Electropharmacology

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The goal of the research of the Nattel lab is to gain new clinically-relevant insights into the basic mechanisms controlling cardiac bioelectricity and arrhythmogenesis, in order to develop innovative therapeutic approaches. To this end, the lab uses a wide range of models at the molecular, cellular, whole-animal and theoretical level to gain insights into the fundamental factors controlling normal cardiac electrical  activity and its derangement in disease models, as well as to identify novel therapeutic targets and candidates. Methods used include whole-animal models (including large and small animal models of human heart disease), single-channel and whole-cell patch clamp on isolated cardiomyocytes and fibroblasts, studies of isolated cardiomyocyte and fibroblast nuclei, biochemistry, cell culture and pacing, molecular biology, conventional and optimal mapping and mathematical models of cardiac electrical activity.  Manipulations include pharmacological approaches, viral-mediated gene-transfer, transgenesis, chronic in vivo instrumentation and pacing, and radiofrequency ablation. Some important contributions of Dr. Nattel’s group have included the discovery of a novel atrial-specific K+ channel in the human heart, the cloning, characterization and functional analysis of novel K+-channel subunits, the delineation of the molecular and functional basis of atrial fibrillation and the identification of a variety of novel targets for antiarrhythmic drug therapy.

Team members

Xiaoyan Qi - Associate
Xiaoyan is a Research Associate. Her tasks include student support and personal projects on : EPS in vitro, calcium imaging, cell isolation/characterization and patch clamp.

Ange Maguy - Associate
Ange Maguy is a Research Associate and tasks include student support and personal projects on: western blot, biochemistry, molecular biology and lab protocol development.

Nathalie L'Heureux - Technician (Animals)
Nathalie is responsible for planning and coordinating all technical aspects of experiments and animal care/preparing animal procedures. She takes care of submitting the appropriate documentation to the MHI's deontology committee for the various reseach projects in the lab. She also plays a key role in the management of the budgets.

Chantal St-Cyr - Technician (Molecular Biology)
Chantal is responsible for infrastructure and supply organization/ordering for biochemistry, patch-clamp, imaging and molecular biology. She also prepares solutions , does genotyping and ensures culture room maintenance.

Jennifer Bacchi - Editorial Manager for the Canadian Journal of Cardiology and Executive Assistant to Dr Stanley Nattel
Her main role is to act as the Editorial Manager for the Canadian Journal of Cardiology. She manages the administrative part of the journal, verifies that submissions adhere to the Instructions for Authors and helps plan/organize/follow up focus/theme issues for the journal.
Her other tasks include administrative support for Dr Nattel. She also coordinates new student arrival and responds to existing students inquiries

Research projects

1.   Atrial fibrillation (AF) mechanisms in in vivo models. AF is the most common arrhythmia in man and is associated wityh increased morbidity and mortality. In these studies, we are developing novel animal models of AF to explore specific underlying mechanisms and identify promising new mechanism-based therapeutic targets.

Work in this area addresses 3 main hypotheses: 1. AF-related atrial fibrotic remodeling results from a program of microRNA changes acting on cardiac fibroblasts. 2. Altered angiotensin nuclear-receptor signalling plays a role in AF. 3. Sustained long-term endurance training produces a substrate for AF maintenance by a combination of structural and autonomic remodeling.

2.   Role of atrial ion current and transporter remodeling in AF. AF and the pathologies that lead to it alter important cellular bioelectrical properties. These alterations cause likelihood of the arrhythmia and determine its response to a wide range of therapeutic interventions. In these studies, we use molecular biology, patch clamp and calcium imaging methods to determine precisely the changes in cellular ion-handling mechanisms that lead to AF and govern its response to medical intervention.

Specific hypotheses being addressed are: 1. Small-conductance Ca2+-dependent K+-channels participate in AF occurrence via regionally determined and remodeling-induced differences in atrial repolarization. 2. Cardiac fibroblast K+-channels are remodelled in AF-promoting paradigms and control proliferative behaviour and extracellular matrix protein production by modulating Ca2+-entry. 3. Transient Receptor Potential 3 (TRPC3) channels regulate atrial fibroblast Ca2+-entry and contribute to the fibrotic AF substrate under the control of microRNA-26.

3.   Molecular mechanisms controlling ventricular repolarization and arrhythmogenesis. In this project, we are addressing the factors that lead to life-threatening ventricular arrhythmias, particularly at the level of cardiac ion channels that control the restoration of cardiac cells to the resting state after they have been fired. Abnormalities in this process destabilize cardiac rhythm and can lead to sudden unexpected death in otherwise well individuals.

Hypotheses under evaluation include: 1. Repolarizing-current remodeling and Ca2+-handling changes are linked in the production of arrhythmias associated with excessive repolarization delay. 2. Sustained abnormalities in heart rate cause discrete forms of arrhythmogenic transmural ion-channel remodeling via specific molecular mechanisms. 3. Beta-subunit composition is a key determinant of K+-channel function.

