Transcriptome and proteome mapping in the sheep atria reveal molecular features of atrial fibrillation progression.

Abstract:

AIMS:Atrial fibrillation (AF) is a progressive cardiac arrhythmia that increases the risk of hospitalization and adverse cardiovascular events. There is a clear demand for more inclusive and large-scale approaches to understand the molecular drivers responsible for AF, as well as the fundamental mechanisms governing the transition from paroxysmal to persistent and permanent forms. In this study, we aimed to create a molecular map of AF and find the distinct molecular programs underlying cell type-specific atrial remodelling and AF progression. METHODS AND RESULTS:We used a sheep model of long-standing, tachypacing-induced AF, sampled right and left atrial tissue and isolated cardiomyocytes from control, intermediate (transition) and late time points during AF progression, and performed transcriptomic and proteome profiling. We have merged all these layers of information into a meaningful 3-component space in which we explored the genes and proteins detected and their common patterns of expression. Our data-driven analysis points at extracellular matrix remodelling, inflammation, ion channel, myofibril structure, mitochondrial complexes, chromatin remodelling, and genes related to neural function, as well as critical regulators of cell proliferation as hallmarks of AF progression. Most important, we prove that these changes occur at early transitional stages of the disease, but not at later stages, and that the left atrium undergoes significantly more profound changes than the right atrium in its expression program. The pattern of dynamic changes in gene and protein expression replicate the electrical and structural remodelling demonstrated previously in the sheep and in humans, and uncover novel mechanisms potentially relevant for disease treatment. CONCLUSIONS:Transcriptomic and proteomic analysis of AF progression in a large animal model shows that significant changes occur at early stages, and that among others involve previously undescribed increase in mitochondria, changes to the chromatin of atrial cardiomyocytes, and genes related to neural function and cell proliferation. TRANSLATIONAL PERSPECTIVE:We have generated a detailed molecular map of AF progression in a clinically relevant large-animal model. Such data would be very difficult if not impossible to obtain from patients. Our results provide a framework for a comprehensive molecular analysis of the disease, pointing to novel avenues of research toward identifying early events that can lead to therapeutically targets to prevent AF-induced atrial remodelling.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Alvarez-Franco A,Rouco R,Ramirez RJ,Guerrero-Serna G,Tiana M,Cogliati S,Kaur K,Saeed M,Magni R,Enriquez JA,Sanchez-Cabo F,Jalife J,Manzanares M

doi

10.1093/cvr/cvaa307

subject

Has Abstract

pub_date

2020-10-29 00:00:00

eissn

0008-6363

issn

1755-3245

pii

5942974

pub_type

杂志文章
  • Adenosine inhibits norepinephrine release in the postischemic rat heart: the mechanism of neuronal stunning.

    abstract:OBJECTIVE:Numerous studies support the concept of impaired postischemic sympathetic neurotransmission in the heart. We hypothesized that postischemic neuronal dysfunction (neuronal stunning) is caused by a transient suppression of exocytotic norepinephrine (NE) release from sympathetic nerve terminals. Furthermore, we ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(00)00309-6

    authors: Burgdorf C,Richardt D,Kurz T,Seyfarth M,Jain D,Katus HA,Richardt G

    更新日期:2001-03-01 00:00:00

  • A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome.

    abstract:OBJECTIVE:Jervell and Lange-Nielsen syndrome (JLNS) is a recessively inherited long QT syndrome (LQTS) characterised by profound sensorineural deafness and predisposition to syncope and sudden cardiac death. Mutation analysis has established the presence of mutations in affected individuals in the genes KCNQ1 and KCNE1...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(01)00350-9

    authors: Huang L,Bitner-Glindzicz M,Tranebjaerg L,Tinker A

    更新日期:2001-09-01 00:00:00

  • Oxidative stress and left ventricular remodelling after myocardial infarction.

