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Unveiling unique clinical phenotypes of hip fracture patients and the temporal association with cardiovascular events
Cardiovascular events (CVEs) are the leading cause of death among hip fracture patients. Here, the authors show the findings on subphenotyping the heterogeneous spectrum of hip fracture patients in both Hong Kong and the United Kingdom older adult populations and temporal associations with CVEs across all subphenotypes.
- Warrington W. Q. Hsu
- , Xiaowen Zhang
- & Ching-Lung Cheung
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| Open Access
Elevated 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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Statins 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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| Open Access
ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice
Cardiac macrophage contributes to the onset of cardiac fibrosis, but the underneath mechanisms remain unclear. Here the authors show that mouse cardiac macrophages from circulating monocytes may trans-differentiate into myofibroblast under hypertensive conditions for fibrosis development, with an AKLBH5/IL11 molecular axis modulating this macrophage-to-myofibroblast transition.
- Tao Zhuang
- , Mei-Hua Chen
- & Cheng-Chao Ruan
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Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice
HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.
- Sara Ranjbarvaziri
- , Aliya Zeng
- & Jin Yang
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DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts
This study uncovers a critical link between DNMT3A-driven CHIP and heart failure and, in particular, it shows that DNMT3A inactivation in monocytes boosts the release of HB-EGF, which activates fibroblasts inducing diffuse fibrosis in the heart.
- Mariana Shumliakivska
- , Guillermo Luxán
- & Stefanie Dimmeler
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Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development
The pathobiology of heart failure (HF) is incompletely understood. The authors identify 37 circulating proteins and 5 protein modules associated with HF risk, with several demonstrating causal effects on HF, risk factors, or cardiac dysfunction by Mendelian randomization analysis.
- Amil M. Shah
- , Peder L. Myhre
- & Bing Yu
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Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
- Liam G. Hall
- , Juliane K. Czeczor
- & Sean L. McGee
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| Open Access
Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells
Cardiac fibroblasts play an essential role in heart development. Here Fernandes et al. describe a human pluripotent stem cell-derived epicardial organoid system to investigate the role of fibroblasts in cardiovascular development and disease.
- Ian Fernandes
- , Shunsuke Funakoshi
- & Gordon Keller
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GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis
Cytoskeletal remodeling is known to facilitate mitophagy, but the mechanism is not fully understood. Here, the authors show that damaged mitochondria recruit a RhoA GTPase activating protein that promotes their capture and encasement by autophagosomes.
- Qiang Zhu
- , Matthew E. Combs
- & Joan M. Taylor
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Cis-trans isomerization of peptoid residues in the collagen triple-helix
The cis-peptide bond is rare in natural proteins and its impact on protein folding is elusive. Here the authors break the conventional understanding that cis-amide-favoring residues destabilize proteins, elucidate the principles of peptoid cis-trans isomerization in collagen folding, and showcase the use of cis-amide-favoring residues in building programmable and functional peptidomimetics.
- Rongmao Qiu
- , Xiaojing Li
- & Yang Li
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Eicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction
Systemic inflammation is recognized as a central pathobiologic feature in heart failure with preserved ejection fraction (HFpEF). Here, the authors report 70 pro- and anti-inflammatory eicosanoid and eicosanoid-related metabolites associated with HFpEF status.
- Emily S. Lau
- , Athar Roshandelpoor
- & Jennifer E. Ho
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IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice
Cardiac fibrosis is a common feature of chronic heart failure, and the mechanisms of cardiac fibrosis are unclear. Here, the authors show that iroquois homeobox 2 (IRX2) regulates the early growth response factor 1 (EGR1) pathway upon fibrotic stimulation and drives cardiac fibrosis.
- Zhen-Guo Ma
- , Yu-Pei Yuan
- & Qi-Zhu Tang
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Lysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34
iPLA2β produces lipid mediators and induces nuclear shrinkage in caspase-independent cell death. Here, the authors show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death mediated through GPR34 in pressure-overloaded mouse hearts, leading to cardiac dysfunction.
