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| Open AccessMultiscale mapping of transcriptomic signatures for cardiotoxic drugs
Using a new computational pipeline for identification of drug-selective transcriptomic responses and FAERS data, the authors identified potential pathways and genomic variants indicative of cancer drug cardiotoxicity in iPSC-derived cardiomyocytes.
- Jens Hansen
- , Yuguang Xiong
- & Ravi Iyengar
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Article
| Open AccessMaglev-fabricated long and biodegradable stent for interventional treatment of peripheral vessels
The interventional treatment of limb-threatening ischemia calls for a medical stent. Herein, a long and biodegradable stent appropriate for below-the-knee artery is developed based on a metal-polymer composite material, where a magnetic levitation is employed to achieve a homogeneous coating.
- Wanqian Zhang
- , Xian Gao
- & Jiandong Ding
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| Open AccessDetection of distant relatedness in biobanks to identify undiagnosed cases of Mendelian disease as applied to Long QT syndrome
Analysis of shared chromosomal segments is applied to identify distantly related, previously undiagnosed carriers of a rare KCNE1 variant. The carriers are shown to have the Long QT Syndrome phenotype with incomplete penetrance.
- Megan C. Lancaster
- , Hung-Hsin Chen
- & Jennifer E. Below
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| Open AccessFacile engineering of interactive double network hydrogels for heart valve regeneration
Regenerative heart valve prostheses rely on interactive materials that can adapt to the remodeling process, but these materials are often based on complex designs. Using 1,1’-thiocarbonyldiimidazole chemistry, the authors propose a double network hydrogel formulation for heart valve regeneration.
- Jinsheng Li
- , Weihua Qiao
- & Yuzhou Wu
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Article
| Open AccessPotassium dependent structural changes in the selectivity filter of HERG potassium channels
HERG channel inactivation is critical for normal heart rhythm. Authors determine structures of open and non-conducting states of HERG and identify a key role for S620 on the pore helix in coordinating transitions between open and inactivated states.
- Carus H. Y. Lau
- , Emelie Flood
- & Jamie I. Vandenberg
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Article
| Open AccessPTPN14 aggravates neointimal hyperplasia via boosting PDGFRβ signaling in smooth muscle cells
PDGF signaling plays a vital role in promoting neointimal hyperplasia. Here the authors show that PTPN14 dephosphorylates PDGFRβ Y692, which enhances PDGFRβ signaling activation, thereby aggravating neointimal hyperplasia.
- Qiannan Ma
- , Xue He
- & Jinlong He
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Article
| Open AccessAberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis
Macrophages and their metabolism are known to contribute to inflammation in the atherosclerotic plaques, but the underpinning molecular level regulatory processes are lesser known. Here authors show that under inflammatory conditions, macrophages express VCAM-1 within the atherosclerotic plaques, which leads to increased mitochondrial DNA synthesis via activation of the transcription factor C/EBPα, which in turn triggers inflammation by STING signalling.
- Niranjana Natarajan
- , Jonathan Florentin
- & Partha Dutta
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| Open AccessMacrophage ILF3 promotes abdominal aortic aneurysm by inducing inflammatory imbalance in male mice
Here the authors investigate the involvement of the immune modulator ILF3 in abdominal aortic aneurysm, showing that macrophage ILF3 promotes aneurysm progression by increasing NF-kB activity and inhibiting Keap1-Nrf2 signaling.
- Zhao-yang Wang
- , Jie Cheng
- & Ming-xiang Zhang
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Article
| Open AccessLamin A/C deficiency-mediated ROS elevation contributes to pathogenic phenotypes of dilated cardiomyopathy in iPSC model
LMNA-related dilated cardiomyopathy (DCM) is an inherited cardiomyopathy featured by early-onset lethal arrhythmias, but the underlying mechanisms remain unclear. Here, the authors show that manipulation of impaired SIRT1 activity and excessive oxidative stress may offer new therapeutic strategies for LMNA-related DCM.
