Stanley Nattel

Université du Québec à Montréal, Montréal, Quebec, Canada

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Publications (538)3980.04 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The nuclear envelope encloses the genome as well as the molecular machinery responsible for both the replication and transcription of DNA as well as the maturation of nascent RNA. Recent studies ascribe a growing number of functions to the nuclear membrane, in addition to sequestering the DNA, through receptors and their effectors, ion channels, as well as ion pumps and transporters located within the nuclear membrane itself. Despite the obvious structural and functional importance of the nucleus, certain aspects remain poorly understood due to the challenges associated with its accessibility in vivo, as well as isolating nuclei intact and with sufficient purity from cardiac cells to permit studies in vitro. Here, we present a detailed protocol for isolation of intact nuclei from both myocardial tissue and freshly isolated adult ventricular cardiomyocytes. These methods are based on partial permeabilization of plasma membrane with digitonin and cell disruption, followed by differential and discontinuous sucrose density centrifugation. These preparations provide for rapid separation of nonnuclear membranes and cytosol from nuclei.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1234:69-80. · 1.29 Impact Factor
  • The Canadian journal of cardiology 11/2014; · 3.12 Impact Factor
  • Xiaobin Luo, Baofeng Yang, Stanley Nattel
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    ABSTRACT: Atrial fibrillation (AF), the most common sustained arrhythmia in clinical practice, is an important contributor to cardiac morbidity and mortality. Pharmacological approaches currently available to treat patients with AF lack sufficient efficacy and are associated with potential adverse effects. Even though ablation is generally more effective than pharmacotherapy, this invasive procedure has considerable potential complications and is limited by long-term recurrences. Novel therapies based on the underlying molecular mechanisms of AF can provide useful alternatives to current treatments. MicroRNAs (miRNAs), endogenous short RNA sequences that regulate gene expression, have been implicated in the control of AF, providing novel insights into the molecular basis of the pathogenesis of AF and suggesting miRNA targeting as a potential approach for the management of this common arrhythmia. In this Review, we provide a comprehensive analysis of the current experimental evidence supporting miRNAs as important factors in AF and discuss their therapeutic implications. We first provide background information on the pathophysiology of AF and the biological determinants of miRNA synthesis and action, followed by experimental evidence for miRNA-mediated regulation of AF, and finally provide a comprehensive overview of miRNAs as potential novel therapeutic targets for AF.
    Nature Reviews Cardiology 11/2014; · 10.40 Impact Factor
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    ABSTRACT: Fibroblasts are activated in heart failure (HF) and produce fibrosis, which plays a role in maintaining atrial fibrillation (AF). The effect of HF on fibroblast ion currents and its potential role in AF are unknown. Here, we used a patch-clamp technique to investigate the effects of HF on atrial fibroblast ion currents, and mathematical computation to assess the potential impact of this remodeling on atrial electrophysiology and arrhythmogenesis. Atrial fibroblasts were isolated from control and tachypacing-induced HF dogs. Tetraethylammonium-sensitive voltage-gated fibroblast current (IKv,fb) was significantly downregulated (by ?44%), whereas the Ba(2+)-sensitive inward rectifier current (IKir,fb) was upregulated by 79%, in HF animals versus controls. The fibroblast resting membrane potential was hyperpolarized (?53 ± 2 mV vs. ?42 ± 2 mV in controls) and the capacitance was increased (29.7 ± 2.2 pF vs. 17.8 ± 1.4 pF in controls) in HF. These experimental findings were implemented in a mathematical model that included cardiomyocyte-fibroblast electrical coupling. IKir,fb upregulation had a profibrillatory effect through shortening of the action potential duration and hyperpolarization of the cardiomyocyte resting membrane potential. IKv,fb downregulation had the opposite electrophysiological effects and was antifibrillatory. Simulated pharmacological blockade of IKv,fb successfully terminated reentry under otherwise profibrillatory conditions. We conclude that HF induces fibroblast ion-current remodeling with IKv,fb downregulation and IKir,fb upregulation, and that, assuming cardiomyocyte-fibroblast electrical coupling, this remodeling has a potentially important effect on atrial electrophysiology and arrhythmogenesis, with the overall response depending on the balance of pro- and antifibrillatory contributions. These findings suggest that fibroblast K(+)-current remodeling is a novel component of AF-related remodeling that might contribute to arrhythmia dynamics.
    Biophysical journal. 11/2014; 107(10):2444-55.
