Showing papers by "Stanley Nattel published in 2017"
Johns Hopkins University1, Leipzig University2, Korea University3, Yale University4, West Virginia University5, University of Barcelona6, St George's, University of London7, Indiana University8, National Yang-Ming University9, Cleveland Clinic10, Aarhus University11, University at Buffalo12, Imperial College London13, Primary Children's Hospital14, Erasmus University Rotterdam15, Yeshiva University16, Ghent University17, Baylor University18, Virginia Commonwealth University19, Harvard University20, Federal University of São Paulo21, University of California, San Francisco22, Beaumont Hospital23, Boston University24, University of Oklahoma25, Carlos III Health Institute26, University of Michigan27, University of Melbourne28, Saint Louis University29, Université de Montréal30, University of Pennsylvania31, McGill University32, Mayo Clinic33, Lahey Hospital & Medical Center34, Royal Adelaide Hospital35, University of Milan36, University of Toronto37, Loyola University Chicago38, Jikei University School of Medicine39
TL;DR: This 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies.
1,626 citations
Johns Hopkins University1, Leipzig University2, Humanitas University3, Korea University4, Yale University5, West Virginia University6, University of Barcelona7, St George's, University of London8, Indiana University9, National Yang-Ming University10, Cleveland Clinic11, Aarhus University12, University at Buffalo13, Imperial College London14, Primary Children's Hospital15, Erasmus University Rotterdam16, Yeshiva University17, Ghent University18, Baylor University19, Virginia Commonwealth University20, Harvard University21, Federal University of São Paulo22, University of California, San Francisco23, Beaumont Hospital24, Boston University25, University of Oklahoma26, University of Michigan27, Carlos III Health Institute28, University of Melbourne29, Saint Louis University30, Université de Montréal31, University of Pennsylvania32, McGill University33, Mayo Clinic34, Lahey Hospital & Medical Center35, Royal Adelaide Hospital36, University of Milan37, University of Toronto38, Loyola University Chicago39, Jikei University School of Medicine40
TL;DR: This 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies.
Abstract: During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure.
In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.2 The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic.
The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardiacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B.
In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations.
The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.3,4 It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended.
The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group.
Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.5,6 This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient.
The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.
521 citations
TL;DR: An integrated care model is proposed to incorporate risk factor modification as the fourth pillar of AF care in conjunction with established pillars of rate control, rhythm control, and anticoagulation therapy.
Abstract: There has been increasing focus on the rising burden of atrial fibrillation (AF) since the turn of the millennium. The AF epidemic is projected not only to have an impact on morbidity and mortality, but also to result in increasing healthcare use and cost. Intensive research over the previous decades has improved our understanding of this complex arrhythmia while unraveling more knowledge gaps and inadequacies of current therapeutic options. Specifically, the advances in catheter ablation technology and strategies have not translated into significant gains in procedural success rates over recent years. Therefore, strategies aiming at lowering the risk of AF development and progression are urgently needed to curtail the AF epidemic and improve outcomes in affected individuals. Recent research has highlighted the potential beneficial effects of lifestyle and risk factor management for AF as upstream noninvasive therapy. The evidence supporting this treatment paradigm beyond routine clinical AF management argues for change in the delivery of care to patients who have this debilitating arrhythmia. In this review, we highlight the contributory role of risk factors to AF pathogenesis from both bench and bedside studies. Next, we discuss the rationale and potential benefits of risk factor modification for sinus rhythm maintenance. Last, we propose an integrated care model to incorporate risk factor modification as the fourth pillar of AF care in conjunction with established pillars of rate control, rhythm control, and anticoagulation therapy.
409 citations
TL;DR: It is hoped that an improved understanding of the mechanisms controlling atrial fibrosis will open up new opportunities for AF prevention and management.
265 citations
Johns Hopkins University1, Leipzig University2, Humanitas University3, Korea University4, Yale University5, West Virginia University6, University of Barcelona7, St George's, University of London8, Indiana University9, National Yang-Ming University10, Cleveland Clinic11, Aarhus University12, University at Buffalo13, Imperial College London14, Primary Children's Hospital15, Erasmus University Rotterdam16, Yeshiva University17, Ghent University18, Baylor University19, Virginia Commonwealth University20, Harvard University21, Federal University of São Paulo22, University of California, San Francisco23, Beaumont Hospital24, Boston University25, University of Oklahoma26, University of Michigan27, Carlos III Health Institute28, University of Melbourne29, Saint Louis University30, Université de Montréal31, University of Pennsylvania32, University of Duisburg-Essen33, McGill University34, Mayo Clinic35, Lahey Hospital & Medical Center36, Royal Adelaide Hospital37, University of Adelaide38, University of Milan39, University of Toronto40, Loyola University Chicago41, Jikei University School of Medicine42
TL;DR: The 2017 Consensus Statement on Catheter and Surgical Atrial Fibrillation (CA-ABlation) as mentioned in this paper provides a state-of-the-art review of the field of catheter and surgical ablation of atrial fibrillation and to report the findings of a writing group, convened by these five international societies.
