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| 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 AccessThrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom
Population-based studies can provide information on the safety of COVID-19 vaccines. Here the authors report the rates thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom and compare them with the background (expected) rates in the general population.
- Edward Burn
- , Xintong Li
- & Daniel Prieto-Alhambra
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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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| Open AccessA formal validation of a deep learning-based automated workflow for the interpretation of the echocardiogram
Deep learning can automate the interpretation of medical imaging tests. Here, the authors formally assess the interchangeability of deep learning algorithms with expert human measurements for interpreting echocardiographic studies.
- Jasper Tromp
- , David Bauer
- & Scott D. Solomon
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Article
| Open AccessMETTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury
The benefit of regular exercise on the heart has been well documented but the role of RNA m6A modification in exercise-induced cardiac remodelling remains largely unknown. In this study, the authors report that METTL14 plays an important role in RNA m6A modification in exercise-induced physiological cardiac hypertrophy.
- Lijun Wang
- , Jiaqi Wang
- & Junjie Xiao
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| Open AccessDusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction
Dusp6, an ERK specific phosphatase, was identified as a regenerative repressor during zebrafish heart regeneration. Here, the authors show that Dusp6 deficiency improves post infarctional cardiac repair by predominantly attenuating neutrophil-mediated myocardial damage in mammalian hearts.
- Xiaohai Zhou
- , Chenyang Zhang
- & Jing-Wei Xiong
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Article
| Open AccessMitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure
Mitochondria power the beating heart. Here, Donnarumma et al. show that loss of the inner mitochondrial membrane protein MTFP1 in cardiomyocytes reduces bioenergetic efficiency and cell death resistance leading to heart failure in mice.
- Erminia Donnarumma
- , Michael Kohlhaas
- & Timothy Wai
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Article
| Open AccessJAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development remains unknown. Here, the authors show that JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
- Rida Al-Rifai
- , Marie Vandestienne
- & Hafid Ait-Oufella
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Article
| Open AccessHIF1α-AS1 is a DNA:DNA:RNA triplex-forming lncRNA interacting with the HUSH complex
Using a composite bioinformatics approach, the DNA:DNA:RNA triplex-forming lncRNAs HIF1α-AS1 was identified in human endothelial cells which recruits an epigenetic silencing complex to limit expression of triplex target genes.
- Matthias S. Leisegang
- , Jasleen Kaur Bains
- & Ralf P. Brandes
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Article
| Open AccessKynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis
Failed cardiac regeneration to repair adult acute myocardial ischemia is the leading cause of heart failure. Here, the authors show that IDO1-derived kynurenine metabolism promotes cardiomyocyte proliferation and cardiac angiogenesis via cytoplasmic aryl hydrocarbon receptor (AhR) and nucleic AhR translocation signalling.
- Donghong Zhang
- , Jinfeng Ning
- & Ming-Hui Zou
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Article
| Open AccessMyocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors
Baroreflex control of cardiac contractility is essential to maintain cardiocirculatory homeostasis. Here, Oda et al show that α1 adrenoceptor-stimulated Zn2+ entry through TRPC6 channels boosts β adrenoceptor-dependent myocardial positive inotropy.
- Sayaka Oda
- , Kazuhiro Nishiyama
- & Motohiro Nishida
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Article
| Open AccessE-cigarettes and their lone constituents induce cardiac arrhythmia and conduction defects in mice
The use of E-cigarettes has increased despite the unknown long-term effects. Here the authors show that e-cigarette aerosols alter cardiac conduction, repolarization, and autonomic regulation in mice, contingent on the chemical composition of e-liquids and partly through parasympathetic modulation.
- Alex P. Carll
- , Claudia Arab
- & Daniel J. Conklin
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Article
| Open AccessNIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart
Phosphorylation of the essential myosin light chain (ELC) influence actin-myosin crossbridge cycling in the heart. Here, the authors show upregulated ELC-phosphorylation in systolic heart failure and identify NIMArelated kinase 9 to bind to ELC mediating its calcium-dependent phosphorylation.