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    ABSTRACT: Several lines of evidence suggest that intracellular angiotensin II (Ang-II) contributes to the regulation of cardiac contractility, renal salt reabsorption, vascular tone and metabolism; however, work on intracrine Ang-II signalling has been limited to indirect approaches because of a lack of selective intracellularly-acting probes. Here, we aimed to synthesize and characterize cell-permeable Ang-II analogues that are inactive without uncaging, but release active Ang-II upon exposure to a flash of ultraviolet light, as novel tools to study intracrine Ang-II physiology. We prepared three novel caged Ang-II analogues, [Tyr(DMNB)4]Ang-II, Ang-II-ODMNB and [Tyr(DMNB)4]Ang-II-ODMNB, based upon the incorporation of the photolabile moiety 4,5-dimethoxy-2-nitrobenzyl (DMNB). Compared to Ang-II, the caged Ang-II analogues showed 2–3 orders of magnitude reduced affinity toward both angiotensin type-1 (AT1R) and type-2 (AT2R) receptors in competition binding assays, and greatly-reduced potency in contraction assays of rat thoracic aorta. Following ultraviolet irradiation, all three caged Ang-II analogues released Ang-II and potently induced contraction of rat thoracic aorta. [Tyr(DMNB)4]Ang-II showed the most rapid photolysis upon ultraviolet irradiation and was the focus of subsequent characterization. Whereas Ang-II and photolysed [Tyr(DMNB)4]Ang-II increased ERK1/2 phosphorylation (via AT1R) and cGMP production (AT2R), caged [Tyr(DMNB)4]Ang-II did not. Cellular uptake of [Tyr(DMNB)4]Ang-II was 4-fold greater than that of Ang-II and significantly greater than uptake driven by the positive-control HIV TAT(48–60) peptide. Intracellular photolysis of [Tyr(DMNB)4]Ang-II induced an increase in nucleoplasmic Ca2+ ([Ca2+]n), and initiated 18S rRNA and NF-κB mRNA synthesis in adult cardiac cells. We conclude that caged Ang-II analogues represent powerful new tools to selectively study intracrine signalling via Ang-II.This article is protected by copyright. All rights reserved
    The Journal of Physiology 11/2014; · 4.38 Impact Factor
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    ABSTRACT: Recent trials of fish oil for the prevention of atrial fibrillation (AF) recurrence have provided mixed results. Notable uncertainties in the existing evidence base include the roles of high-dose fish oil, inflammation, and oxidative stress in patients with paroxysmal or persistent AF not receiving conventional antiarrhythmic (AA) therapy.
    Journal of the American College of Cardiology 10/2014; 64(14):1441-8. · 14.09 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is an extremely common clinical problem with an important population morbidity and mortality burden. The management of AF is complex and fraught with many uncertain and contentious issues, which are being addressed by extensive ongoing basic and clinical research. The Canadian Cardiovascular Society AF Guidelines Committee produced an extensive set of evidence-based AF management guidelines in 2010 and updated them in the areas of anticoagulation and rate/rhythm control in 2012. In late 2013, the committee judged that sufficient new information regarding AF management had become available since 2012 to warrant an update to the Canadian Cardiovascular Society AF Guidelines. After extensive evaluation of the new evidence, the committee has updated the guidelines for: (1) stroke prevention principles; (2) anticoagulation of AF patients with chronic kidney disease; (3) detection of AF in patients with stroke; (4) investigation and management of subclinical AF; (5) left atrial appendage closure in stroke prevention; (6) emergency department management of AF; (7) periprocedural anticoagulation management; and (8) rate and rhythm control including catheter ablation. This report presents the details of the updated recommendations, along with their background and rationale. In addition, a complete set of presently applicable recommendations, those that have been updated and those that remain in force from previous guideline versions, is provided in the Supplementary Material.
    The Canadian journal of cardiology 10/2014; 30(10):1114-30. · 3.12 Impact Factor
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    ABSTRACT: Cardiac arrhythmias are a major contributor to population morbidity and mortality. Enormous advances in arrhythmia management have occurred over the 60 years since the founding of the Montreal Heart Institute, but important challenges remain. The purpose of this article is to identify the areas of cardiac arrhythmia therapy that need improvement and to discuss the evolving approaches that promise solutions. Challenges in diagnosis, detection, and risk-stratification include difficulties in separating benign from high-risk syncope and pinpointing the underlying causes, the detection of silent atrial fibrillation in patients at risk of stroke, and inadequate identification of sudden-death risk. Implantable devices are limited by the need for battery and device replacements, device complications like infection and dysfunction, and lead complications like fracture, infection, or displacement. Antiarrhythmic drug therapy, although widely used, is plagued by a very limited range of available agents, supply issues, insufficient efficacy, and significant adverse effect risk. Health economic concerns include the high cost of new technologies, challenges in establishing cost effectiveness, and restrictive practices of government or third-party payers. Major improvements in arrhythmia management can be expected from new discoveries and technological developments in genetics, innovative diagnostic tools for arrhythmia monitoring, imaging and analysis, new approaches to antiarrhythmic drug development, biological therapies, and continuing improvement in implantable device technology like further miniaturization, leadless technology, and use of novel energy sources. As exciting as the developments in arrhythmia management have been in the past, we can look forward to exponential improvement in our ability to manage arrhythmia patients in the near future.
    The Canadian journal of cardiology 09/2014; · 3.12 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) ablation is widely performed and is progressively supplanting drug therapy. Catheter-based AF ablation modalities have evolved progressively in parallel to our understanding of underlying mechanisms. Initial attempts to mimic the surgical maze procedure, which were based on the multiple wavelet model, failed because of adverse outcomes and insufficient effectiveness. A major advance was the targeting of pulmonary veins, which is highly effective for paroxysmal AF. Active research on the underlying mechanisms continues. The main challenge is reconnection, but procedures to minimize this are being developed. Ablation procedures for persistent AF are presently limited by suboptimal success rates and long-term disease progression that causes recurrences. Basic research into the underlying mechanisms has led to promising driver mechanism-directed clinical approaches along with pathways toward the prevention of atrial remodeling. Here, we review the role of basic research in the development of presently used AF-ablation procedures and look toward future contributions in improving outcomes.
    Journal of the American College of Cardiology 08/2014; 64(8):823–831. · 14.09 Impact Factor
  • Stanley Nattel
    Cardiovascular research. 08/2014;
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    ABSTRACT: Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart-rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, autoantibodies targeting the cardiac voltage-gated KCNQ1 K(+)-channel were associated with shortened QTc-intervals. However, the electrophysiological actions of KCNQ1 autoimmunity have not been assessed experimentally in a direct fashion.
    Heart rhythm: the official journal of the Heart Rhythm Society 07/2014; · 4.56 Impact Factor
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    ABSTRACT: Upregulation of the intermediate filament protein nestin was identified in a subpopulation of fibroblasts during reactive and reparative fibrosis and directly contributed to the enhanced proliferative phenotype. The present study tested the hypothesis that nestin was expressed in lung fibroblasts and the pattern of expression represented a distinct marker of pulmonary remodeling secondary to myocardial infarction and type I diabetes. Nestin((+)) fibroblasts were detected in rat lungs and a subpopulation exhibited a myofibroblast phenotype delineated by the co-expression of smooth muscle α-actin. In the lungs of myocardial infarcted rats, interstitial collagen content and nestin mRNA/protein levels were significantly increased despite the absence of secondary pulmonary hypertension, whereas smooth muscle α-actin protein expression was unchanged. Exposure of rat pulmonary fibroblasts to pro-fibrotic stimuli angiotensin II and transforming growth factor-β significantly increased nestin protein levels. In the lungs of type I diabetic rats, the absence of a reactive fibrotic response was associated with a significant downregulation of nestin mRNA/protein expression. Nestin was reported a target of miR-125b, albeit miR-125b levels were unchanged in pulmonary fibroblasts treated with pro-fibrotic stimuli. Nestin((+)) cells lacking smooth muscle α-actin/collagen staining were also identified in rodent lungs and a transgenic approach revealed that expression of the intermediate filament protein was driven by intron 2 of the nestin gene. The disparate regulation of nestin characterized a distinct pattern of pulmonary remodeling secondary to myocardial infarction and type I diabetes and upregulation of the intermediate filament protein in lung fibroblasts may have facilitated in part the reactive fibrotic response. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 06/2014; · 4.22 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%-26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca(2+)-handling abnormalities, (3) structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure, myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca(2+)-handling abnormalities that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease. Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to develop improved methods for AF prevention and management.
    Circulation Research 04/2014; 114(9):1453-68. · 11.86 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca(2+)-handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management.
    Circulation Research 04/2014; 114(9):1483-99. · 11.86 Impact Factor
  • Kunihiro Nishida, Stanley Nattel
    Circulation Research 04/2014; 114(9):1447-52. · 11.86 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is a common complication of heart failure. The aim of the present study was to investigate the effects of a new pure docosahexaenoic acid derivative called F 16915 in experimental models of heart failure-induced atria dysfunction. The atrial dysfunction-induced AF was investigated (1) in a dog model of tachypacing-induced congestive heart failure and (2) in a rat model of heart failure induced by occlusion of left descending coronary artery and 2 months reperfusion. F 16915 (5 g/day for 4 weeks) significantly reduced the mean duration of AF induced by burst pacing in the dog model (989 ± 111 s in the vehicle group to 79 ± 59 s with F 16915, P < 0.01). This dose of F 16915 also significantly reduced the incidence of sustained AF (5/5 dogs in the vehicle group versus 1/5 with F 16915, P < 0.05). In the rat model, the percentage of shortening fraction in the F 16915 group (100 mg/kg p.o. daily) was significantly restored after 2 months (32.6 ± 7.4 %, n = 9 vs 17.6 ± 3.4 %, n = 9 in the vehicle group, P < 0.01). F 16915 also reduced the de-phosphorylation of connexin43 from atria tissue. The present results show that treatment with F 16915 reduced the heart dilation, resynchronized the gap junction activity, and reduced the AF duration in models of heart failure. Thus, F 16915 constitutes a promising new drug as upstream therapy for the treatment of AF in patients with heart failure.
    Archiv für Experimentelle Pathologie und Pharmakologie 04/2014; · 2.15 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is generally considered a progressive disease, typically evolving from paroxysmal through persistent to 'permanent' forms, a process attributed to electrical and structural remodelling related to both the underlying disease and AF itself. Medical treatment has yet to demonstrate clinical efficacy in preventing progression. Large clinical trials performed to date have failed to show benefit of rhythm control compared with rate control, but these trials primarily included patients at late stages in the disease process. One possible explanation is that intervention at only an early stage of progression may improve prognosis. Evolving observations about the progressive nature of AF, along with the occurrences of major complications such as strokes upon AF presentation, led to the notion that earlier and more active approaches to AF detection, rhythm-reversion, and maintenance of sinus rhythm may be a useful strategy in AF management. Approaches to early and sustained rhythm control include measures that prevent development of the AF substrate, earlier catheter ablation, and novel antiarrhythmic drugs. Improved classifications of AF mechanism, pathogenesis, and remodelling may be helpful to enable patient-specific pathophysiological diagnosis and therapy. Potential novel therapeutic options under development include microRNA-modulation, heatshock protein inducers, agents that influence Ca(2+) handling, vagal stimulators, and more aggressive mechanism-based ablation strategies. In this review, of research into the basis and management of AF in acute and early settings, it is proposed that progression from paroxysmal to persistent AF can be interrupted, with potentially favourable prognostic impact.
    European Heart Journal 02/2014; · 14.72 Impact Factor
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    ABSTRACT: β-Adrenoceptor activation contributes to sudden-death risk in heart failure (HF). Chronic beta-adrenergic stimulation, as occurs in HF patients, causes potentially-arrhythmogenic reductions in slow delayed-rectifier K(+)-current (IKs). To assess the molecular mechanisms of IKs-downregulation caused by chronic beta-adrenergic activation, particularly the role of Exchange protein directly activated by cyclic-AMP (Epac). Isolated guinea-pig left-ventricular (LV)-cardiomyocytes were incubated in primary culture and exposed to isoproterenol (1-µmol/L) or vehicle for 30 hrs. Sustained isoproterenol-exposure decreased IKs-density (whole-cell patch-clamp) by 58% (P<0.0001), with corresponding decreases in KCNE1 mRNA and membrane-protein expression (by 45%, 51% respectively). KCNQ1 mRNA-expression was unchanged. The β1-adrenoceptor antagonist CGP-20712A prevented isoproterenol-induced IKs-downregulation, whereas the β2-antagonist ICI-118551 had no effect. The selective Epac-activator 8-pCPT decreased IKs-density to an extent similar to isoproterenol-exposure, and adenoviral-mediated knockdown of Epac1 prevented isoproterenol-induced IKs/KCNE1-downregulation. In contrast, protein-kinase A inhibition with a cell-permeable highly-selective peptide blocker did not affect IKs-downregulation. BAPTA-AM, cyclosporine and INCA6 prevented IKs-reduction by isoproterenol and INCA6 suppressed isoproterenol-induced KCNE1-downregulation, consistent with signal-transduction via the Ca(2+)/calcineurin/NFAT pathway. Isoproterenol induced nuclear NFATc3/c4 translocation (immunofluorescence), which was suppressed by Epac1-knockdown. Chronic in-vivo administration of isoproterenol to guinea pigs reduced IKs-density and KCNE1 mRNA- and protein expression, while inducing cardiac dysfunction and action-potential prolongation. Selective in vivo activation of Epac via sp-8-pCPT-infusion decreased IKs-density and KCNE1 mRNA/protein-expression. Prolonged β1-adrenoceptor stimulation suppresses IKs by downregulating KCNE1 mRNA and protein via Epac-mediated Ca(2+)/calcineurin/NFAT signaling. These results provide new insights into the molecular basis of K(+)-channel remodeling under sustained adrenergic stimulation.
