Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlar...Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.展开更多
Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A la...Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A large clinical database,based on（1） prospective population studies or（2） cross-sectional,prospective studies or randomized controlled trials（RCTs） of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ＇omics＇-based biomarkers to identify the risk of developing heart failure and/or comorbidities.Population studies,patient cohorts and RCTs are eligible for inclusion in the common database,if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors.Currently,the HOMAGE database includes 43,065 subjects,from 20 studies in eight European countries,including healthy subjects from three population studies in France,Belgium and Italy（n = 7,124）,patients with heart failure（n = 4,312） from four cohorts in the UK,Spain and Switzerland and patients at high risk for cardiovascular disease（n = 31,629） in 13 cohorts.It is anticipated that more partners will join the consortium and enlarge the pooled data.This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.展开更多
Cardiac arrest remains a leading cause of death and permanent disability worldwide. Although many victims are initially resuscitated, they often succumb to the extensive ischemia-reperfusion injury inflicted on the in...Cardiac arrest remains a leading cause of death and permanent disability worldwide. Although many victims are initially resuscitated, they often succumb to the extensive ischemia-reperfusion injury inflicted on the internal organs, especially the brain. Cardiac arrest initiates a complex cellular injury cascade encompassing reactive oxygen and nitrogen species, Ca2+ overload, ATP depletion, pro- and anti-apoptotic proteins, mitochondrial dysfunction, and neuronal glutamate excitotoxity, which injures and kills cells, compromises function of internal organs and ignites a destructive systemic inflammatory response. The sheer complexity and scope of this cascade challenges the development of experimental models of and effective treatments for cardiac arrest. Many experimental animal preparations have been developed to decipher the mechanisms of damage to vital internal organs following cardiac arrest and cardiopulmonary resuscitation(CPR), and to develop treatments to interrupt the lethal injury cascades. Porcine models of cardiac arrest and resuscitation offer several important advantages over other species, and outcomes in this large animal are readily translated to the clinical setting. This review summarizes porcine cardiac arrest-CPR models reported in the literature, describes clinically relevant phenomena observed during cardiac arrest and resuscitation in pigs, and discusses numerous methodological considerations in modeling cardiac arrest/CPR. Collectively, published reports show the domestic pig to be a suitable large animal model of cardiac arrest which is responsive to CPR, defibrillatory countershocks and medications, and yields extensive information to foster advances in clinical treatment of cardiac arrest.展开更多
In an era when cardiac transplant patients are surviving more immediate issues of rejection and infection,the prevalence of more chronic issues such as cardiac allograft vasculopathy(CAV)is rising.This case describes ...In an era when cardiac transplant patients are surviving more immediate issues of rejection and infection,the prevalence of more chronic issues such as cardiac allograft vasculopathy(CAV)is rising.This case describes a man 20 years after cardiac transplant with his first presentation of CAV.Acute myocardial infarction was diagnosed on the basis of symptoms and biochemical markers and on coronary angiography,and he was found to have a critical stenosis of the midportion of the left anterior descending artery.It was elected to treat this percutaneously with a fully bioresorbable vascular scaffold(BVS)because of the diffuse nature of the disease process.This was successfully performed with optical coherence tomography guidance.The use of BVS in CAV has not been well studied.This is one of few case reports describing the use of BVS in CAV.展开更多
Objective To observe the anti-CVB3 （ Coxsackievirus B3 ） effect of sophocarpine （SC） extracted from Sophora flavescens, a traditional Chinese herb in vitro. Methods Cardiomyocytes from the neonatal rat were cultur...Objective To observe the anti-CVB3 （ Coxsackievirus B3 ） effect of sophocarpine （SC） extracted from Sophora flavescens, a traditional Chinese herb in vitro. Methods Cardiomyocytes from the neonatal rat were cultured to establish the viral myocarditis model The cells were divided into four groups： infected group （ infected by CVB3 ） , SC treated group （ added SC 100 μg/mL after viral infection ）, SC control group （ added SC 100 μg/mL only）, and normal control group. The cytopathic effect （CPE） and the beating frequency of the myocardial cells were observed and the LDH levels in the supernatant were measured at day 2,3, and 5. The cultured myocytes were added different concentrations of SC （ 12. 5 -400 μg/mL ） after infection with CVB3, the CPE was observed and the concentrations of LDH were measured and compared at day 2, 3, and 5. Results In the SC treated group （ 100 μg/mL ） , the cytopathic effect was lighter and the LDH level was lower than the infected group. SC in a concentration of 12. 5 - 300 μg/mL could relieve the CPE and lower the LDH level, while in a higher concentration （400 μ/m ） , it exacerbated the CPE caused by the virus, and the LDH levels were higher than the infected cells. Conclusion SC in certain concentration could protect the cultured rat cardiomyocytes from CVB3 infection.展开更多
