Stanley Nattel

Université du Québec à Montréal, Montréal, Quebec, Canada

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Publications (577)4270.26 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In the absence of structural heart disease, sudden cardiac death is frequently caused by inherited arrhythmia syndromes, such as long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. Managing these conditions often requires a combination of lifestyle modification, pharmacotherapy and less frequently, invasive therapy. Over the past decade, patient management has been greatly enhanced by tailored pharmacotherapy as a result of a deeper appreciation for arrhythmia mechanisms and supportive evidence from multicenter cohort studies. This article reviews current knowledge regarding drug therapy for inherited arrhythmias. Anti-arrhythmic mechanisms and available clinical evidence are highlighted while maintaining a practical perspective on patient management.
    Expert Review of Cardiovascular Therapy 05/2015; DOI:10.1586/14779072.2015.1049156
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    ABSTRACT: In this issue, Baris et al. (2015) describe cardiac rhythm abnormalities in a mouse model of mitochondrial dysfunction in widely distributed cells of the aging human heart. How do a few metabolically challenged cells disrupt cardiac rhythm? We suggest that these cells provide "crystallization centers" for latent dysfunctional zones to allow arrhythmia emergence. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 05/2015; 21(5):662-3. DOI:10.1016/j.cmet.2015.04.024 · 16.75 Impact Factor
  • Martin Aguilar, Stanley Nattel
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    ABSTRACT: Despite major advances in arrhythmia therapy, atrial fibrillation (AF) remains a challenge. A significant limitation in AF management is the lack of safe and effective drugs to restore and/or maintain sinus rhythm. The rational design of a new generation of AF-selective Na-channel blockers (NCBs) is emerging as a promising AF-suppressing strategy. Recent theoretical and experimental advances have generated insights into the mechanisms underlying AF maintenance and termination by antiarrhythmic drugs. Our understanding of antiarrhythmic drug-induced proarrhythmia has also grown in sophistication. These discoveries have created new possibilities in therapeutic targeting and renewed interest in improved NCB antiarrhythmic drugs. Recently-described differences in atrial versus ventricular electrophysiology can be exploited in the prospective design of atrial-selective NCBs. Furthermore, state-dependent block has been shown to be an important modulator of NCB rate-selectivity. Together, differential atrial-ventricular electrophysiological actions and state-dependent block form the backbone for the rational design of an AF-selective NCB. Synergistic combinations incorporating both NCB and block of K-currents may allow for further enhancement of AF-selectivity. Future work on translating these basic research advances into the development of an optimized AF-selective NCB has the potential to provide safer and more effective pharmacotherapeutic options for AF, thereby fulfilling a major unmet clinical need.
    Journal of cardiovascular pharmacology 04/2015; DOI:10.1097/FJC.0000000000000271 · 2.11 Impact Factor
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    ABSTRACT: We have previously reported a physiologically relevant interaction between KCNQ1 (Q1) and KCNH2 (H2). While the H2 C-terminus has been suggested to play a role, so far, no more detailed information regarding the interaction site is available. The methods used in the study are cell culture, PCR for mutagenesis, patch clamp for ion current recordings, co-immunoprecipitation for determination of protein interaction. Co-expression of Q1 and H2 resulted in an increase of I H2 (tails after +50 mV; Q1 + H2, 36 ± 6 pA/pF; H2, 14 ± 2 pA/pF; n = 10; 12; P < 0.05). Upon expressing a non-conductive (dominant-negative) Q1-pore mutation (dnQ1), there was still an increase in I H2 (tails after +50 mV; H2 + dnQ1, 24 ± 4 pA/pF; n = 10; P < 0.05) making the pore region unlikely as an interaction site. Experiments using the KCNH2-pore blocking agent quinidine supported these findings. If Q1 and H2 formed hetero-tetramers, steric changes within the pore should change the quinidine half-inhibitory concentrations (IC50). However, I H2 sensitivity did not significantly change in the presence or absence of Q1 (IC50 341 ± 63 vs. 611 ± 293 nmol/L, respectively, P = n.s.), providing further evidence that the pore is not a likely H2-Q1 interaction site. To obtain further insights into the role of intra-cytoplasmic structures, we used both C- and N-terminally truncated mutant H2 proteins. Both H2 mutants co-immunoprecipitated with Q1, suggesting no specific role of C- or N-termini. Accordingly, rather than these, the transmembrane domains of the α-subunits appear relevant for the interaction. Our results largely exclude the formation of hetero-tetramers between H2 and Q1 comprising the pore region or H2 C- or N-termini.
    Archiv für Experimentelle Pathologie und Pharmakologie 03/2015; DOI:10.1007/s00210-015-1108-3 · 2.36 Impact Factor
  • Jason G Andrade, Stanley Nattel, Laurent Macle
    Europace 03/2015; 17(5). DOI:10.1093/europace/euv033 · 3.05 Impact Factor
