters are both insufficient and inconvenient. Here the authors report on a commercial coin battery-sized high-performance inertia-driven triboelectric nanogenerator based on body motion and gravity that can be used to charge a lithium-ion battery and integrated into a cardiac pacemaker.
- Hanjun Ryu
- , Hyun-moon Park
- & Sang-Woo Kim
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Article
| Open AccessIn utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease
Lysosomal storage diseases like mucopolysaccharidosis type I (MPS I) cause pathology before birth and result in early morbidity and mortality. Here, the authors show that in utero base editing mediates multi-organ phenotypic and survival benefits in a mouse model recapitulating a common human MPSI mutation.
- Sourav K. Bose
- , Brandon M. White
- & William H. Peranteau
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| Open AccessPost-myocardial infarction heart failure dysregulates the bone vascular niche
Hematopoiesis influences the progression of cardiovascular disease, yet the influence of cardiovascular disease on the bone vasculature is unknown. Hoffmann, Luxán, Abplanalp et al. describe the response of the bone cell composition to myocardial infarction and provide a rationale for using anti-inflammatory therapies to prevent the deterioration of the bone vascular niche
- Jedrzej Hoffmann
- , Guillermo Luxán
- & Stefanie Dimmeler
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Article
| Open AccessThbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy
Beneficial and detrimental effects have been ascribed to the different Thrombospondin (Thbs) proteins in the adult mammalian heart. Here, the authors show that Thbs1-mediated activation of PERK-eIF2α-ATF4-induced autophagy regulates adult cardiomyocyte size in the stressed heart.
- Davy Vanhoutte
- , Tobias G. Schips
- & Jeffery D. Molkentin
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Article
| Open AccessCell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease
Previous studies have shown that the CD40L-CD40 signaling axis plays a role in atherosclerosis. Here the authors investigate the cell-specific functions of the most relevant CD40L-expressing cell types in atherosclerosis. Deficiency of T cell-derived CD40L reduces and stabilizes plaques through impaired Th1 polarization while platelet-derived CD40L ameliorates atherothrombosis.
- Michael Lacy
- , Christina Bürger
- & Esther Lutgens
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Article
| Open AccessGenome sequencing unveils a regulatory landscape of platelet reactivity
Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.
- Ali R. Keramati
- , Ming-Huei Chen
- & Andrew D. Johnson
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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 AccessStructure and mechanism of the human NHE1-CHP1 complex
Sodium/proton exchanger 1 (NHE1) and its obligate binding partner Calcineurin B-homologous protein 1 (CHP1) regulate intracellular pH and volume homeostasis. Structures of the human NHE1-CHP1 complex offer insight into the regulation of NHE1 pH-sensitivity by CHP1 and into the interactions with NHE1 inhibitors.
- Yanli Dong
- , Yiwei Gao
- & Yan Zhao
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Article
| Open AccessThe C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets
As more intersection points between platelets and the immune system are found, the role of platelets for vessel growth in the adult organism remains unclear. The authors demonstrate that platelets negatively modulate revascularization through CXCL4 secretion induced by activation C5aR1 on their surface.
- Henry Nording
- , Lasse Baron
- & Harald F. Langer
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| Open AccessAn antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage
Mechanisms underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin treatment during anticancer therapy remain poorly understood. Here the authors show that treatment with an antibody against the L1 cell adhesion molecule inhibits nuclear L1CAM translocation, thereby controlling vascular DNA damage and preventing cardiotoxicity.
- Jae-Kyung Nam
- , A-Ram Kim
- & Yoon-Jin Lee
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Article
| Open AccessZinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle
Metals such as calcium and potassium have long been known to regulate the diameter of arteries that control blood flow. Here, we report that zinc causes relaxation of blood vessels and reduces blood pressure by its coordinated action in sensory nerves, endothelium and smooth muscle cells.
- Ashenafi H. Betrie
- , James A. Brock
- & Scott Ayton
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Article
| Open AccessTargeting Gα13-integrin interaction ameliorates systemic inflammation
Bacterial or viral infection can lead to lethal systemic inflammation and thrombosis. Here, the authors show that inhibiting integrin outside-in signaling in leukocytes and platelets alleviates inflammation/clotting and improved survival in septic mice.
- Ni Cheng
- , Yaping Zhang
- & Xiaoping Du
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Article
| Open AccessGeneration of mature compact ventricular cardiomyocytes from human pluripotent stem cells
Cardiomyocytes of heart ventricles consist of subpopulations of trabecular and compact subtypes. Here the authors describe the generation of structurally, metabolically and functionally mature compact ventricular cardiomyocytes as well as mature atrial cardiomyocytes from human pluripotent stem cells.
- Shunsuke Funakoshi
- , Ian Fernandes
- & Gordon Keller
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Article
| Open AccessA human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells
Analyzing memory B cell repertoires of the healthy elderly enabled Michalon et al. to develop a recombinant human antibody selective for transthyretin amyloid. This antibody removes cardiac amyloid through recruitment of phagocytic immune cells.
- Aubin Michalon
- , Andreas Hagenbuch
- & Jan Grimm
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Article
| Open AccessAlteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis
Alteration of circadian rhythms is often observed in patients with chronic kidney disease (CKD). Here, the authors show that CKD-induced dysfunction of the circadian clock increases the expression of G protein-coupled receptor 68 in circulating monocytes and that their cardiac infiltration exacerbates inflammation and fibrosis of heart.
- Yuya Yoshida
- , Naoya Matsunaga
- & Shigehiro Ohdo
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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 AccessArtificial intelligence-enabled fully automated detection of cardiac amyloidosis using electrocardiograms and echocardiograms
Cardiac amyloidosis is difficult to identify, given low prevalence and similarity of the symptoms to more prevalent disorders. Here the authors present a multi-modality, artificial intelligence-enabled pipeline, that enables automated detection of cardiac amyloidosis from inexpensive and accessible measures.
- Shinichi Goto
- , Keitaro Mahara
- & Rahul C. Deo
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Article
| Open AccessFUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis
Mitochondria-associated ER membranes (MAMs) are involved in the regulation of many cellular functions. Here, the authors report that FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes play an essential role in the process of angiogenesis and neoangiogenesis.
- Cheng Wang
- , Xiaoyan Dai
- & Ming-Hui Zou
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Article
| Open AccessThe lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis
Long noncoding RNAs (lncRNAs) have been shown to play a role in cardiac physiology and disease. Here the authors identify the lncRNA Caren as a cytoplasmic RNA that decreases the translation of a distant gene encoding Hint1, thereby maintaining cardiomyocyte function due to inactivation of the DNA damage response and activation of mitochondrial bioenergetics.
- Michio Sato
- , Tsuyoshi Kadomatsu
- & Yuichi Oike
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Article
| Open AccessDistinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia
Cardiac function fluctuates greatly across the day and night, but this is not simply a consequence of our changing behaviour. The authors highlight the role of the body’s circadian clock in regulating the heart electrical activity, including a time-of-day dependent susceptibility to cardiac arrhythmias.
- Edward A. Hayter
- , Sophie M. T. Wehrens
- & David A. Bechtold
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Article
| Open AccessLoss of endothelial glucocorticoid receptor accelerates diabetic nephropathy
The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.
- Swayam Prakash Srivastava
- , Han Zhou
- & Julie Goodwin
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Article
| Open AccessDeletion of Mfsd2b impairs thrombotic functions of platelets
The mechanisms by which platelets release sphingosine-1-phosphate (S1P) is not well characterized. Here the authors show that Mfsd2b is required for S1P release from both resting and activated platelets and that deletion of Mfsd2b impairs thrombotic functions of platelets.
- Madhuvanthi Chandrakanthan
- , Toan Quoc Nguyen
- & Long N. Nguyen
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Article
| Open AccessChromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices
The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.
- Pradeep Natarajan
- , Akhil Pampana
- & Gina M. Peloso
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Article
| Open AccessCardiac macrophages prevent sudden death during heart stress
Cardiac immune cells play various roles in the maintenance of homeostasis and diseases in the heart. Here the authors show that cardiac resident macrophages are a critical regulator of cardiac impulse conduction through amphiregulin production, contributing to the prevention of sudden death.
- Junichi Sugita
- , Katsuhito Fujiu
- & Issei Komuro