    abstract::In acute myocardial infarction (MI), reactive oxygen species (ROS) are generated in the ischaemic myocardium especially after reperfusion. ROS directly injure the cell membrane and cause cell death. However, ROS also stimulate signal transduction to elaborate inflammatory cytokines, e.g. tumour necrosis factor-alpha (...

    journal_title:Cardiovascular research

    pub_type: 杂志文章,评审

    doi:10.1093/cvr/cvn335

    authors: Hori M,Nishida K

    更新日期:2009-02-15 00:00:00

  • Quantitative evaluation of postectopic beats in the normal and failing human heart using indices derived from catheter-tip manometer readings.

    abstract::Postextrasystolic potentiation was studied by means of a catheter-tip manometer in patients with and without cardiomyopathy. The results imply that the enhancement of the left ventricular contraction is increased in patients with cardiomyopathy. ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/9.3.336

    authors: Kvasnicka J,Liander B,Broman H,Varnauskas E

    更新日期:1975-05-01 00:00:00

  • Pathophysiological significance of coronary collaterals for preservation of the myocardium during coronary occlusion and reperfusion in anaesthetised dogs.

    abstract::The significance of pre-existing coronary collaterals for preservation of the myocardium during coronary occlusion and reperfusion was studied in anaesthetised open-chest dogs. The extent of myocardial ischaemic damage was assessed by the accumulation of calcium in the central zone of the ischaemic area and the size o...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/14.5.288

    authors: Tanabe M,Fujiwara S,Ohta N,Shimamoto N,Hirata M

    更新日期:1980-05-01 00:00:00

  • Role of human smooth muscle cell progenitors in atherosclerotic plaque development and composition.

    abstract:AIMS:We analysed the possible protective role of human endothelial (EPCs) and smooth muscle (SPCs) progenitor cells on atherosclerosis development in apoE(-/-)RAG2(-/-) mice. We determined plasma levels of SPCs in coronary patients. METHODS AND RESULTS:ApoE(-/-)RAG2(-/-) mice received four intravenous injections of sa...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvm034

    authors: Zoll J,Fontaine V,Gourdy P,Barateau V,Vilar J,Leroyer A,Lopes-Kam I,Mallat Z,Arnal JF,Henry P,Tobelem G,Tedgui A

    更新日期:2008-02-01 00:00:00

  • Cardiac protection by ischaemic preconditioning is not mediated by myocardial stunning.

    abstract:OBJECTIVE:Previous studies have shown that cardiac protection by ischaemic preconditioning wanes before contractile function recovers; thus stunning is insufficient to cause preconditioning. To test whether reduced contractile effort is necessary for preconditioning induced protection, the effect on myocardial infarct ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/27.4.585

    authors: Matsuda M,Catena TG,Vander Heide RS,Jennings RB,Reimer KA

    更新日期:1993-04-01 00:00:00

  • A key role of TRPC channels in the regulation of electromechanical activity of the developing heart.

    abstract:AIMS:It is well established that dysfunction of voltage-dependent ion channels results in arrhythmias and conduction disturbances in the foetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC (transient receptor potential canonical) channels remains unclear. We assessed the hypothesis tha...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvr167

    authors: Sabourin J,Robin E,Raddatz E

    更新日期:2011-11-01 00:00:00

  • Effects of adrenaline on a compartment of slowly-exchangeable calcium in the perfused rat heart.

    abstract::The effects of adrenaline on kinetically-distinct compartments of exchangeable calcium in the spontaneously-beating perfused rat heart were investigated under steady-state conditions using a 45Ca2+ outflow technique together with a nonlinear least-squares curve fitting procedure and 51Cr-EDTA to monitor the loss of fr...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/17.2.88

    authors: Lamont SV,Barritt GJ

    更新日期:1983-02-01 00:00:00

  • Microangiographic assessment of collateral vessel formation following direct gene transfer of vascular endothelial growth factor in rats.