Abstract: During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure.
In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.2 The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic.
The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardiacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B.
In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations.
The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.3,4 It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended.
The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group.
Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.5,6 This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient.
The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.
145 citations
TL;DR: The authors consider critically the added clinical value of this concept and its meaningfulness, and discuss how atrial cardiomyopathic properties might guide stroke prevention, rhythm maintenance, and rate control in atrial fibrillation.
131 citations
Johns Hopkins University1, Leipzig University2, Humanitas University3, Korea University4, Yale University5, West Virginia University6, University of Barcelona7, St George's, University of London8, Indiana University – Purdue University Indianapolis9, National Yang-Ming University10, Cleveland Clinic11, Aarhus University12, University at Buffalo13, Imperial College London14, Primary Children's Hospital15, Erasmus University Rotterdam16, Yeshiva University17, Ghent University18, Baylor University19, Virginia Commonwealth University20, Harvard University21, National Health Service22, Federal University of São Paulo23, University of California, San Francisco24, Beaumont Hospital25, Boston University26, University of Oklahoma27, University of Michigan28, University of Melbourne29, Saint Louis University30, Université de Montréal31, University of Pennsylvania32, McGill University33, Mayo Clinic34, Lahey Hospital & Medical Center35, Royal Adelaide Hospital36, University of Milan37, University of Toronto38, Loyola University Chicago39, Jikei University School of Medicine40
TL;DR: The next generation of teachers and researchers will shape the future of teaching and learning in the developing world through a generation of interpreters and interpreters.
115 citations
TL;DR: Comparing and contrast the current recommendations, and highlighting the important differences, in the American College of Cardiology/American Heart Association/Heart Rhythm Society, European Society of cardiology, and Canadian Cardiovascular Society atrial fibrillation (AF) guidelines are compared.
88 citations
TL;DR: Atrial tissue from patients with persistent AF reveals activation of autophagy and induction of ER stress, which correlates with markers of cardiomyocyte damage, and the potential therapeutic action of the ER‐stress inhibitor 4‐phenyl butyrate is demonstrated.
Abstract: BackgroundDerailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self‐perpetuating nature of atrial fibrillation (AF), the mo...
86 citations
TL;DR: This Review discusses competing observations about the role of spatially confined rotors, short-lived rotors clustered at the edge of fibrotic zones, endocardial–epicardial interactive breeder properties and transmural re-entry, as well as studies underway to resolve them.
Abstract: Spiral-wave generators, or 'rotors', have been identified by advanced mapping methods in experimental and clinical atrial fibrillation (AF). In this Review, Nattel and colleagues describe the concepts of phase mapping and spiral-wave rotors, and summarize the ways in which rotor sources might be involved in AF maintenance. They also consider the relevance of spiral-wave rotors to the management of patients with AF. Treatment of atrial fibrillation (AF), the most common arrhythmia in clinical practice, remains challenging. Improved understanding of underlying mechanisms is needed to improve therapy. Functional re-entry is central to AF maintenance. The first detailed, quantitative theory of functional re-entry, the 'leading circle' model, was developed 40 years ago. Subsequently, an alternative paradigm based on 'spiral waves' has evolved. Spiral-wave generators, or 'rotors', have been identified using advanced mapping methods in experimental and clinical AF. A central tool in the analysis of spiral-wave rotors is the phase transformation, allowing for easier visualization of rotors and tracking of 'phase singularity' points at the rotor tip. In contrast to leading circle theory, which is expressed in terms familiar to (and easily understood by) cardiologists, the ideas needed to understand rotors are much more theoretical and harder for clinicians to apply. In this Review, we summarize the basic notions of phase mapping and spiral-wave rotors, and the ways in which rotor sources might be involved in AF maintenance. We discuss competing observations about the role of spatially confined rotors, short-lived rotors clustered at the edge of fibrotic zones, endocardial–epicardial interactive breeder properties and transmural re-entry, as well as studies underway to resolve them. We conclude with consideration of the clinical relevance of the issues discussed and their potential implications for the management of patients with AF.
72 citations
TL;DR: JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA- fibrogenesis and might be a potential target for LA-Fibrosis prevention.