- Ryuta Sugihara
- , Manabu Taneike
- & Kinya Otsu
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| Open Access
Cysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR)
Oxidation of ryanodine receptor calcium channels play a critical role in the onset of many cardiac diseases. Here, authors identify specific amino acids that cause ryanodine receptor malfunction during oxidative stress.
- Roman Nikolaienko
- , Elisa Bovo
- & Aleksey V. Zima
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Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI
Modulating pro-inflammatory immune cell kinetics after myocardial infarction is a critical step to prevent heart dysfunction. In this study, the authors show that Ezh2 pharmacological inhibition, acting as an epigenetic checkpoint in monocytes and macrophages, prevents myocardial infarction-induced cardiac dysfunction.
- Julie Rondeaux
- , Déborah Groussard
- & Sylvain Fraineau
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| Open Access
Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.
- Danielle Rasooly
- , Gina M. Peloso
- & Juan P. Casas
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Tisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice
Cardiac I/R injury is a deleterious issue in the clinic. Here, the authors show that Tisp40 facilitates HBP flux and protein O-GlcNAcylation through binding to the promoter of GFPT1, thereby preventing cardiac I/R injury.
- Xin Zhang
- , Can Hu
- & Qi-Zhu Tang
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RPL3L-containing ribosomes determine translation elongation dynamics required for cardiac function
RPL3L is a paralog of the ribosomal protein RPL3 and specifically expressed in heart and skeletal muscle. Here, the authors show that RPL3L-containing ribosomes regulate translation elongation dynamics especially for the transcripts related to cardiac muscle contraction.
- Chisa Shiraishi
- , Akinobu Matsumoto
- & Keiichi I. Nakayama
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Extracellular vesicles engineering by silicates-activated endothelial progenitor cells for myocardial infarction treatment in male mice
Extracellular vesicle therapy has shown great potential for the treatment of myocardial infarction. Here, the authors show a silicate biomaterials-based approach to engineer extracellular vesicles from endothelial progenitor cells with high yield and bioactivity for treating myocardial infarction.
- Bin Yu
- , Hekai Li
- & Caiwen Ou
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| Open Access
P2X3 receptor antagonism attenuates the progression of heart failure
Despite medications, heart failure worsens with time with many patients dying within five years of diagnosis. Here the authors show that blocking purinergic receptors in the carotid body stops heart failure progression, improves its function, reduces sleep apneas and systemic inflammation in male rats.
- Renata M. Lataro
- , Davi J. A. Moraes
- & Julian F. R. Paton
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| Open Access
Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice
Although the role of FGFs in cardiovascular disease has attracted extensive attention, the potential role of FGF18 in pathological cardiac hypertrophy remains unknown. Here, the authors show the cardioprotective effect of FGF18 is mediated by maintaining redox homeostasis through FYN/Nox4 signaling.
- Gen Chen
- , Ning An
- & Xu Wang
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Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice
The current challenges for diabetic cardiomyopathy (DCM) are unclear mechanisms and no effective therapy in clinics. Here, the authors found that the decrease of cardiac retinol dehydrogenase 10 in type 2 diabetes leads to retinol metabolism disorder, cardiac lipid toxicity and cardiomyopathy development, suggesting that correcting the imbalance of cardiac retinol metabolism may be an effective strategy for the treatment of DCM.
- Yandi Wu
- , Tongsheng Huang
- & Weibin Cai
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| Open Access
The KLF7/PFKL/ACADL axis modulates cardiac metabolic remodelling during cardiac hypertrophy in male mice
Myocardial substrate metabolism in cardiac hypertrophy or heart failure shifts from fatty acid oxidation to a greater reliance on glycolysis. Here, the authors show that KLF7 can simultaneously regulate key enzymes in glycolysis and fatty acid oxidation to mitigate metabolic imbalance during cardiac hypertrophy.
- Cao Wang
- , Shupei Qiao
- & Weiming Tian
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| Open Access
Genome-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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Mitochondrial 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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Intramyocardial hemorrhage drives fatty degeneration of infarcted myocardium
It is unclear why hemorrhagic myocardial infarctions (hMI) are destined for adverse outcomes. Here, the authors show that hMI drives fatty degeneration of infarct territories and contributes to adverse remodeling of the heart, which can be mitigated via timely depletion of iron within the hMI zone.