    abstract:OBJECTIVE:The development of collateral microvessels following therapeutic angiogenesis with vascular endothelial growth factor (VEGF) was investigated using a new system of microangiography that employs monochromatic synchrotron radiation (SR) and a high definition video system to visualize arteries with a spatial res...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(97)00157-0

    authors: Takeshita S,Isshiki T,Mori H,Tanaka E,Tanaka A,Umetani K,Eto K,Miyazawa Y,Ochiai M,Sato T

    更新日期:1997-09-01 00:00:00

  • Intra- and extracellular electrolytes and sarcolemmal ATPase in the failing heart due to pressure overload in dogs.

    abstract::An investigation of changes in the Mg2+ -dependent, Na+ -K+ -stimulated sarcolemmal ATPase and of intracellular electrolytes in the left failing heart due to pressure overload (aortic banding) was carried out in dogs. There was no change in the sarcolemmal Mg2+ -ATPase of the left or right ventricle for the whole dura...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/13.2.95

    authors: Prasad K,Khatter JC,Bharadwaj B

    更新日期:1979-02-01 00:00:00

  • Cardiac genomic response following preconditioning stimulus.

    abstract::This review focuses on the genomic response following a preconditioning stimulus. Initial studies demonstrated that classical ischemic preconditioning mediated by cyclic episodes of short durations of reversible ischemia and reperfusion could result in the reprogramming of gene expression. Some of these genes are tran...

    journal_title:Cardiovascular research

    pub_type: 杂志文章,评审

    doi:10.1016/j.cardiores.2006.02.023

    authors: Das DK,Maulik N

    更新日期:2006-05-01 00:00:00

  • 17 beta-estradiol inhibits proliferation and migration of human vascular smooth muscle cells: similar effects in cells from postmenopausal females and in males.

    abstract:OBJECTIVES:Cardiovascular disease is rare in premenopausal women, but increases after the menopause when hormone replacement therapy reduces coronary events. Vascular smooth muscle cell (SMC) proliferation and migration occur in atherosclerosis, restenosis and venous graft disease. We studied the effects of 17 beta-est...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:

    authors: Dai-Do D,Espinosa E,Liu G,Rabelink TJ,Julmy F,Yang Z,Mahler F,Lüscher TF

    更新日期:1996-11-01 00:00:00

  • Platelet function and conjugated diene concentrations in diabetic and non-diabetic survivors of acute myocardial infarction.

    abstract:STUDY OBJECTIVE:The aim was to compare platelet function in diabetic and non-diabetic survivors of acute myocardial infarction and to relate it to an index of free radical activity in these patients. DESIGN:In vivo and in vitro indices of platelet function and diene conjugate molar ratios were measured in diabetic and...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/25.8.676

    authors: Hendra TJ,Wickens DG,Dormandy TL,Yudkin JS

    更新日期:1991-08-01 00:00:00

  • Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction.

    abstract::Mechanical stress signals transmitted through the heart walls during hemodynamic loading are sensed by the myocytes, which respond with changes in contractile performance and gene expression. External forces play an important role in physiological heart development and hypertrophy, but disruption of the well-balanced ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章,评审

    doi:10.1016/j.cardiores.2007.03.029

    authors: Linke WA

    更新日期:2008-03-01 00:00:00

  • Segmental volume distensibility of the canine thoracic aorta in vivo.

    abstract::Segments of the canine ascending aorta, upper descending thoracic aorta, and middle descending thoracic aorta were instrumented with ultrasonic dimension gauges and a cathetertip manometer simultaneously to measure changes in segment diameter, length, and intravascular pressure. Volume distensibility (EV) was calculat...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/22.6.385

    authors: Gentile BJ,Gross DR,Chuong CJ,Hwang NH

    更新日期:1988-06-01 00:00:00

  • Cbx3 inhibits vascular smooth muscle cell proliferation, migration, and neointima formation.

    abstract:Aims:To investigate the role of chromobox protein homolog 3 (Cbx3) in vascular smooth muscle cell (VSMC) proliferation, migration, and neointima formation following vascular injury. Methods and results:Overexpression of Cbx3 led to a significant increase in VSMC contractile gene expression and VSMC apoptosis as well a...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvx236

    authors: Zhang C,Chen D,Maguire EM,He S,Chen J,An W,Yang M,Afzal TA,Luong LA,Zhang L,Lei H,Wu Q,Xiao Q