- Marion Müller
- , Rose Eghbalian
- & Benjamin Meder
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Article
| Open AccessWhole genome sequence analysis of blood lipid levels in >66,000 individuals
Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.
- Margaret Sunitha Selvaraj
- , Xihao Li
- & Pradeep Natarajan
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| Open AccessAllele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage
The authors use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. The findings emphasize the importance of allele-specific insight into gene regulation in development, homeostasis and disease.
- Gayan I. Balasooriya
- & David L. Spector
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Article
| Open AccessIntrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome
The developmental mechanisms responsible for the structural defects observed in hypoplastic left heart syndrome remain controversial. Using rbfox-deficient zebrafish, the authors implicate impaired cardiac function as a primary driver of disease.
- Mengmeng Huang
- , Alexander A. Akerberg
- & Caroline E. Burns
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Article
| Open AccessSingle-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Identifying the mechanisms underlying the early inflammatory phase of aortic valve disease is crucial for disease prevention. Here the authors perform single-cell RNA sequencing to show the immunomodulatory role of PPARγ in valvular endothelial cells during hyperlipidemia.
- Seung Hyun Lee
- , Nayoung Kim
- & Jae-Hoon Choi
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Article
| Open AccessThe complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure
Right ventricular (RV) failure is clinically crucial, but there is no specific therapy. Here, the authors show that the complement alternative pathway is activated in RV failure and that blockade of the pathway ameliorates RV failure in mice.
- Shogo Ito
- , Hisayuki Hashimoto
- & Shinsuke Yuasa
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Article
| Open AccessMild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells
Obesity and inflammation have been associated to cancer progression. Here, the authors show that high fat and cholesterol diet, in a non-obese context, promotes tumourigenesis through increasing inflammatory monocytes and myeloid-derived pro-angiogenic factors.
- Thi Tran
- , Jean-Remi Lavillegrand
- & Stephane Potteaux
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| Open AccessClonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease
Clonal hematopoiesis, often caused by mutations in DNMT3A and TET2, is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by DNMT3A vs. TET2 mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.
- M d Mesbah Uddin
- , Ngoc Quynh H. Nguyen
- & Karen N. Conneely
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Article
| Open AccessBeiging of perivascular adipose tissue regulates its inflammation and vascular remodeling
Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.
- Yusuke Adachi
- , Kazutaka Ueda
- & Issei Komuro
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Article
| Open AccessIdentification of risk loci for primary aldosteronism in genome-wide association studies
Detection of primary aldosteronism, the most common form of secondary arterial hypertension, is essential for targeted management and prevention of cardiovascular complications. Here, the authors identify genetic loci associated with primary aldosteronism, suggesting new mechanisms of disease.
- Edith Le Floch
- , Teresa Cosentino
- & Maria-Christina Zennaro
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Article
| Open AccessEndophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes
Accurate classification of genetic variants is critical for research and patient care. Here, the authors report that population-based associations between rare variants and quantitative endophenotypes for monogenic diseases can provide support for variant pathogenicity.
- Jennifer L. Halford
- , Valerie N. Morrill
- & Steven A. Lubitz
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Article
| Open AccessWhole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals
Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.
- Usman A. Tahir
- , Daniel H. Katz
- & Robert E. Gerszten
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Article
| Open AccessSpatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts
Cellular composition and function are not clearly defined in heart failure after myocardial infarction. Here, using single cell and spatial transcriptomics in a MI-HF mouse model, the authors show that macrophages expressing Trem2 are found within the infarcts and this could be a useful biomarker.
- Seung-Hyun Jung
- , Byung-Hee Hwang
- & Yeun-Jun Chung
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Article
| Open AccessGenome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.
- Catherine M. Francis
- , Matthias E. Futschik
- & Paul M. Matthews
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Article
| Open AccessCDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation
Phosphorylation catalyzed by kinases is a key event in signaling pathways involved in cardiomyocyte hypertrophy. Here the authors show that the kinase CLK4 ameliorates cardiac hypertrophy by phosphorylating NEXN.