    Circulation Research 02/2014; · 11.86 Impact Factor
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    ABSTRACT: The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca(2+)-leak via the ryanodine receptor (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study tested the hypothesis that enhanced RyR2-mediated Ca(2+)-release underlies the development of a substrate for sAF and to understand the underlying mechanisms. CREM-IbΔC-X transgenic (CREM)-mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM-mice was preceded by enhanced diastolic Ca(2+)-release, atrial enlargement and marked conduction abnormalities. Genetic inhibition of CaMKII-mediated RyR2-S2814 phosphorylation in CREM-mice normalized open probability of RyR2-channels and SR Ca(2+)-release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation and forestalled atrial conduction-abnormalities. Hyperactive RyR2-channels directly stimulated the Ca(2+)-dependent hypertrophic pathway NFAT/Rcan1-4, suggesting a role for the NFAT/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. RyR2-mediated SR Ca(2+)-leak directly underlies the development of a substrate for sAF in CREM-mice, the first demonstration of a molecular mechanism underlying AF-progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca(2+) release in AF may not be restricted to the generation of atrial ectopy, but extends to the development of atrial remodeling underlying the AF substrate.
    Circulation 01/2014; · 15.20 Impact Factor
  • Stanley Nattel, Xiao Yan Qi
    Cardiovascular Research 01/2014; · 5.81 Impact Factor

Publication Stats

19k Citations
3,980.04 Total Impact Points


  • 2004–2014
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
  • 1988–2014
    • Montreal Heart Institute
      • • Department of Medicine
      • • Research Centre
      Montréal, Quebec, Canada
  • 2013
    • Hungarian Academy of Sciences
      Budapeŝto, Budapest, Hungary
    • University of Duisburg-Essen
      • Faculty of Medicine
      Essen, North Rhine-Westphalia, Germany
    • The University of Calgary
      Calgary, Alberta, Canada
    • Laval University
      Québec, Quebec, Canada
    • University of Barcelona
      • Department of Medicine
      Barcino, Catalonia, Spain
  • 2011–2013
    • Chang Gung Memorial Hospital
      T’ai-pei, Taipei, Taiwan
  • 2009–2013
    • Centre hospitalier de l'Université de Montréal (CHUM)
      Montréal, Quebec, Canada
    • Mayo Foundation for Medical Education and Research
      • Department of Anesthesiology
      Scottsdale, AZ, United States
  • 1990–2013
    • Université de Montréal
      • • Department of Physiology
      • • Department of Medicine
      • • Center for Mathematical Research
      • • Department of Pharmacology
      Montréal, Quebec, Canada
  • 1987–2013
    • McGill University
      • • Department of Pharmacology and Therapeutics
      • • Department of Physiology
      Montréal, Quebec, Canada
  • 2012
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • The University of Western Ontario
      London, Ontario, Canada
    • University of Toyama
      Тояма, Toyama, Japan
  • 2010–2012
    • Universität Heidelberg
      • Faculty of Medicine Mannheim and Clinic Mannheim
      Heidelberg, Baden-Wuerttemberg, Germany
    • St George's, University of London
      Londinium, England, United Kingdom
    • Cardiology Wellness Center
      Nashville, Tennessee, United States
  • 2003–2011
    • Complutense University of Madrid
      • Departamento de Medicina
      Madrid, Madrid, Spain
    • State University of New York Upstate Medical University
      • Department of Pharmacology
      Syracuse, NY, United States
  • 2008–2010
    • Technische Universität Dresden
      Dresden, Saxony, Germany
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • University of Florence
      • Interuniversitary Center of Molecular Medicine and Applied Biophysics (CIMMBA)
      Florence, Tuscany, Italy
  • 2008–2009
    • Goethe-Universität Frankfurt am Main
      • Zentrum der Inneren Medizin
      Frankfurt am Main, Hesse, Germany
  • 2006
    • Kosin University
      Tsau-liang-hai, Busan, South Korea
  • 2005
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 2002–2004
    • The University of Hong Kong
      • Institute of Cardiovascular Science and Medicine
      Hong Kong, Hong Kong
  • 1999
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Harbin Medical University
      • Department of Pharmacology
      Harbin, Heilongjiang Sheng, China
  • 1995
    • Collège de Maisonneuve
      Montréal, Quebec, Canada
  • 1991
    • Uniformed Services University of the Health Sciences
      • Department of Medicine
      Bethesda, MD, United States