  • Stanley Nattel
    The Canadian journal of cardiology 03/2015; 31(5). DOI:10.1016/j.cjca.2015.03.013 · 3.94 Impact Factor
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    ABSTRACT: Atrial fibrillation (AF) is the most common clinically relevant arrhythmia, but the methods available for treating AF and its complications (of which the most important is thrombogenesis), as well as for assessing AF risk and underlying pathophysiology, are largely limited. Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF. That evidence includes elevated serum levels of inflammatory biomarkers in AF subjects, the expression of inflammatory markers in cardiac tissues of AF patients and animal models of AF, and beneficial effects of anti-inflammatory drugs in experimental AF paradigms. Inflammation is suggested to be linked to various pathological processes, such as oxidative stress, apoptosis, and fibrosis, that promote AF substrate formation. Inflammation has also been associated with endothelial dysfunction, platelet activation, and coagulation cascade activation, leading to thrombogenesis. Thus, inflammation may contribute to both the occurrence/maintenance of AF and its thromboembolic complications. Here, we review the evidence for a role of inflammation and inflammatory biomarkers in the risk management and treatment of AF. We also summarize the current knowledge of inflammation-dependent cellular and molecular mechanisms in AF pathophysiology and their potential as therapeutic targets. (Circ J 2015; 79: 495-502).
    Circulation Journal 02/2015; 79(3):495-502. DOI:10.1253/circj.CJ-15-0138 · 3.69 Impact Factor
  • Stanley Nattel
    Circulation Arrhythmia and Electrophysiology 02/2015; 8(1):5-7. DOI:10.1161/CIRCEP.115.002673 · 5.42 Impact Factor
  • Stanley Nattel
    The Canadian journal of cardiology 01/2015; 31(1):1-2. DOI:10.1016/j.cjca.2014.11.022 · 3.94 Impact Factor
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    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 01/2015; 1234:69-80. DOI:10.1007/978-1-4939-1755-6_7 · 1.29 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 01/2015; 230(1). DOI:10.1002/jcp.24696 · 3.87 Impact Factor
  • The Canadian journal of cardiology 11/2014; DOI:10.1016/j.cjca.2014.10.006 · 3.94 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; 12(2). DOI:10.1038/nrcardio.2014.178 · 10.15 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. DOI:10.1016/j.bpj.2014.10.014 · 3.83 Impact Factor
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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 Ca(2+) ([Ca(2+)]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. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 11/2014; 593(3). DOI:10.1113/jphysiol.2014.279109 · 4.54 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 11/2014; 11(11). DOI:10.1016/j.hrthm.2014.07.033 · 4.92 Impact Factor
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    ABSTRACT: BACKGROUND 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. OBJECTIVES The aim of this study was to evaluate the influence of high-dose fish oil on AF recurrence, inflammation, and oxidative stress parameters. METHODS We performed a double-blind, randomized, placebo-controlled, parallel-arm study in 337 patients with symptomatic paroxysmal or persistent AF within 6 months of enrollment. Patients were randomized to fish oil (4 g/day) or placebo and followed, on average, for 271 +/- 129 days. RESULTS The primary endpoint was time to first symptomatic or asymptomatic AF recurrence lasting >30 s. Secondary endpoints were high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO). The primary endpoint occurred in 64.1% of patients in the fish oil arm and 63.2% of patients in the placebo arm (hazard ratio: 1.10; 95% confidence interval: 0.84 to 1.45; p = 0.48). hs-CRP and MPO were within normal limits at baseline and decreased to a similar degree at 6 months (Delta hs-CRP, 11% vs. -11%; DMPO, -5% vs. -9% for fish oil vs. placebo, respectively; p value for interaction = NS). CONCLUSIONS High-dose fish oil does not reduce AF recurrence in patients with a history of AF not receiving conventional AA therapy. Furthermore, fish oil does not reduce inflammation or oxidative stress markers in this population, which may explain its lack of efficacy. (Multi-center Study to Evaluate the Effect of N-3 Fatty Acids [OMEGA-3] on Arrhythmia Recurrence in Atrial Fibrillation [AFFORD]; NCT01235130) (C) 2014 by the American College of Cardiology Foundation.
    Journal of the American College of Cardiology 10/2014; 64(14):1441-8. DOI:10.1016/j.jacc.2014.07.956 · 15.34 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. DOI:10.1016/j.cjca.2014.08.001 · 3.94 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; DOI:10.1016/j.cjca.2014.09.027 · 3.94 Impact Factor
  • Stanley Nattel
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    ABSTRACT: Cardiac rhythm disorders, or 'arrhythmias', are major sources of morbidity and mortality, and have been challenging to treat because classic pharmacological therapies are often ineffective and sometimes dangerous. In the past decade, groundbreaking developments have revolutionized the management of arrhythmias and prepared the groundwork for new advances in the future.
    Nature Reviews Cardiology 09/2014; 11(11). DOI:10.1038/nrcardio.2014.133 · 10.15 Impact Factor