    更新日期:2018-03-01 00:00:00

  • Regional and global contributions of air pollution to risk of death from COVID-19.

    abstract:AIMS:The risk of mortality from the coronavirus disease that emerged in 2019 (COVID-19) is increased by comorbidity from cardiovascular and pulmonary diseases. Air pollution also causes excess mortality from these conditions. Analysis of the first severe acute respiratory syndrome coronavirus (SARS-CoV-1) outcomes in 2...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvaa288

    authors: Pozzer A,Dominici F,Haines A,Witt C,Münzel T,Lelieveld J

    更新日期:2020-12-01 00:00:00

  • Nitric oxide regulates vascular calcification by interfering with TGF- signalling.

    abstract:AIMS:Vascular calcification often occurs with advancing age, atherosclerosis, and metabolic disorders such as diabetes mellitus and end-stage renal disease. Vascular calcification is associated with cardiovascular events and increased mortality. Nitric oxide (NO) is crucial for maintaining vascular function, but little...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvm049

    authors: Kanno Y,Into T,Lowenstein CJ,Matsushita K

    更新日期:2008-01-01 00:00:00

  • An N-/L-type calcium channel blocker, cilnidipine, suppresses autonomic, electrical, and structural remodelling associated with atrial fibrillation.

    abstract:AIMS:Autonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca2+-channels (NTCCs) at sympathetic nerve terminals mediate Ca2+-entry that triggers neurotransmitter release. AF-associated remodelling plays an important role in AF pathophysiology but the effects of NTCC ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvz136

    authors: Tajiri K,Guichard JB,Qi X,Xiong F,Naud P,Tardif JC,Costa AD,Aonuma K,Nattel S

    更新日期:2019-12-01 00:00:00

  • Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm.

    abstract:OBJECTIVE:We recently demonstrated in our swine model of coronary artery spasm that enhanced myosin light chain (MLC) phosphorylations (both MLC mono- and diphosphorylations) play a central role in the pathogenesis of the spasm. However, the molecular mechanism for and the phosphorylation sites for the enhanced MLC pho...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(99)00144-3

    authors: Shimokawa H,Seto M,Katsumata N,Amano M,Kozai T,Yamawaki T,Kuwata K,Kandabashi T,Egashira K,Ikegaki I,Asano T,Kaibuchi K,Takeshita A

    更新日期:1999-09-01 00:00:00

  • Reversal of pulmonary vascular remodelling following hypoxic exposure: no effect of infusion of atrial natriuretic factor and neutral endopeptidase inhibitor.

    abstract:OBJECTIVE:The aim was to investigate whether infusion of either atrial natriuretic factor (ANF, 800 ng.h-1.rat-1) or a specific inhibitory of neutral endopeptidase 24.11 (NEI, UK 73,967, 5.4 mg.kg-1.d-1) can influence the reversal of the pulmonary vascular remodelling produced by exposure to hypoxia. METHODS:Male Wist...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/28.4.519

    authors: Zhao L,Hughes JM,Winter RJ

    更新日期:1994-04-01 00:00:00

  • Role of nitric oxide, cyclic GMP and superoxide in inhibition by adenosine of calcium current in rabbit atrioventricular nodal cells.

    abstract:OBJECTIVE:To study the intracellular pathways which mediate the inhibitory actions of adenosine on isoprenaline-stimulated calcium current (ICa) in atrioventricular (AV) nodal myocytes. METHODS:The whole-cell patch-clamp technique was used to record ICa from rabbit AV nodal cells, isolated by enzymatic and mechanical ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(97)00043-6

    authors: Martynyuk AE,Kane KA,Cobbe SM,Rankin AC

    更新日期:1997-05-01 00:00:00

  • Cardiovascular reflex responses induced by epicardial chemoreceptor stimulation.