Dear Editor,Small extracellular vesicles(sEVs)are membranous nanovesicles involved in intercellular,communication that carry distinct cellderived molecular cargo.1 We previously characterised sEVs from human non-malig...Dear Editor,Small extracellular vesicles(sEVs)are membranous nanovesicles involved in intercellular,communication that carry distinct cellderived molecular cargo.1 We previously characterised sEVs from human non-malignant pancreatic duct cells(HPDE,hTERT-HPNE)and from PDAC cells(AsPC-1,BxPC-3 and MIA PaCa-2)2 and identified protein cargo-specific to cancer-associated sEVs?Among the proteins uniquely expressed in cancer sEVs but not in those from non-malignant cells,we focused on SLC5A3,also known as SMIT1(sodium-coupled Myo-inositol transporter-1).展开更多
In a recent Cell study,Xie et al.1 introduce a novel mass spectrometry-based methodology for the sensitive detection and enrichment of native sialic acid-containing glycoRNA on cell surfaces.This work represents a sig...In a recent Cell study,Xie et al.1 introduce a novel mass spectrometry-based methodology for the sensitive detection and enrichment of native sialic acid-containing glycoRNA on cell surfaces.This work represents a significant advancement in the emerging field of glycoRNA biology.The authors linked acp3U,a modified uridine which was first described five decades ago,with RNA glycosylation in mammalian cells.展开更多
基金supported by grants from NHMRC(Grant No.1125514 and 2029334 to JRM,and 1120129 to JRM and CEH)National Heart Foundation of Australia(Vanguard-105720)+6 种基金the Victorian Government’s Operational Infrastructure Support Programsupported by a joint Baker Heart and Diabetes Institute-La Trobe University doctoral scholarshipsupported by Future Leader Fellowships from the National Heart Foundation of Australia(Grant No.102536 to EJH,102539 to KLW,and 102206 to ALG)supported by an Alice Baker and Eleanor Shaw Fellowship(The Baker Foundation,Australia)supported by a NHMRC Senior Research(Grant No.1078985)Baker Fellowship(The Baker Foundation,Australia)Cardiovascular Research Capacity Program-Research Leadership GrantsCardiovascular Research Capacity Program-Research Leadership Grants(NSW Health)。
文摘Background:Elucidating mechanisms underlying atrial myopathy,which predisposes individuals to atrial fibrillation(AF),will be critical for preventing/treating AF.In a serendipitous discovery,we identified atrial enlargement,fibrosis,and thrombi in mice with reduced phosphoinositide 3-kinase(PI3K)in cardiomyocytes.PI3K(p110a)is elevated in the heart with exercise and is critical for exercise-induced ventricular enlargement and protection,but the role in the atria was unknown.Physical inactivity and extreme endurance exercise can increase AF risk.Therefore,our objective was to investigate whether too little and/or too much PI3K alone induces cardiac pathology.Methods:New cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110a)activity were generated.Multi-omics was conducted in mouse atrial tissue,and lipidomics in human plasma.Results:Elevated PI3K led to an increase in heart size with preserved/enhanced function.Reduced PI3K led to atrial dysfunction,fibrosis,arrhythmia,increased susceptibility to atrial enlargement and thrombi,and dysregulation of monosialodihexosylganglioside(GM3),a lipid that regulates insulin-like growth factor-1(IGF1)-PI3K signaling.Proteomic profiling identified distinct signatures and signaling networks acrossatria with varying degrees of dysfunction,enlargement,and thrombi,including commonalities with the human AF proteome.PI3K-related lipids were dysregulated in plasma from athletes with AF.Conclusion:PI3K(p110a)is a critical regulator of atrial biology and function in mice.This work provides a proteomic resource of candidates for further validation as potential new drug targets and biomarkers for atrial myopathy.Further investigation of PI3K-related lipids as markers for identifying individuals at risk of AF is warranted.Dysregulation of PI3K may contribute to the association between increased cardiac risk with physical inactivity and extreme endurance exercise.
文摘Heart failure is common in older people and its prevalence is increasing.The Heart ＇omics＇ in AGEing（HOMAGE） project aims to provide a biomarker approach that will improve the early diagnosis of heart failure.A large clinical database,based on（1） prospective population studies or（2） cross-sectional,prospective studies or randomized controlled trials（RCTs） of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ＇omics＇-based biomarkers to identify the risk of developing heart failure and/or comorbidities.Population studies,patient cohorts and RCTs are eligible for inclusion in the common database,if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors.Currently,the HOMAGE database includes 43,065 subjects,from 20 studies in eight European countries,including healthy subjects from three population studies in France,Belgium and Italy（n = 7,124）,patients with heart failure（n = 4,312） from four cohorts in the UK,Spain and Switzerland and patients at high risk for cardiovascular disease（n = 31,629） in 13 cohorts.It is anticipated that more partners will join the consortium and enlarge the pooled data.This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.
