Stanley Nattel

Université du Québec à Montréal, Montréal, Quebec, Canada

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Publications (533)3959.02 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
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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: 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
  • Stanley Nattel
    The Canadian journal of cardiology 01/2014; 30(1):1-2. · 3.12 Impact Factor
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    ABSTRACT: Background Atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) is associated with PV to left atrium re-conduction. Effective lesion creation necessitates adequate contact force between the ablation catheter and myocardium. Objective We prospectively studied the utility of contact force guided ablation on immediate and long-term outcomes. Methods Seventy-five patients with highly symptomatic paroxysmal AF underwent wide circumferential PVI using an irrigated tip radiofrequency catheter. In 25 patients ablation was guided by real-time contact force measurements (CF group; SmartTouch; Biosense-Webster), whereas a control group of 50 patients underwent PVI using a standard non-force sensing catheter (Standard Group; Thermocool; Biosense-Webster). Post PVI all patients underwent adenosine testing to unmask dormant conduction. Patients were followed at 3, 6, and 12 months, as well as with trans-telephonic monitors. Results Dormant conduction was unmasked and subsequently eliminated in 4 PV pairs (8%; 16% of patients) in the CF group and 35 PV pairs (35%; 52% of patients) in the standard group (P=0.0004 per PV pair, and P=0.0029 per patient). The single procedure off antiarrhythmic drug freedom from recurrent atrial arrhythmias at one year was 88% in the CF group vs. 66% in the standard group (P=0.047). Procedure duration and fluoroscopy time were significantly longer in the CF group (P=0.0038, and P=0.0001). Conclusions The use of real-time contact force guidance results in a significant reduction in the prevalence of dormant conduction with improved long-term freedom from recurrent arrhythmias. The utility of a contact force guided approach requires evaluation in a long-term prospective randomized study.
    Heart Rhythm. 01/2014;
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    ABSTRACT: Sex-differences in cardiac electrophysiological properties and arrhythmia differences are evident in epidemiological and investigative studies, as well as in daily patient care. At the supraventricular level, women are at increased risk of sick sinus syndrome and atrioventricular nodal reentrant tachycardia, while men manifest more atrioventricular block and accessory pathway-mediated arrhythmias. At the ventricular level, women are generally at higher risk of long-QT associated arrhythmias, whereas men are more likely to present early repolarization, idiopathic ventricular fibrillation and Brugada syndromes. Great advances have been made in unravelling the fundamental mechanisms underlying sex-differences in ventricular arrhythmias, particularly those associated with abnormal repolarization. On the other hand, the basis for male-predominant arrhythmic risk in structural heart disease and differences in supraventricular arrhythmia susceptibility are poorly understood. Beyond biological differences, arrhythmia occurrence and patient care decisions are also influenced by gender-related factors. This paper reviews the current knowledge regarding the nature and underlying mechanisms of sex differences in basic cardiac electrophysiology and clinical arrhythmias.
    The Canadian journal of cardiology 01/2014; · 3.12 Impact Factor
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    Journal of the American Heart Association. 01/2014; 3(4).
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    ABSTRACT: Structural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role. To define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics. High throughput real-time RT-PCR was used to quantify the expression patterns of 84 ion-channel, calcium cycling, connexin and related gene transcripts from sites in the LV, septum, and RV in 8 patients undergoing transplantation. An additional eight non-diseased donor human hearts served as controls. To relate local ion channel expression change to VF dynamics localized VF mapping was performed on the explanted myopathic hearts right adjacent to sampled regions. Compared to non-diseased ventricles, significant differences (p<0.05) were identified in the expression of 23 genes in the myopathic LV and 32 genes in the myopathic RV. Within the myopathic hearts significant regional (LV vs septum vs RV) expression differences were observed for 13 subunits: Nav1.1, Cx43, Ca3.1, Cavα2δ2, Cavβ2, HCN2, Na/K ATPase-1, CASQ1, CASQ2, RYR2, Kir2.3, Kir3.4, SUR2 (p<0.05). In a subset of genes we demonstrated differences in protein expression between control and myopathic hearts, which were concordant with the mRNA expression profiles for these genes. Variability in the expression of Cx43, hERG, Na(+)/K(+) ATPase ß1 and Kir2.1 correlated to variability in local VF dynamics (p<0.001). To better understand the contribution of multiple ion channel changes on VF frequency, simulations of a human myocyte model were conducted. These simulations demonstrated the complex nature by which VF dynamics are regulated when multi-channel changes are occurring simultaneously, compared to known linear relationships. Ion channel expression profile in myopathic human hearts is significantly altered compared to normal hearts. Multi-channel ion changes influence VF dynamic in a complex manner not predicted by known single channel linear relationships.
    PLoS ONE 01/2014; 9(1):e82179. · 3.53 Impact Factor

Publication Stats

19k Citations
3,959.02 Total Impact Points

Institutions

  • 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