- Hangyuan Qiu
- , Yaxun Sun
- & Ping Liang
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Article
| Open AccessSRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling
How post-translational SUMOylation regulates the SRF activity in cardiovascular disease is unclear. Here, the authors report that SRF SUMOylation increased by SENP1 deficiency switches vascular smooth muscle cells from a healthy contractile phenotype to a disease-associated synthetic phenotype.
- Yue Xu
- , Haifeng Zhang
- & Wang Min
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Article
| Open AccessAI hybrid survival assessment for advanced heart failure patients with renal dysfunction
Here the authors show an AI-powered assessment system (AIHFLevel, www.hf-ai-survival.com) empowering healthcare professionals for continuous risk monitoring and prognosis assessment of patients who have advanced heart failure with renal dysfunction.
- Ge Zhang
- , Zeyu Wang
- & Junnan Tang
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Article
| Open AccessIn situ assembly of an injectable cardiac stimulator
Heart pacing devices are bulky or rely on surgery. Here, the authors present an injectable cardiac stimulator based on a nanoparticle solution which attaches to the heart and forms a conductive path to the skin for external connection. It can regulate heartbeats and is thereafter cleared from the body.
- Umut Aydemir
- , Abdelrazek H. Mousa
- & Roger Olsson
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Article
| Open AccessRisk of stroke in male and female patients with atrial fibrillation in a nationwide cohort
Sex has been suggested as a risk modifier for stroke in patients with atrial fibrillation. Here we show that among patients with atrial fibrillation, the excess stroke risk for female patients vs male patients has been declining, with risk-score adjusted relative risk estimates suggesting limited difference in most recent years.
- Peter Brønnum Nielsen
- , Rasmus Froberg Brøndum
- & Gregory Y. H. Lip
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Article
| Open AccessReprogramming the myocardial infarction microenvironment with melanin-based composite nanomedicines in mice
Myocardial infarction (MI) is the most common emergent manifestation of cardiovascular diseases. Here, the authors designed a nanomedicine that can reprogram MI microenvironment by converting the detrimental substances (H+, ROS and hypoxia) into beneficial elements (O2 and H2O), as such demonstrates promising potential for the clinical application.
- Yamei Liu
- , Shuya Wang
- & Yongping Bai
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Article
| Open AccessGasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation
ICI-induced myocarditis is fatal, but its mechanism is unclear. Here, the authors identify GSDME as a key driver by promoting cGAS-STING signaling, enhancing our understanding of its pathogenesis.
- Si-Jia Sun
- , Xiao-Dong Jiao
- & Pei Wang
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Article
| Open AccessLipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis
The mechanisms and consequences of bioactive lipids release from lipid droplets remain poorly understood. Here the authors link a lipid droplet enzyme to mobilization of esters of regulatory sterols in foam cells and protection against atherosclerosis.
- Young-Hwa Goo
- , Janeesh Plakkal Ayyappan
- & Antoni Paul
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Article
| Open AccessTregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice
After myocardial infarction, excessive inflammation impairs heart repair, leading to reduced cardiac function. Here, the authors show that treatment with anti-inflammatory immune cells (regulatory T cells) improves cardiac repair by modulating the activity of a specific subset of macrophages in the heart.
- Yasmin K. Alshoubaki
- , Bhavana Nayer
- & Mikaël M. Martino
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Article
| Open AccessDeterminants of transthyretin levels and their association with adverse clinical outcomes among UK Biobank participants
Though the role of transthyretin (TTR) in the development of cardiac amyloidosis has been recognized, the determinants of TTR levels remain unexplored. Here, the authors present the clinical correlates of transthyretin levels and show that reduced TTR levels are associated with an increase risk of cardiovascular disease and mortality.