基金Supported by Grants from The United States National Institute of Neurological Disorders and Stroke,No.R01 NS076975-03a predoctoral fellowship from the United States National Institute of Aging,Training in the Neurobiology of Aging,No.T31 AG020494a predoctoral fellowship from the University of North Texas Health Science Center’s Physician Scientist Program
文摘Cardiac arrest remains a leading cause of death and permanent disability worldwide. Although many victims are initially resuscitated, they often succumb to the extensive ischemia-reperfusion injury inflicted on the internal organs, especially the brain. Cardiac arrest initiates a complex cellular injury cascade encompassing reactive oxygen and nitrogen species, Ca2+ overload, ATP depletion, pro- and anti-apoptotic proteins, mitochondrial dysfunction, and neuronal glutamate excitotoxity, which injures and kills cells, compromises function of internal organs and ignites a destructive systemic inflammatory response. The sheer complexity and scope of this cascade challenges the development of experimental models of and effective treatments for cardiac arrest. Many experimental animal preparations have been developed to decipher the mechanisms of damage to vital internal organs following cardiac arrest and cardiopulmonary resuscitation(CPR), and to develop treatments to interrupt the lethal injury cascades. Porcine models of cardiac arrest and resuscitation offer several important advantages over other species, and outcomes in this large animal are readily translated to the clinical setting. This review summarizes porcine cardiac arrest-CPR models reported in the literature, describes clinically relevant phenomena observed during cardiac arrest and resuscitation in pigs, and discusses numerous methodological considerations in modeling cardiac arrest/CPR. Collectively, published reports show the domestic pig to be a suitable large animal model of cardiac arrest which is responsive to CPR, defibrillatory countershocks and medications, and yields extensive information to foster advances in clinical treatment of cardiac arrest.
文摘In an era when cardiac transplant patients are surviving more immediate issues of rejection and infection,the prevalence of more chronic issues such as cardiac allograft vasculopathy(CAV)is rising.This case describes a man 20 years after cardiac transplant with his first presentation of CAV.Acute myocardial infarction was diagnosed on the basis of symptoms and biochemical markers and on coronary angiography,and he was found to have a critical stenosis of the midportion of the left anterior descending artery.It was elected to treat this percutaneously with a fully bioresorbable vascular scaffold(BVS)because of the diffuse nature of the disease process.This was successfully performed with optical coherence tomography guidance.The use of BVS in CAV has not been well studied.This is one of few case reports describing the use of BVS in CAV.
文摘Objective To observe the anti-CVB3 （ Coxsackievirus B3 ） effect of sophocarpine （SC） extracted from Sophora flavescens, a traditional Chinese herb in vitro. Methods Cardiomyocytes from the neonatal rat were cultured to establish the viral myocarditis model The cells were divided into four groups： infected group （ infected by CVB3 ） , SC treated group （ added SC 100 μg/mL after viral infection ）, SC control group （ added SC 100 μg/mL only）, and normal control group. The cytopathic effect （CPE） and the beating frequency of the myocardial cells were observed and the LDH levels in the supernatant were measured at day 2,3, and 5. The cultured myocytes were added different concentrations of SC （ 12. 5 -400 μg/mL ） after infection with CVB3, the CPE was observed and the concentrations of LDH were measured and compared at day 2, 3, and 5. Results In the SC treated group （ 100 μg/mL ） , the cytopathic effect was lighter and the LDH level was lower than the infected group. SC in a concentration of 12. 5 - 300 μg/mL could relieve the CPE and lower the LDH level, while in a higher concentration （400 μ/m ） , it exacerbated the CPE caused by the virus, and the LDH levels were higher than the infected cells. Conclusion SC in certain concentration could protect the cultured rat cardiomyocytes from CVB3 infection.
基金supported by National Health and Medical Research Council(NHMRC,MRF2015523,APP1141946)Helen Amelia Hains Fellowship(D.W.G.)and Department of Defense(PR230065)supported by the Snow Medical Research Fellowship,NHMRC Investigator 2027300 and Philip Hemstritch Fellowship.
文摘Dear Editor,Small extracellular vesicles(sEVs)are membranous nanovesicles involved in intercellular,communication that carry distinct cellderived molecular cargo.1 We previously characterised sEVs from human non-malignant pancreatic duct cells(HPDE,hTERT-HPNE)and from PDAC cells(AsPC-1,BxPC-3 and MIA PaCa-2)2 and identified protein cargo-specific to cancer-associated sEVs?Among the proteins uniquely expressed in cancer sEVs but not in those from non-malignant cells,we focused on SLC5A3,also known as SMIT1(sodium-coupled Myo-inositol transporter-1).
基金supported by a physician scientist programme fellowship from the Helmholtz Institute for Translational AngioCardioScience(HI-TAC)supported by grants from the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation programme(MODVASC,grant agreement No 759248)+1 种基金the German Research Foundation DFG(CRC1366 C07,project number 394046768)the Health+Life Science Alliance Heidelberg Mannheim GmbH and the Helmholtz Institute for Translational AngioCardioScience(HI-TAC).
文摘In a recent Cell study,Xie et al.1 introduce a novel mass spectrometry-based methodology for the sensitive detection and enrichment of native sialic acid-containing glycoRNA on cell surfaces.This work represents a significant advancement in the emerging field of glycoRNA biology.The authors linked acp3U,a modified uridine which was first described five decades ago,with RNA glycosylation in mammalian cells.