Publication Stats

25k Citations
4,270.26 Total Impact Points

Institutions

  • 1995–2015
    • Université du Québec à Montréal
      • Department of Sociology
      Montréal, Quebec, Canada
  • 1988–2015
    • Montreal Heart Institute
      • • Department of Medicine
      • • Research Centre
      Montréal, Quebec, Canada
  • 1990–2014
    • Université de Montréal
      • • Department of Medicine
      • • Department of Pharmacology
      Montréal, Quebec, Canada
  • 1985–2013
    • McGill University
      • • Department of Pharmacology and Therapeutics
      • • Department of Medicine
      • • Department of Physiology
      Montréal, Quebec, Canada
  • 2012
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
    • Ming Chuan University
      Hsin-chu-hsien, Taiwan, Taiwan
  • 2011
    • Complutense University of Madrid
      Madrid, Madrid, Spain
    • University of Illinois at Chicago
      • Section of Pulmonary, Critical Care, Sleep and Allergy
      Chicago, IL, United States
  • 2008
    • Hôpital du Sacré-Coeur de Montréal
      Montréal, Quebec, Canada
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2007
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 2006
    • Kosin University
      Tsau-liang-hai, Busan, South Korea
  • 2005
    • University of Nantes
      Naoned, Pays de la Loire, France
    • University of California, Santa Barbara
      • Department of Molecular, Cellular, and Developmental Biology
      Santa Barbara, California, United States
    • The University of Calgary
      Calgary, Alberta, Canada
  • 2003
    • State University of New York Upstate Medical University
      • Department of Pharmacology
      Syracuse, NY, United States
  • 2002
    • Centre de recherche du diabète de Montréal
      Montréal, Quebec, Canada
    • Keio University
      Edo, Tōkyō, Japan
    • The University of Hong Kong
      • Institute of Cardiovascular Science and Medicine
      Hong Kong, Hong Kong
    • Zhongshan University
      中山, Guangdong, China
  • 1999–2002
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Harbin Medical University
      • Department of Pharmacology
      Harbin, Heilongjiang Sheng, China
  • 1991
    • Uniformed Services University of the Health Sciences
      • Department of Medicine
      Bethesda, MD, United States