- Jian Huang
- , Luxin Wang
- & Yi-Han Chen
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Article
| Open AccessTargeting transcription in heart failure via CDK7/12/13 inhibition
In this study, Hsu et al. show that inhibition of CDK7/12/13 attenuates maladaptive transcriptional activation in cultured cardiomyocytes and a mouse model of heart failure, suggesting that targeting the transcription machinery might be a therapeutic approach to treat heart failure with reduced ejection fraction.
- Austin Hsu
- , Qiming Duan
- & Saptarsi M. Haldar
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Article
| Open AccessSingle-cell transcriptome atlas of the human corpus cavernosum
The corpus cavernosum is the most important structure for penile erection, and its dysfunction causes physiological and psychological problems. Here the authors perform single-cell RNA-sequencing on corpus cavernosum samples from males with normal erection and erectile dysfunction patients, providing insights into this pathology.
- LiangYu Zhao
- , Sha Han
- & Zheng Li
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Article
| Open AccessA SOX17-PDGFB signaling axis regulates aortic root development
Little is known about the developmental causes of aortic root defects. Here the authors show that the inactivation of Sox17 in aortic root endothelium results in aortic root defects affecting aortic valve and coronary ostium.
- Pengfei Lu
- , Ping Wang
- & Bin Zhou
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Article
| Open AccessCardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy
Functional succinate dehydrogenase (SDH) complex is vital to mitochondrial homeostasis. Here the authors show that disruption of SDH assembly in the heart causes dilated cardiomyopathy via impairing the mitochondrial integrity and metabolism and that mitochondrial interventions can be an effective approach to ameliorate the disease progression.
- Xueqiang Wang
- , Xing Zhang
- & Zhihui Feng
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Article
| Open AccessSex differences in heart mitochondria regulate diastolic dysfunction
In this paper, the authors show that sex differences in mitochondrial DNA levels and function in the heart contribute to sex biases in functions relevant to heart failure, identifying Acsl6 as a mitochondrial sex-biased regulator of diastolic function.
- Yang Cao
- , Laurent Vergnes
- & Aldons J. Lusis
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Article
| Open AccessT cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
Cholesterol efflux is mediated by specific transporters in T cells. Here the authors show that when the ABCA1/ABCG1 cholesterol transporters are absent, peripheral T cell numbers are reduced but activation increased with a premature aging phenotype of T cell senescence and apoptosis in middle aged Ldlr−/− mice.
- Venetia Bazioti
- , Anouk M. La Rose
- & Marit Westerterp
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| Open AccessAge and sex-specific risks of myocarditis and pericarditis following Covid-19 messenger RNA vaccines
There have been reports of myocarditis and pericarditis following mRNA COVID-9 vaccination. Here, the authors use nationwide data from France and find increased risks of these outcomes in the first week following vaccination, for both the first and second dose, and present age- and sex-specific rates.
- Stéphane Le Vu
- , Marion Bertrand
- & Mahmoud Zureik
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| Open AccessMapping the cardiac vascular niche in heart failure
The cardiac vascular niche is of major importance in homeostasis and disease, but knowledge of its complexity in response to injury remains limited. Here we combine lineage tracing with single cell RNA sequencing to show alterations in fibroblasts, endothelial and mural cells in hypertrophic remodeling.
- Fabian Peisker
- , Maurice Halder
- & Rafael Kramann
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Article
| Open AccessBlocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure
Here the authors use modified RNA and VHH libraries to generate intrabodies that target dysregulated interactions between two calcium handling proteins in failing cardiomyocytes. Heart specific expression of the intrabodies in a murine heart failure model results in improved cardiac function.
- Erwin De Genst
- , Kylie S. Foo
- & Kenneth R. Chien
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Article
| Open AccessOmega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
Pulmonary hypertension is a fatal disease that causes right heart failure due to pulmonary artery stenosis. Here, the authors find that ω-3 epoxides produced by the phospholipase PAF-AH2 in mast cells regulate pulmonary vascular remodeling.