Abstract: Aims Left-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis. Methods and results LA-remodelling was studied in dogs with heart failure (HF) induced by ventricular tachypacing (VTP, 240 bpm), and in mice with left-ventricular (LV) dysfunction due to myocardial infarction (MI). The selective STAT-3 inhibitor S3I-201 was administered to fibroblasts in vitro or mice in vivo (10 mg/kg/d, osmotic mini-pump). HF-dogs developed LA-selective fibrosis and AF-susceptibility at 1-week VTP. The mRNA-expression of platelet-derived growth factor (PDGF, a JAK-STAT activator) isoforms A, C and D, as well as JAK2, increased in LA fibroblasts from 1-week VTP. HF upregulated protein-expression of PDGF-receptor-β and phosphorylated (activated) signal transducer and activator of transcription 3 (STAT3) in LA. PDGF-AB stimulation of LA fibroblasts increased PDGFR-α, STAT3 and phosphorylated-STAT3 expression, as well as collagen-1 and fibronectin-1 protein secretion (by 1.6- to 20-fold), with smaller changes in LV fibroblasts. Phosphorylated-STAT3 and collagen upregulation were suppressed by the JAK2 inhibitor AG-490, PDGF receptor inhibitor AG1296 and STAT3-inhibitor SI3-201. In vivo S3I-201 treatment of MI-mice attenuated LA-fibrosis, LA-dilation and P-wave duration changes versus vehicle-control. Conclusions HF activates the LA JAK-STAT system and enhances PDGF-signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA-fibrogenesis and might be a potential target for LA-fibrosis prevention.
TL;DR: These results improve the understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis, identifying MYL4 as a key gene required for atrial contractile, electrical and structural integrity.
Abstract: BackgroundThere is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritabl...
TL;DR: Results show for the first time that nuclear angiotensin‐II receptor activation and intracrine Ang‐II signaling control fibroblast function and may have pathophysiological significance.
Abstract: BackgroundCardiac fibroblasts play important functional and pathophysiological roles. Intracellular (“intracrine”) angiotensin‐II (Ang‐II) signaling regulates intercellular communication, excitabil...
TL;DR: The possibilities of developing novel therapeutic strategies that act by modulating cardiac metabolic processes during AF, and the information available about AF-induced metabolic changes and their pathophysiological contribution are reviewed.
Abstract: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice and is associated with morbidity and mortality. Over the past 2 decades, there have been major advances in understanding AF pathophysiology, but important knowledge gaps, particularly about targetable basic mechanisms, remain. Recent metabolomic and proteomic studies have shown changes in the expression of molecules involved in metabolic pathways in human and experimental AF, indicating a role for metabolic alterations in AF pathophysiology. AF is characterized by irregular high-frequency excitation and contraction that affect atrial energy demands, circulation and oxygen supply, and change the balance between metabolic demand and supply, causing metabolic stress. Here, we review the information available about AF-induced metabolic changes and their pathophysiological contribution. We also discuss the possibilities of developing novel therapeutic strategies that act by modulating cardiac metabolic processes during AF.
TL;DR: If drug shortages are here to stay, clinicians, drug manufacturers, and relevant organizations should work together to increase accountability for drug availability and adaptation to shortages, and to create more effective tools with which to anticipate and respond to critical supply fluctuations.
TL;DR: There is evidence that adipocytes produce biologically active molecules that directly promote the development of Atrial Fibrillation (AF), and there are suggestions that weight loss as part of a structured risk-factor intervention program or as a result of bariatric surgery reduces AF risk.
TL;DR: It is shown that, under physiological stimulation conditions, IKur does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation, and channel dynamics are determined principally by activation kinetics.
TL;DR: This editorial refers to ‘A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation’, by D.F. Gudbjartsson et al.
Abstract: This editorial refers to ‘A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation’†, by D.F. Gudbjartsson et al. , on page 27.
A review of the literature published a decade ago reported that almost nothing was known about the genetics of atrial fibrillation (AF), but suggested that ‘Identifying the gene of susceptibility, coupled with defining the sequence and function of the protein that it encodes, has the potential to provide both insight into the pathophysiology of the arrhythmia and diagnostic tools with which to identify susceptible individuals’.1 Subsequent work has richly confirmed the validity of this statement. A recent review listed 33 rare variants and 14 genetic loci associated with AF, and discussed the importance of their discovery for pathophysiological understanding and clinical practice.2 Of the rare variants, the most common motifs are variants in ion-channel subunits (in 21) and transcription factors (in 6). AF clearly has a strong heritable basis2 and it is likely that the discovery of novel AF-associated loci will continue to occur and to improve our understanding of this widely prevalent condition.