- Ivan Cokic
- , Shing Fai Chan
- & Rohan Dharmakumar
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Myocardial 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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Kynurenine 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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The 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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Spatiotemporal 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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Targeting 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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The RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis
Here the authors show that a RalGAPα1-RalA signal nexus regulates calcium homeostasis in cardiomyocytes via the calcium pump SERCA2a, which plays a protective role to maintain cardiac function under pressure overload conditions.
- Sangsang Zhu
- , Chao Quan
- & Shuai Chen
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| Open Access
Post-recovery COVID-19 and incident heart failure in the National COVID Cohort Collaborative (N3C) study
The relationship between post-recovery COVID-19 and incident heart failure has not been investigated at scale. Here, the authors use electronic health records for ~600,000 patients in the US and find a higher rate of post-discharge incident heart failure in those hospitalised with COVID-19 than without.
- Husam M. Salah
- , Marat Fudim
- & Melissa C. Caughey
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Cardiac 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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Sex 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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Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis
Cardiac fibrosis is a hallmark of heart failure. Here the authors use single-cell RNA-sequencing, spatial transcriptomics, and genetic manipulations, to show that Htra3 regulates cardiac fibrosis by keeping fibroblasts quiescent and by degrading TGF-beta.
- Toshiyuki Ko
- , Seitaro Nomura
- & Issei Komuro
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| Open Access
Mapping 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 Access
Predicting 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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| Open Access
Phospholamban 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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| Open Access
Structure 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 Access
Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover
Decreased expression of BAG3 in the heart is associated with contractile dysfunction and heart failure. Here the authors show that this is due to decreased BAG3-dependent sarcomere protein turnover, which impairs mechanical function, and that sarcomere force-generating capacity is restored with BAG3 gene therapy.
- Thomas G. Martin
- , Valerie D. Myers
- & Jonathan A. Kirk
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| Open Access
Cardiac 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
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| Open Access
Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction
Heart failure with preserved ejection fraction (HFpEF) is a global, major health issue for which no effective therapies are available. Here, the authors discover that the interplay between two transcription factors, Xbp1s and FoxO1, is critical for metabolic adaptation and lipid handling in HFpEF-stressed cardiomyocytes.
- Gabriele G. Schiattarella
- , Francisco Altamirano
- & Joseph A. Hill
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| Open Access
Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling
Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8+ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.
- Icia Santos-Zas
- , Jeremie Lemarié
- & Hafid Ait-Oufella
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| Open Access
Eosinophils improve cardiac function after myocardial infarction
Blood eosinophil (EOS) counts may serve as risk factors for human coronary heart diseases. Here the authors show that increased circulating and myocardial EOS after myocardial infarction play a cardioprotective role by reducing cardiomyocyte death, cardiac fibroblast activation and fibrosis, and endothelium activation-mediated inflammatory cell accumulation.
- Jing Liu
- , Chongzhe Yang
- & Guo-Ping Shi
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| Open Access
Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy
Little is known about how cardiac metabolism remodels following cardiac injury. Here, the authors show that mitochondrial CaMKII plays an important role in remodeling cardiac metabolism after injury and that replacement of mitochondrial creatine kinase improves energetics and protects against adverse remodeling.
- Elizabeth D. Luczak
- , Yuejin Wu
- & Mark E. Anderson
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| Open Access
Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure
The pathophysiological role of dopamine D1 receptor (D1R) in chronic heart failure remains elusive. Here the authors show that D1R-expressing cardiomyocytes appear in chronic heart failure and play a pivotal role in triggering lethal ventricular arrhythmias.
- Toshihiro Yamaguchi
- , Tomokazu S. Sumida
- & Issei Komuro
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| Open Access
A nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation
Ischemia and reperfusion damage contribute to early graft dysfunction and recipient’s death. Here the authors show the feasibility and safety of a non-ischemic heart preservation method for heart transplantation in a non-randomized trial.
- Johan Nilsson
- , Victoria Jernryd
- & Stig Steen
Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis