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| Open AccessStructure of the native myosin filament in the relaxed cardiac sarcomere
A cryo-electron tomography study reports the structure of thick myosin filaments of mouse cardiac muscle in the relaxed state in situ and the MyBP-C links that connect them with the surrounding thin actin filaments.
- Davide Tamborrini
- , Zhexin Wang
- & Stefan Raunser
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Article
| Open AccessA foundation model for generalizable disease detection from retinal images
RETFound, a foundation model for retinal images that learns generalizable representations from unlabelled images, is trained on 1.6 million unlabelled images by self-supervised learning and then adapted to disease detection tasks with explicit labels.
- Yukun Zhou
- , Mark A. Chia
- & Pearse A. Keane
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Article |
Transfer learning enables predictions in network biology
A context-aware, attention-based deep learning model pretrained on single-cell transcriptomes enables predictions in settings with limited data in network biology and could accelerate discovery of key network regulators and candidate therapeutic targets.
- Christina V. Theodoris
- , Ling Xiao
- & Patrick T. Ellinor
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Article |
Spatial multi-omic map of human myocardial infarction
A time-resolved high-resolution map of human cardiac remodelling after myocardial infarction, integrating single-cell transcriptomic, chromatin accessibility and spatial transcriptomic data, provides a valuable resource for the field.
- Christoph Kuppe
- , Ricardo O. Ramirez Flores
- & Rafael Kramann
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Article |
Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion
Inhibiting the asialoglycoprotein receptor ASGR1 increases cholesterol excretion to the bile and then faeces, providing a unique way to lower cholesterol, and therefore providing a safe and effective way to treat cardiovascular disease.
- Ju-Qiong Wang
- , Liang-Liang Li
- & Bao-Liang Song
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Article |
Integrated multi-omic characterization of congenital heart disease
Single-nuclear transcriptomic and proteomic analyses identify molecular characteristics shared by multiple classes of congenital heart disease, including phenotypes associated with insulin resistance.
- Matthew C. Hill
- , Zachary A. Kadow
- & James F. Martin
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Article |
Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy
- Mark Chaffin
- , Irinna Papangeli
- & Patrick T. Ellinor
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Article |
Neuroimmune cardiovascular interfaces control atherosclerosis
The peripheral nervous system uses neuroimmune cardiovascular interfaces to assemble a structural artery–brain circuit, and therapeutic intervention in the artery–brain circuit attenuates atherosclerosis.
- Sarajo K. Mohanta
- , Li Peng
- & Andreas J. R. Habenicht
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Article |
Combinatorial, additive and dose-dependent drug–microbiome associations
An analysis of 2,173 individuals from the MetaCardis cohort quantifies the individual and combinatorial effects of a range of drugs on host health, metabolome and gut microbiome in cardiometabolic disease.
- Sofia K. Forslund
- , Rima Chakaroun
- & Peer Bork
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Article |
APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans
The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.
- Dimitrios Tsiantoulas
- , Mahya Eslami
- & Christoph J. Binder
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Article |
MARK4 controls ischaemic heart failure through microtubule detyrosination
MARK4 regulates cardiomyocyte contractility by promoting MAP4 phosphorylation, which facilitates the access of VASH2 to microtubules for the detyrosination of α-tubulin; MARK4 deficiency after acute myocardial infarction limits the reduction in the left ventricular ejection fraction.
- Xian Yu
- , Xiao Chen
- & Xuan Li
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Article |
In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood.
- Kiran Musunuru
- , Alexandra C. Chadwick
- & Sekar Kathiresan
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Article |
PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism
Aggressive cerebral cavernous malformations (CCMs) are found to grow through a three-hit cancer-like mechanism, involving gain of function of a gene that promotes vascular growth, and loss of function of genes that suppress it.
- Aileen A. Ren
- , Daniel A. Snellings
- & Mark L. Kahn
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Review Article |
The changing landscape of atherosclerosis
This Review discusses recent research that has transformed our understanding of the biology of atherosclerosis, and examines its implications for the treatment of atherosclerotic cardiovascular disease.
