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 Resjournal_title
Cardiovascular researchauthors
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 Mdoi
10.1093/cvr/cvaa307subject
Has Abstractpub_date
2020-10-29 00:00:00eissn
0008-6363issn
1755-3245pii
5942974pub_type
杂志文章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
更新日期:2001-03-01 00:00:00
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
更新日期:2001-09-01 00:00:00
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
更新日期:2009-02-15 00:00:00
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
更新日期:1975-05-01 00:00:00
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
更新日期:1980-05-01 00:00:00
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
更新日期:2008-02-01 00:00:00
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
更新日期:1993-04-01 00:00:00
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
更新日期:2011-11-01 00:00:00
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
更新日期:1983-02-01 00:00:00
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
更新日期:1997-09-01 00:00:00
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
更新日期:1979-02-01 00:00:00
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
更新日期:2006-05-01 00:00:00
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:
更新日期:1996-11-01 00:00:00
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
更新日期:1991-08-01 00:00:00
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
更新日期:2008-03-01 00:00:00
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
更新日期:1988-06-01 00:00:00
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
更新日期:2018-03-01 00:00:00
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
更新日期:2020-12-01 00:00:00
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
更新日期:2008-01-01 00:00:00
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
更新日期:2019-12-01 00:00:00
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
更新日期:1999-09-01 00:00:00
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
更新日期:1994-04-01 00:00:00
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
更新日期:1997-05-01 00:00:00
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
更新日期:2000-01-01 00:00:00
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
更新日期:1984-12-01 00:00:00
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
更新日期:1978-11-01 00:00:00
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
更新日期:1999-07-01 00:00:00
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
更新日期:1991-05-01 00:00:00
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
更新日期:1978-06-01 00:00:00
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
更新日期:1999-01-01 00:00:00