Publications

1.  Luo X, Pan Z, Shan H, Xiao J, Sun X, Wang N, Lin H, Xiao L, Maguy A, Qi XY, Li Y, Gao X, Dong D, Zhang Y, Bai Y, Ai J, Sun L, Lu H, Luo XY, Wang Z, Lu Y, Yang B, Nattel S. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest. 2013 May 1;123(5):1939-51.

2.  Xiao L, Koopmann TT, Ordög B, Postema PG, Verkerk AO, Iyer V, Sampson KJ, Boink GJ, Mamarbachi MA, Varro A, Jordaens L, Res J, Kass RS, Wilde AA, Bezzina CR, Nattel S. Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition: A Potential Molecular Link to Idiopathic Ventricular Fibrillation. Circ Res. 2013 May 10;112(10):1310-22.

3.  Dawson K, Wakili R, Ordög B, Clauss S, Chen Y, Iwasaki Y, Voigt N, Qi XY, Sinner MF, Dobrev D, Kääb S, Nattel S. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. Circulation. 2013 Apr 9;127(14):1466-75.

4. Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y, Kamiya K, Murohara T, Kodama I, Tardif JC, Schotten U, Van Wagoner DR, Dobrev D, Nattel S. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation. 2012 Oct 23;126(17):2051-64.

5.  Nattel S, Dobrev D. The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. Eur Heart J. 2012 Aug;33(15):1870-7.

6.  Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov. 2012 Mar 30;11(4):275-91.

7. Wakili R, Voigt N, Kääb S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011 Aug;121(8):2955-68.

8.  Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002 Jan 10;415(6868):219-26.

9. Kneller J, Zou R, Vigmond EJ, Wang Z, Leon LJ, Nattel S. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties. Circ Res. 2002 May 17;90(9):E73-87.

10.  Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999 Jul 6;100(1):87-95.

Awards and distinctions

Since 2005:

2013 : Margaret and Theodore Marr Family Endowed Lectureship in Electrophysiology, University of Ottawa Heart Institute
2013 : Founder’s Lectureship Award, Heart Rhythm Society 
2013 : Visiting Professorship in Medical Research, Royal College of Physicians and Surgeons of Canada 
2012 : Honorary Professor, Harbin Medical University, Harbin, China 
2011 : Prix Michel Sarrazin (career research award), Club de recherches cliniques du Québec 
2009 : Distinguished visiting professor, Heart and Stroke Richard Lewar Center of Excellence in Cardiovascular Research, University of Toronto 
2009 : Ronald Campbell Lecturer, Meeting on atrial fibrillation and heart failure, Bologna. 
2009 : Woldemar-Mobitz Award (for work performed by a trainee, Niels Voigt) German Society of Cardiology 
2007 : Jonathan Ballon Award (highest-rated grant application to Quebec Heart and Stroke Foundation, Heart and Stroke Foundation of Quebec)
2005 : Elected to Fellowship Academy of Sciences, Royal Society of Canada 
2006 : Kenneth W.G. Brown Memorial Lecturer, University of Toronto 

Contact

Jennifer Bacchi
Assistant
514-376-3330 X 3587
jenniferanne.bacchi@icm-mhi.org 

Team members

Xiaoyan Qi - Associate
Xiaoyan is a Research Associate. Her tasks include student support and personal projects on : EPS in vitro, calcium imaging, cell isolation/characterization and patch clamp.

Ange Maguy - Associate
Ange Maguy is a Research Associate and tasks include student support and personal projects on: western blot, biochemistry, molecular biology and lab protocol development.

Nathalie L'Heureux - Technician (Animals)
Nathalie is responsible for planning and coordinating all technical aspects of experiments and animal care/preparing animal procedures. She takes care of submitting the appropriate documentation to the MHI's deontology committee for the various reseach projects in the lab. She also plays a key role in the management of the budgets.

Chantal St-Cyr - Technician (Molecular Biology)
Chantal is responsible for infrastructure and supply organization/ordering for biochemistry, patch-clamp, imaging and molecular biology. She also prepares solutions , does genotyping and ensures culture room maintenance.

Jennifer Bacchi - Editorial Manager for the Canadian Journal of Cardiology and Executive Assistant to Dr Stanley Nattel
Her main role is to act as the Editorial Manager for the Canadian Journal of Cardiology. She manages the administrative part of the journal, verifies that submissions adhere to the Instructions for Authors and helps plan/organize/follow up focus/theme issues for the journal.
Her other tasks include administrative support for Dr Nattel. She also coordinates new student arrival and responds to existing students inquiries

Research projects

1.   Atrial fibrillation (AF) mechanisms in in vivo models. AF is the most common arrhythmia in man and is associated wityh increased morbidity and mortality. In these studies, we are developing novel animal models of AF to explore specific underlying mechanisms and identify promising new mechanism-based therapeutic targets.

Work in this area addresses 3 main hypotheses: 1. AF-related atrial fibrotic remodeling results from a program of microRNA changes acting on cardiac fibroblasts. 2. Altered angiotensin nuclear-receptor signalling plays a role in AF. 3. Sustained long-term endurance training produces a substrate for AF maintenance by a combination of structural and autonomic remodeling.

2.   Role of atrial ion current and transporter remodeling in AF. AF and the pathologies that lead to it alter important cellular bioelectrical properties. These alterations cause likelihood of the arrhythmia and determine its response to a wide range of therapeutic interventions. In these studies, we use molecular biology, patch clamp and calcium imaging methods to determine precisely the changes in cellular ion-handling mechanisms that lead to AF and govern its response to medical intervention.

Specific hypotheses being addressed are: 1. Small-conductance Ca2+-dependent K+-channels participate in AF occurrence via regionally determined and remodeling-induced differences in atrial repolarization. 2. Cardiac fibroblast K+-channels are remodelled in AF-promoting paradigms and control proliferative behaviour and extracellular matrix protein production by modulating Ca2+-entry. 3. Transient Receptor Potential 3 (TRPC3) channels regulate atrial fibroblast Ca2+-entry and contribute to the fibrotic AF substrate under the control of microRNA-26.

3.   Molecular mechanisms controlling ventricular repolarization and arrhythmogenesis. In this project, we are addressing the factors that lead to life-threatening ventricular arrhythmias, particularly at the level of cardiac ion channels that control the restoration of cardiac cells to the resting state after they have been fired. Abnormalities in this process destabilize cardiac rhythm and can lead to sudden unexpected death in otherwise well individuals.

Hypotheses under evaluation include: 1. Repolarizing-current remodeling and Ca2+-handling changes are linked in the production of arrhythmias associated with excessive repolarization delay. 2. Sustained abnormalities in heart rate cause discrete forms of arrhythmogenic transmural ion-channel remodeling via specific molecular mechanisms. 3. Beta-subunit composition is a key determinant of K+-channel function.

Publications

1.  Luo X, Pan Z, Shan H, Xiao J, Sun X, Wang N, Lin H, Xiao L, Maguy A, Qi XY, Li Y, Gao X, Dong D, Zhang Y, Bai Y, Ai J, Sun L, Lu H, Luo XY, Wang Z, Lu Y, Yang B, Nattel S. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest. 2013 May 1;123(5):1939-51.

2.  Xiao L, Koopmann TT, Ordög B, Postema PG, Verkerk AO, Iyer V, Sampson KJ, Boink GJ, Mamarbachi MA, Varro A, Jordaens L, Res J, Kass RS, Wilde AA, Bezzina CR, Nattel S. Unique Cardiac Purkinje Fiber Transient Outward Current β-Subunit Composition: A Potential Molecular Link to Idiopathic Ventricular Fibrillation. Circ Res. 2013 May 10;112(10):1310-22.

3.  Dawson K, Wakili R, Ordög B, Clauss S, Chen Y, Iwasaki Y, Voigt N, Qi XY, Sinner MF, Dobrev D, Kääb S, Nattel S. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. Circulation. 2013 Apr 9;127(14):1466-75.

4. Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y, Kamiya K, Murohara T, Kodama I, Tardif JC, Schotten U, Van Wagoner DR, Dobrev D, Nattel S. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation. 2012 Oct 23;126(17):2051-64.

5.  Nattel S, Dobrev D. The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. Eur Heart J. 2012 Aug;33(15):1870-7.

6.  Dobrev D, Carlsson L, Nattel S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov. 2012 Mar 30;11(4):275-91.

7. Wakili R, Voigt N, Kääb S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011 Aug;121(8):2955-68.

8.  Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002 Jan 10;415(6868):219-26.

9. Kneller J, Zou R, Vigmond EJ, Wang Z, Leon LJ, Nattel S. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties. Circ Res. 2002 May 17;90(9):E73-87.

10.  Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999 Jul 6;100(1):87-95.

Links

1. http://scholar.google.com/citations?user=ndwxvv4AAAAJ

2. http://www.ncbi.nlm.nih.gov/pubmed/?term=nattel+s

Awards and distinctions

Since 2005:

2013 : Margaret and Theodore Marr Family Endowed Lectureship in Electrophysiology, University of Ottawa Heart Institute
2013 : Founder’s Lectureship Award, Heart Rhythm Society 
2013 : Visiting Professorship in Medical Research, Royal College of Physicians and Surgeons of Canada 
2012 : Honorary Professor, Harbin Medical University, Harbin, China 
2011 : Prix Michel Sarrazin (career research award), Club de recherches cliniques du Québec 
2009 : Distinguished visiting professor, Heart and Stroke Richard Lewar Center of Excellence in Cardiovascular Research, University of Toronto 
2009 : Ronald Campbell Lecturer, Meeting on atrial fibrillation and heart failure, Bologna. 
2009 : Woldemar-Mobitz Award (for work performed by a trainee, Niels Voigt) German Society of Cardiology 
2007 : Jonathan Ballon Award (highest-rated grant application to Quebec Heart and Stroke Foundation, Heart and Stroke Foundation of Quebec)
2005 : Elected to Fellowship Academy of Sciences, Royal Society of Canada 
2006 : Kenneth W.G. Brown Memorial Lecturer, University of Toronto 

Contact

Jennifer Bacchi
Assistant
514-376-3330 X 3587
jenniferanne.bacchi@icm-mhi.org