- Peter Libby
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Article |
The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis
Accelerated atherosclerosis in a mouse model of clonal haematopoiesis is prevented by genetic interruption of AIM2 inflammasome activation or by inhibition of interleukin-1β.
- Trevor P. Fidler
- , Chenyi Xue
- & Alan R. Tall
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Article |
ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies
An autoantibody found in a mouse model of atherosclerosis recognizses ALDH4A1, and infusion of the antibody delays plaque formation in mice.
- Cristina Lorenzo
- , Pilar Delgado
- & Almudena R. Ramiro
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Article |
Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia
Heart atria produce a large pool of calcitonin (previously well-recognized as a thyroid-secreted hormone with roles in calcium and bone metabolism) that in the heart acts as a paracrine signal controlling atrial fibrosis and fibrillation.
- Lucia M. Moreira
- , Abhijit Takawale
- & Svetlana Reilly
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Article |
Genetic and functional insights into the fractal structure of the heart
A genome-wide association study shows that myocardial trabeculae are an important determinant of cardiac performance in the adult heart, identifies conserved pathways that regulate structural complexity and reveals the influence of trabeculae on the susceptibility to cardiovascular disease.
- Hannah V. Meyer
- , Timothy J. W. Dawes
- & Declan P. O’Regan
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Article |
Position-specific oxidation of miR-1 encodes cardiac hypertrophy
The 8-oxoguanine modification of the microRNA miR-1 results in redirected recognition and silencing of target genes and leads to cardiac hypertrophy in mice.
- Heeyoung Seok
- , Haejeong Lee
- & Sung Wook Chi
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Article
| Open AccessRepositioning of the global epicentre of non-optimal cholesterol
From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.
- Cristina Taddei
- , Bin Zhou
- & Majid Ezzati
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Article |
Video-based AI for beat-to-beat assessment of cardiac function
A video-based deep learning algorithm—EchoNet-Dynamic—accurately identifies subtle changes in ejection fraction and classifies heart failure with reduced ejection fraction using information from multiple cardiac cycles.
- David Ouyang
- , Bryan He
- & James Y. Zou
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Article |
An acute immune response underlies the benefit of cardiac stem cell therapy
Cardiac stem cell therapy in mouse models of ischaemia–reperfusion injury demonstrates that improvement in heart function is linked to an immune response characterized by the induction of CCR2+ and CX3CR1+ macrophages.
- Ronald J. Vagnozzi
- , Marjorie Maillet
- & Jeffery D. Molkentin
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Article |
Structural insights into the mechanism of human soluble guanylate cyclase
Cryo-electron microscopy structures of human soluble guanylate cyclase in inactive and activated states shed light on the activation mechanism of this enzyme by nitric oxide.
- Yunlu Kang
- , Rui Liu
- & Lei Chen
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Letter |
Targeting cardiac fibrosis with engineered T cells
Adoptive transfer of CAR T cells against the fibroblast marker FAP reduces cardiac fibrosis and restores function after cardiac injury in mice, providing proof-of-principle for the development of immunotherapeutic treatments for cardiac disease.
- Haig Aghajanian
- , Toru Kimura
- & Jonathan A. Epstein
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Article |
Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy
A disease model using cardiomyocytes derived from induced pluripotent stem cells of patients with mutated LMNA-related dilated cardiomyopathy reveals that the abnormal activation of the PDGF pathway is associated with the arrhythmic phenotypes of patients.
- Jaecheol Lee
- , Vittavat Termglinchan
- & Joseph C. Wu
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Letter |
Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death
Histone H4 is released from neutrophil extracellular traps and induces membrane lysis in vascular smooth muscle cells, leading to the destabilization of atherosclerotic plaques.
- Carlos Silvestre-Roig
- , Quinte Braster
- & Oliver Soehnlein
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Letter |
SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis
The SR-B1 receptor partners with DOCK4 and RAC1 to drive the uptake and transcytosis of LDL in endothelial cells, thereby promoting atherosclerosis in mice.
- Linzhang Huang
- , Ken L. Chambliss
- & Philip W. Shaul
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Article |
Nitrosative stress drives heart failure with preserved ejection fraction
iNOS-driven dysregulation of the IRE1α–XBP1 pathway leads to cardiomyocyte dysfunction in mice and recapitulates the systemic and cardiovascular features of human heart failure with preserved ejection fraction.
- Gabriele G. Schiattarella
- , Francisco Altamirano
- & Joseph A. Hill
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Letter |
Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation
Singlet molecular oxygen, produced by indoleamine 2,3-dioxygenase 1 activity, gives rise to a signalling molecule that regulates arterial relaxation under inflammatory conditions.
- Christopher P. Stanley
- , Ghassan J. Maghzal
- & Roland Stocker
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Letter |
Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease
Integrin β7-dependent Glp1rhigh natural gut intraepithelial T lymphocytes that reside in the small intestine modulate dietary metabolism in mice by restricting the bioavailability of GLP-1.
- Shun He
- , Florian Kahles
- & Filip K. Swirski
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Letter |
Consistent success in life-supporting porcine cardiac xenotransplantation
α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and human thrombomodulin require non-ischaemic preservation with continuous perfusion and post-transplantation growth control to ensure long-term orthotopic function of the xenograft in baboons.
- Matthias Längin
- , Tanja Mayr
- & Jan-Michael Abicht
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Letter |
Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice
A single-chain variable fragment of the antibody E06, which binds to the phosphocholine headgroup of oxidized phospholipids, blocks the uptake of oxidized low-density lipoprotein by macrophages, and reduces inflammation and atherosclerosis in hypercholesterolaemic mice.
- Xuchu Que
- , Ming-Yow Hung
- & Joseph L. Witztum
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Letter |
Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation
A new model of cardiac trabeculation in mice is presented in which NOTCH1 and NRG1 have opposing roles in extracellular matrix degradation and synthesis that are essential for defining trabecular architecture.
- Gonzalo del Monte-Nieto
- , Mirana Ramialison
- & Richard P. Harvey
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Letter |
Electromechanical vortex filaments during cardiac fibrillation
Using optical mapping and 3D ultrasound, the dynamics and interactions between electrical and mechanical phase singularities were analysed by simultaneously measuring the membrane potential, intracellular calcium concentration and mechanical contractions of the heart during normal rhythm and fibrillation.
- J. Christoph
- , M. Chebbok
- & S. Luther
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Article |
Salt-responsive gut commensal modulates TH17 axis and disease
High salt intake changed the gut microbiome and increased TH17 cell numbers in mice, and reduced intestinal survival of Lactobacillus species, increased the number of TH17 cells and increased blood pressure in humans.
- Nicola Wilck
- , Mariana G. Matus
- & Dominik N. Müller
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Letter |
IL-11 is a crucial determinant of cardiovascular fibrosis
Fibroblast-specific Il-11 expression causes heart and kidney fibrosis and organ failure, whereas IL-11 inhibition prevents fibroblast activation and organ fibrosis, indicating that IL-11 inhibition is a potential therapeutic strategy to treat fibrotic diseases.
- Sebastian Schafer
- , Sivakumar Viswanathan
- & Stuart A. Cook
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Letter |
Hippo pathway deficiency reverses systolic heart failure after infarction
Deletion of the Hippo pathway component Salvador in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function.
- John P. Leach
- , Todd Heallen
- & James F. Martin
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Article |
The extracellular matrix protein agrin promotes heart regeneration in mice
The extracellular matrix protein agrin promotes cardiac regeneration in adult mice after myocardial infarction; it modulates cardiac differentiation and proliferation by interacting with the dystrophin–glycoprotein complex, Yap and ERK-mediated signalling.