- Hidenori Moriyama
- , Jin Endo
- & Motoaki Sano
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Article
| Open AccessTransmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation
Stem cell factor (SCF) is a cytokine with great potential for treating ischemia, stroke and heart attack, but therapies using SCF have been limited by acute allergic responses. The work describes a new therapeutic using transmembrane SCF delivered in lipid nanocarriers that is effective in treating ischemia without off-target effects.
- Eri Takematsu
- , Miles Massidda
- & Aaron B. Baker
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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 AccessEndothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling
The molecular mechanisms through which pulmonary endothelial progenitor cells stimulate lung angiogenesis are not clear. Here, authors show that these cells stimulate the growth of alveolar capillaries and alveoli of newborn mice through FOXF1 and FLI1 nuclear protein-activation of the BMP9/ACVRL1/SMAD1 signaling pathway.
- Guolun Wang
- , Bingqiang Wen
- & Vladimir V. Kalinichenko
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Article
| Open AccessGut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy
Intestinal microbiota alterations may affect heart function through the production of gut-derived metabolites. Here the authors found that gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent fatty acid oxidation.
- Mingming Zhao
- , Haoran Wei
- & Lemin Zheng
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Article
| Open AccessAutomated multilabel diagnosis on electrocardiographic images and signals
The application of artificial intelligence for automated diagnosis of electrocardiograms can improve care in remote settings but is limited by the reliance on infrequently available signal-based data. Here, the authors report the development of a multi-label automated diagnosis model for electrocardiographic images.
- Veer Sangha
- , Bobak J. Mortazavi
- & Rohan Khera
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Article
| Open AccessAged bone matrix-derived extracellular vesicles as a messenger for calcification paradox
This study uncovers the role of extracellular vesicles from bone matrix as a messenger in the development of osteoporosis and vascular calcification (calcification paradox) during skeletal aging and menopause by transferring miR-483-5p and miR-2861.
- Zhen-Xing Wang
- , Zhong-Wei Luo
- & Hui Xie
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Article
| Open AccessSpinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control
By combining experimental models with prospective clinical studies, the authors show that spinal cord injury causes a rapid reduction in cardiac function that precedes structural changes, and that the loss of descending sympathetic control is the major cause of reduced cardiac function following spinal cord injury.
- Mary P. M. Fossey
- , Shane J. T. Balthazaar
- & Christopher R. West
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Article
| Open AccessElucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
Many individual genetic risk loci associate with multiple diseases, but the molecular basis of these loci often remains unclear. Here, the authors provide a framework to reveal the genetic cross-disease associations at the PROCR vascular disease locus.
- David Stacey
- , Lingyan Chen
- & Dirk S. Paul
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Article
| Open AccessGenetic associations with carotid intima-media thickness link to atherosclerosis with sex-specific effects in sub-Saharan Africans
Genetic studies of disease-relevant traits have mostly been performed on European populations. Here, the authors perform a genome-wide association study for carotid intima-media thickness, in sub-Saharan African samples, finding population-specific and sex-specific loci.
- Palwende Romuald Boua
- , Jean-Tristan Brandenburg
- & Michèle Ramsay
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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 AccessCaffeine blocks SREBP2-induced hepatic PCSK9 expression to enhance LDLR-mediated cholesterol clearance
Caffeine may reduce cardiovascular disease risk, but the underlying mechanisms for these effects are incompletely understood. Here the authors report that caffeine inhibits the activation of the transcription factor SREBP2 to promote LDLc clearance through the PCSK9-LDLR axis.
- Paul F. Lebeau
- , Jae Hyun Byun
- & Richard C. Austin
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Article
| Open AccessEngineered bacterial voltage-gated sodium channel platform for cardiac gene therapy
In this in vitro, in silico, and in vivo study Nguyen and colleagues show that specific and stable viral gene delivery of engineered prokaryotic voltage-gated sodium channels (BacNav) to cardiomyocytes can directly augment cardiac tissue excitability and conduction.
- Hung X. Nguyen
- , Tianyu Wu
- & Nenad Bursac