- Naman S. Shetty
- , Mokshad Gaonkar
- & Pankaj Arora
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Article
| Open AccessA robust cis-Mendelian randomization method with application to drug target discovery
cis-Mendelian randomization can be used to infer the causal effect of a molecular trait on an outcome. Here, the authors address challenges in current cis-MR studies and present cisMR-cML, a method robust to horizontal pleiotropy and linkage disequilibrium.
- Zhaotong Lin
- & Wei Pan
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| Open AccessInhalable cardiac targeting peptide modified nanomedicine prevents pressure overload heart failure in male mice
Clinical applications of therapeutic agents for long-term management of heart failure have been hindered by the poor delivery efficiency. Here, the authors propose a myocardium-targeted strategy based on inhalable cardiac-targeting peptide-modified nanomedicine for the pharmacological treatment of heart failure.
- Haobo Weng
- , Weijuan Zou
- & Xianhong Shu
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| Open AccessAging aggravates aortic aneurysm and dissection via miR-1204-MYLK signaling axis in mice
How aging induces aortic aneurysm and dissection (AAD) remains unclear. Here, the authors show that aging induces miR-1204 to inhibit MYLK, promoting vascular smooth muscle cells to acquire senescence-associated secretory phenotype, resulting in vascular inflammation, and the aggravation of AAD formation.
- Ze-Long Liu
- , Yan Li
- & Jing-Song Ou
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Article
| Open AccessEfficient and reproducible generation of human iPSC-derived cardiomyocytes and cardiac organoids in stirred suspension systems
Human iPSC-CMs are invaluable for cardiac disease modeling and regeneration. Here, authors developed an optimized suspension culture protocol to efficiently and reproducibly differentiate hiPSCs into cardiomyocytes and cardiac organoids.
- Maksymilian Prondzynski
- , Paul Berkson
- & William T. Pu
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Article
| Open AccessPlasma metabolomics reveals the shared and distinct metabolic disturbances associated with cardiovascular events in coronary artery disease
Investigating metabolic disturbances in coronary artery disease (CAD) may allow the identifications of new prognostic biomarkers. Here the authors perform a metabolomics study to highlight the shared and distinct metabolites characterizing risks of several cardiovascular events in CAD patients.
- Jiali Lv
- , Chang Pan
- & Yuguo Chen
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| Open AccessEffectiveness and safety of continuous low-molecular-weight heparin versus switching to direct oral anticoagulants in cancer-associated venous thrombosis
Whether switching from low-molecular-weight heparin to direct oral anticoagulants (DOACs) in cancer-associated thrombosis patients is safe and effective is unknown. Here, the authors show that switching to DOACs reduced venous thromboembolism and mortality without increasing bleeding.
- Wei Kang
- , Caige Huang
- & Esther W. Chan
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| Open AccessSingle dose of intravenous miR199a-5p delivery targeting ischemic heart for long-term repair of myocardial infarction
Long-term treatment of myocardial infarction remains challenging despite advances in medical technology. Here, the authors show that P-MSN/miR199a-5p nanoparticles can effectively repair myocardial infarction by enhancing contractility and limiting apoptosis, highlighting the therapeutic potential of miR199a-5p for long-term management of myocardial infarction.
- Yu Chen
- , Shuai Liu
- & Xiaozhong Qiu
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Article
| Open AccessThe chromatin regulator Ankrd11 controls cardiac neural crest cell-mediated outflow tract remodeling and heart function
Ankrd11 is a chromatin regulator that is strongly associated with KBG syndrome, a rare disorder that includes heart defects. Here they show that loss of Ankrd11 from neural crest dysregulates cardiac neural crest cell organization and crucial signaling pathways, leading to failed heart outflow tract septation and severe cardiac defects.
- Yana Kibalnyk
- , Elia Afanasiev
- & Anastassia Voronova
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Article
| Open AccessComparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study
CETP inhibitors are being developed for treatment of coronary heart disease. Here, the authors show that the anticipated beneficial effects of lower plasma levels of CETP are shared among individuals of European and East Asian ancestry.