- Elad Bassat
- , Yara Eid Mutlak
- & Eldad Tzahor
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Article |
Endothelial TLR4 and the microbiome drive cerebral cavernous malformations
Lipopolysaccharide derived from gut bacteria can accelerate the formation of cerebral cavernous malformations by activating TLR4 on endothelial cells, and polymorphisms that increase expression of the genes encoding TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans.
- Alan T. Tang
- , Jaesung P. Choi
- & Mark L. Kahn
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Letter |
The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
Conditional deletion of the mitochondrial Na+/Ca2+ exchanger NCLX in adult mouse hearts causes sudden death due to mitochondrial calcium overload, whereas its overexpression limits cell death elicited by ischaemia reperfusion injury and heart failure.
- Timothy S. Luongo
- , Jonathan P. Lambert
- & John W. Elrod
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Letter |
Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow
YAP and TAZ, effectors of the Hippo pathway, sense mechanical forces generated by blood flow and play a role in atherosclerosis pathogenesis.
- Li Wang
- , Jiang-Yun Luo
- & Yu Huang
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Letter |
Control of mitochondrial function and cell growth by the atypical cadherin Fat1
Fragments of the atypical cadherin Fat1 accumulate in the mitochondria of vascular smooth muscle cells where they reduce respiration, leading to a regulated proliferative response to arterial injury.
- Longyue L. Cao
- , Dario F. Riascos-Bernal
- & Nicholas E. S. Sibinga
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Letter |
Hypoxia induces heart regeneration in adult mice
A pathway triggered by chronic severe hypoxia boosts regeneration of injured hearts in adult mice.
- Yuji Nakada
- , Diana C. Canseco
- & Hesham A. Sadek
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Letter |
Genome-wide associations for birth weight and correlations with adult disease
Multi-ancestry genome-wide association analyses for birth weight in 153,781 individuals identified 60 genomic loci in which birth weight and fetal genotype were associated and found an inverse genetic correlation between birth weight and cardiometabolic risk.
- Momoko Horikoshi
- , Robin N. Beaumont
- & Rachel M. Freathy
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Letter |
CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis
Atherosclerotic lesions in mice and humans switch on a ‘don’t eat me’ signal—expression of CD47—that prevents effective removal of diseased tissue; anti-CD47 antibody therapy can normalize this defective efferocytosis, with beneficial results in several mouse models of atherosclerosis.
- Yoko Kojima
- , Jens-Peter Volkmer
- & Nicholas J. Leeper
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Letter |
Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury
The transcription factor Pitx2 is upregulated in injured neonatal and Hippo-deficient mouse hearts, where it interacts with the Hippo effector protein Yap to activate reactive oxygen species scavengers, thus preventing the heart from oxidative damage.
- Ge Tao
- , Peter C. Kahr
- & James F. Martin
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Letter |
Cerebral cavernous malformations arise from endothelial gain of MEKK3–KLF2/4 signalling
Gain of MEKK3 signalling is shown to cause cerebral cavernous malformations (CCMs) via activation of the target genes Klf2 and Klf4; endothelial-specific loss of MEKK3, KLF2 or KLF4 prevents lesion formation and lethality in a mouse CCM model.
- Zinan Zhou
- , Alan T. Tang
- & Mark L. Kahn
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Letter |
The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia
Zinc transporter ZIP12 expression is increased in many cell types in remodelled mammalian pulmonary arterioles in hypoxia-induced pulmonary hypertension.
- Lan Zhao
- , Eduardo Oliver
- & Martin R. Wilkins
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Article |
HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease
Myocardial hypoxia activates HIF1α, which activates the splicing factor SF3B1, which mediates a splice switch of the fructose-metabolising enzyme KHK, so that the C isoform that has superior affinity for fructose is expressed in the heart—pathological heart growth and contractile dysfunction can therefore be suppressed by depleting SF3B1 or deleting KHK.
- Peter Mirtschink
- , Jaya Krishnan
- & Wilhelm Krek