    abstract::The cardiac mechano- and chemoreceptors are broadly distributed in the myocardium and coronary vessels. A portion of these receptors extends over the epicardium and pericardium and therefore can be excited by mechanical or chemical stimuli directly applied to the surface of the heart. Excitation of epicardial receptor...

    journal_title:Cardiovascular research

    pub_type: 评论,杂志文章,评审

    doi:10.1016/s0008-6363(99)00319-3

    authors: Cinca J,Rodríguez-Sinovas A

    更新日期:2000-01-01 00:00:00

  • A comparative study on ischaemia- or anoxia-induced impairment of myocytic structure and cardiac function in the isolated, isovolumicly-contracting, perfused rat heart.

    abstract::Impairment of contractile function and extent of release of several intracellular marker enzymes and DNA were studied in isolated perfused rat hearts after low-flow (0.16 ml . min-1) ischaemia followed by 2 h of reperfusion and after anoxia followed by 2 h of reoxygenation. After varying periods of ischaemia or anoxia...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/18.12.768

    authors: van der Laarse A,Altona JC,Zoet AC,Oemrawsingh P,van Dijkman PR

    更新日期:1984-12-01 00:00:00

  • Anatomical arrangement of muscle tissue in the anterior mitral leaflet in man.

    abstract::Muscle tissue in atrioventricular (A-V) cardiac valve leaflets was studied in 35 human hearts and was found to be more prominent in the anterior leaflet of the mitral (MAL) than in the other valve leaflets. From serial sectioning and wax model reconstruction, the anatomic arrangement of the muscle in the MAL indicates...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/12.11.675

    authors: Boucek RJ,Boucková B,Levy S

    更新日期:1978-11-01 00:00:00

  • Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes.

    abstract:OBJECTIVE:The acute administration of growth hormone (GH) or insulin-like growth factor-1 (IGF-1) improves cardiac performance, possibly contributing to the beneficial effects of GH therapy on heart failure (HF). GH can induce the production of IGF-1 and thus the actions of GH may be mediated through its IGF-1 inductio...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(99)00058-9

    authors: Kinugawa S,Tsutsui H,Ide T,Nakamura R,Arimura K,Egashira K,Takeshita A

    更新日期:1999-07-01 00:00:00

  • Angiotensin-II acts centrally to alter renal sympathetic nerve activity and the intrarenal renin-angiotensin system.

    abstract:STUDY OBJECTIVE:The aim was to evaluate the influence that centrally administered angiotensin-II has on the intrarenal renin-angiotensin system and renal sympathetic nerve activity. DESIGN:Renal responses to centrally administered angiotensin-II (10 micrograms) or saralasin (50 micrograms) were measured in anaesthetis...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/25.5.353

    authors: Weekley LB

    更新日期:1991-05-01 00:00:00

  • Use of chronically-implanted ultrasonic crystals in the intact heart of the cat.

    abstract::Methodology has been developed for utilising ultrasonic crystals in closed chest cats to measure alterations in regional left ventricular function. The technique is a modification of one previously utilised to monitor regional left ventricular length and thickness changes in closed chest dogs. The ultrasonic crystals ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/12.6.387

    authors: Hurlbut TA,Scales F,Buja LM,Willerson JT

    更新日期:1978-06-01 00:00:00

  • Inhibitors of poly (ADP-ribose) synthetase protect rat cardiomyocytes against oxidant stress.

    abstract:OBJECTIVE:Inhibitors of poly (ADP-ribose) synthetase (PARS) activity reduce the infarct size caused by regional myocardial ischaemia and reperfusion in the rabbit and rat in vivo. The mechanism of action of these inhibitors is unclear. Here we investigate the effects of the PARS inhibitor 3-aminobenzamide (3-AB) on inf...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(98)00221-1

    authors: Bowes J,McDonald MC,Piper J,Thiemermann C

    更新日期:1999-01-01 00:00:00