- Diana Dunca
- , Sandesh Chopade
- & Amand F. Schmidt
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Article
| Open AccessCardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities
Cardiac myosin binding protein-C (cMyBP-C) phosphorylation is crucial for heart function. Here, the authors characterize cMyBP-C dephosphorylation by PP1 and PP2A, developing a kinetic model that integrates kinase and phosphatase activities, revealing their distinct roles in health and heart disease.
- Thomas Kampourakis
- , Saraswathi Ponnam
- & Daniel Koch
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Article
| Open AccessEnhancing the diagnosis of functionally relevant coronary artery disease with machine learning
Early detection of coronary artery disease is crucial to mitigate cardiac complications. Here, the authors show how machine learning can enhance risk stratification, and potentially reduce unwarranted invasive testing by integrating widely accessible clinical data and stress test ECG signals.
- Christian Bock
- , Joan Elias Walter
- & Christian Müller
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| Open AccessSmooth muscle NF90 deficiency ameliorates diabetic atherosclerotic calcification in male mice via FBXW7-AGER1-AGEs axis
The accumulation of AGEs is closely related to the atherosclerotic calcification in diabetic patients. Here, the authors find that VSMC NF90 knockout attenuates diabetic atherosclerotic calcification by mediating the metabolic imbalance of AGEs.
- Fei Xie
- , Bin Liu
- & Ming-xiang Zhang
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Article
| Open AccessSpace radiation damage rescued by inhibition of key spaceflight associated miRNAs
In space radiation-exposed cells, targeting specific microRNAs with antagomirs can reduce cardiovascular damage and improve cellular function. Here the authors describe a reduction in inflammation and DNA double-strand break activity within these cells upon antagomir treatment.
- J. Tyson McDonald
- , JangKeun Kim
- & Afshin Beheshti
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Article
| Open AccessDynamics of collagen oxidation and cross linking in regenerating and irreversibly infarcted myocardium
Resorption of myocardial scar and subsequent regeneration may be influenced by the extent of irreversible pyridinoline and deoxypyridinoline collagen cross-links that develop in the scar. Hydroxylation of lysine in collagen may regulate this process.
- Eman A. Akam-Baxter
- , David Bergemann
- & David E. Sosnovik
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| Open AccessMSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease
Coronary artery disease is the leading cause of death among adults worldwide, however current risk stratification methods lack the ability to incorporate new information throughout the life-course or to combine innate genetic risk factors with acquired lifetime risk. Here the authors introduce a multistate model to address these limitations.
- Sarah M. Urbut
- , Ming Wai Yeung
- & Pradeep Natarajan
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Article
| Open AccessSemaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis
Semaglutide is used for glucose control and weight reduction. Here, the authors show that it enhances myocardial metabolism by targeting Creb5/NR4a1, protecting against cardiac remodeling and offering a therapeutic approach for heart failure through metabolic regulation.
- Yu-Lan Ma
- , Chun-Yan Kong
- & Qi-Zhu Tang
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| Open AccessDeep learning of left atrial structure and function provides link to atrial fibrillation risk
In this study, a deep learning-based model of left atrial size in UK Biobank enabled genome-wide association studies in 35,049 healthy participants. Several lines of evidence, including the PITX2 locus, linked left atrial dysfunction to atrial fibrillation risk.
- James P. Pirruccello
- , Paolo Di Achille
- & Patrick T. Ellinor
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| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessE-cardiac patch to sense and repair infarcted myocardium
Infarted myocardium hampers the synchronous electroactivity of the cardiac tissue. Here, the authors showcase a battery-free conductive cardiac patch made of reduced graphene and its therapeutic efficacy for cardiac repair.
- Renjie Qiu
- , Xingying Zhang
- & Leyu Wang
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| Open AccessComparison of intramyocellular lipid metabolism in patients with diabetes and male athletes
Endurance athletes and sedentary type 2 diabetes patients swapped their lifestyle for 8 weeks. Athletes store and utilise saturated fat intensely for performant physical activity, and type 2 diabetes patients reversed their dysmetabolic lipid state after endurance training.