In the present issue of the journal, Gudbjartsson et al. report just such a finding.3 They used highly sophisticated whole-genome sequencing and statistical genetics methods to identify sequence variants linked to early-onset AF in 1799 Icelanders. These approaches revealed a rare frameshift deletion in the atrial myosin light-chain gene MYL4 associating with early-onset AF under recessive inheritance models. Eight homozygous carriers all had early-onset AF, three required pacemakers for sick sinus syndrome, three had strokes (without non-AF risk factors), and one experienced sudden death. ECG intervals were generally unremarkable. The only abnormalities present on early echocardiograms were left atrial dilation in two patients. Late echocardiograms showed …
TL;DR: The potential adverse cardiovascular consequences of psychoactive medications and suggestions for practical approaches to avoiding them are provided.
TL;DR: NCX1 is negatively regulated by miR-135a, a microRNA that is down-regulated in the heart after CAVB in mice, and may contribute to proarrhythmic remodeling afterCAVB.
Johns Hopkins University1, Korea University2, Yale University3, West Virginia University4, University of Barcelona5, St George's, University of London6, Indiana University7, National Yang-Ming University8, Cleveland Clinic9, Aarhus University Hospital10, University at Buffalo11, Imperial College Healthcare12, Intermountain Medical Center13, Erasmus University Rotterdam14, Albert Einstein College of Medicine15, Ghent University Hospital16, Baylor University17, Virginia Commonwealth University18, Harvard University19, National Institutes of Health20, Federal University of São Paulo21, University of California, San Francisco22, Beaumont Health23, Boston Medical Center24, Boston University25, University of Oklahoma Health Sciences Center26, University of Michigan27, Royal Melbourne Hospital28, Saint Louis University29, Montreal Heart Institute30, University of Pennsylvania31, Brigham and Women's Hospital32, McGill University33, Mayo Clinic34, Lahey Hospital & Medical Center35, Royal Adelaide Hospital36, University of Milan37, University of Toronto38, Loyola University Chicago39, Jikei University School of Medicine40
TL;DR: This work shows clear SGO1 expression in post-developmental neuronal cells and cytoplasmic localisation in nucleated cells with a transgenic mice model and immunohistochemistry of wild type mice, and demonstrates extranuclear expression of Sgo1 in the developing heart and gut.
TL;DR: The data presents Sgo1 expression pattern during development, and in post-developmental proliferative and quiescent tissue in developing and adult mouse tissues.
TL;DR: This research attacked the mode of action of the immune response to treat central giant cell granuloma by exploiting its role as a “spatially aggregating immune checkpoint disorder”.
Abstract: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Kirkeveien 166, 4.etg. Bygg 7, 0407 Oslo, Norway; Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada; and Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
TL;DR: A single injection of a cardiotropic adeno-associated virus carrying wild-type calsequestrin-2 is able to produce long-term suppression of the arrhythmic phenotype in mice with a loss-of-function mutation causing catecholaminergic polymorphic ventricular tachycardia (CPVT).
Abstract: Cardiac arrhythmias are a major healthcare problem in the developed world. The American Heart Association 2017 statistical report indicates that atrial fibrillation, the most common cardiac rhythm disorder, has an ≈25% lifetime incidence and annual costs of ≈26 billion dollars, whereas sudden cardiac death (usually caused by malignant arrhythmias) affects fewer individuals (just under 200 000 Americans/year) but has more disastrous consequences.1 There have been a variety of improvements in arrhythmia therapy over the past decades, particularly in the realm of nonpharmacological approaches, but many challenges remain.2
Article, see p 525
One area with great promise is the induced modification of cardiac gene expression to produce the targeted downregulation or overexpression of specific gene products (gene therapy).3 The first reported experimental application of gene therapy was for the control of ventricular response rate in atrial fibrillation.4 Since then, a wide range of developments has occurred in the design of gene therapy, the development of gene delivery systems (including cardiac-selective delivery vectors, promoter-selection and product design, and production methods), and therapeutic-targeting strategy.3
Inherited arrhythmia syndromes caused by ion-channel dysfunction lend themselves naturally to gene therapy because most result from gain or loss of function of a single gene product that can be targeted specifically. In 2014, Denegri et al5 reported a fascinating proof-of-principle study demonstrating that a single injection of a cardiotropic adeno-associated virus (serotype-9, AAV9) carrying wild-type calsequestrin-2 is able to produce long-term suppression (over the full animal life span) of the arrhythmic phenotype in mice with a loss-of-function mutation causing catecholaminergic polymorphic ventricular tachycardia (CPVT). The mutation that was targeted produces a recessive form of CPVT, in which affected individuals produce no functional protein and the only curative treatment possible is to restore the full functional wild-type gene product in the heart. The wild-type …
TL;DR: Khairy et al. as mentioned in this paper report on the heart rate response of spectators during more ordinary Montreal Canadiens games and find that peak heart rate most commonly occurred during overtime and scoring opportunities and were comparable to heart rate increases during significant exercise.