- Alice M. Mezincescu
- , Amelia Rudd
- & Dana Dawson
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Article
| Open AccessSleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes
Sleep disorders increase the risk and mortality of heart disease. Here, the authors show that sleep fragmentation results in elevated copper levels in the male mouse heart and exacerbates myocardial ischemia–reperfusion injury with increased myocardial cuproptosis and apoptosis.
- Na Chen
- , Lizhe Guo
- & E. Wang
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Article
| Open AccessLncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas
Arteriovenous fistulas are the most common vascular access points for hemodialysis, but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia. Here, the author shows that LncDACH1 regulates NIH through the HSP90/ SRPK1/ AKT signaling axis.
- Zhaozheng Li
- , Yao Zhao
- & Jundong Jiao
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Article
| Open AccessBIN1 knockdown rescues systolic dysfunction in aging male mouse hearts
Cardiac dysfunction is a hallmark of aging in humans and mice. Here, the authors show that by restoring youthful Bridging Integrator 1 (BIN1) protein levels in the hearts of 24-month-old mice in vivo cardiac systolic function is rejuvenated, and the aging phenotype partially reversed within two weeks.
- Maartje Westhoff
- , Silvia G. del Villar
- & Rose E. Dixon
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Article
| Open AccessTAD boundary deletion causes PITX2-related cardiac electrical and structural defects
This study identifies an altered chromatin conformation associated to a cardiac disorder observed in 7 independent families. A deletion of 2 diverging CTCF binding sites on 4q25 induces TAD fusion and leads to PITX2 expression dysregulation.
- Manon Baudic
- , Hiroshige Murata
- & Julien Barc
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Article
| Open AccessStatins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1
Endothelial dysfunction has been shown to occur in HFpEF and we know that statins can target endothelial dysfunction by inhibiting miR-133a. Here the authors show that statins improve diastolic dysfunction in HFpEF by increasing the levels of a circRNA which, in turns, binds to miR-133a modulating its downstream targets.
- Bin Li
- , Wen-Wu Bai
- & Shuang-Xi Wang
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Article
| Open AccessPredicting mortality from AI cardiac volumes mass and coronary calcium on chest computed tomography
Chest computed tomography (CT) is one of the most common diagnostic tests. Here, the authors combine two AI models to measure from CT coronary artery calcium, left ventricular mass index, and left and right atrial and ventricular volumes, and show their association with cardiovascular mortality.
- Robert J. H. Miller
- , Aditya Killekar
- & Piotr J. Slomka
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Article
| Open AccessNaked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles
The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals.
- Chris G. Faulkes
- , Thomas R. Eykyn
- & Dunja Aksentijevic
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Article
| Open AccessS100A8/A9 as a prognostic biomarker with causal effects for post-acute myocardial infarction heart failure
Heart failure is the most prevalent complication of acute myocardial infarction. Here, the authors show that circulating S100A8/A9 is a robust predictor and potentially causal medicator for heart failure post-acute myocardial infarction, as such could serve as a promising drug target for cardioprotection.
- Jie Ma
- , Yang Li
- & Yulin Li
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Article
| Open AccessArtificial intelligence-enabled prediction of chemotherapy-induced cardiotoxicity from baseline electrocardiograms
Anthracyclines can induce cancer therapy-related cardiac dysfunction (CTRCD), of which occurrence remains unpredictable. Here, the authors develop an artificial intelligence model to robustly predict CTRCD from a single recording of 12-lead electrocardiogram taken before the initiation of chemotherapy in cancer patients treated with anthracyclines.
- Ryuichiro Yagi
- , Shinichi Goto
- & Rahul C. Deo
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Article
| Open AccessEpigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
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Article
| Open AccessFibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice
Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.
- Yasufumi Katanasaka
- , Harumi Yabe
- & Tatsuya Morimoto