抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Jeffrey L. Anderson, MD, FACC, FAHA, Chair 

Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect 

Nancy M. Albert, PhD, RN, FAHA

Biykem Bozkurt, MD, PhD, FACC, FAHA

Ralph G. Brindis, MD, MPH, MACC

Mark A. Creager, MD, FACC, FAHA[#][1]

Lesley H. Curtis, PhD, FAHA

David DeMets, PhD[#][1]

Robert A

/pdf/2014-aha-acc-hrs-guideline-for-the-management-of-patients-1v8ficsqox.pdf

2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society

During the past decade, catheter ablation of atrial fibrillation (AF) has evolved rapidly from an investigational procedure to its current status as a commonly performed ablation procedure in many major hospitals throughout the world. Surgical ablation of AF, using either standard or minimally invasive techniques, is also performed in many major hospitals throughout the world.

In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society.1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons and the American College of Cardiology. Since the publication of the 2007 document, there has been much learned about AF ablation, and the indications for these procedures have changed. Therefore the purpose of this 2012 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 Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation, including definitions relevant to this topic.

This statement summarizes the opinion of the Task Force 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 undergoing, or are being considered for, catheter or surgical ablation procedures for AF. This statement is not intended to recommend or promote catheter ablation of AF. Rather the ultimate judgment regarding care of a particular patient …

2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design

Preamble 2072

1. Introduction 2074

2. Clinical Characteristics and Evaluation of AF 2076

3. Thromboembolic Risk and Treatment 2077

4. Rate Control: Recommendations 2079

5. Rhythm Control: Recommendations 2080

6. Specific Patient Groups and AF: Recommendations 2086

7. Evidence Gaps and Future Research Directions 2089

References 2090

Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 2095

Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant) 2097

Appendix 3. Initial Clinical Evaluation in Patients With AF 2104

The medical profession should play a central role in evaluating the evidence related to drugs, devices, and procedures for the detection, management, and prevention of disease. When properly applied, expert analysis of available data on the benefits and risks of these therapies and procedures can improve the quality of care, optimize patient outcomes, and favorably affect costs by focusing resources on the most effective strategies. An organized …

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2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary

https://repub.eur.nl/pub/104203/REPUB_104203-OA.pdf

2017 HRS / EHRA / ECAS / APHRS / SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation

Atrial fibrillation (AF) is an extremely common cardiac rhythm disorder that causes substantial morbidity and contributes to mortality. The mechanisms underlying AF are complex, involving both increased spontaneous ectopic firing of atrial cells and impulse reentry through atrial tissue. Over the past ten years, there has been enormous progress in understanding the underlying molecular pathobiology. This article reviews the basic mechanisms and molecular processes causing AF. We discuss the ways in which cardiac disease states, extracardiac factors, and abnormal genetic control lead to the arrhythmia. We conclude with a discussion of the potential therapeutic implications that might arise from an improved mechanistic understanding.

/pdf/recent-advances-in-the-molecular-pathophysiology-of-atrial-24kymccfub.pdf

Recent advances in the molecular pathophysiology of atrial fibrillation

BACKGROUND Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF) maintenance. MicroRNA29 (miR29) targets extracellular matrix proteins. In the present study, we examined miR29b changes in patients with AF and/or CHF and in a CHF-related AF animal model and assessed its potential role in controlling atrial fibrous tissue production. METHODS AND RESULTS Control dogs were compared with dogs subjected to ventricular tachypacing for 24 hours, 1 week, or 2 weeks to induce CHF. Atrial miR29b expression decreased within 24 hours in both whole atrial tissue and atrial fibroblasts (-87% and -92% versus control, respectively; p<0.001 for both) and remained decreased throughout the time course. Expression of miR29b extracellular matrix target genes collagen-1A1 (COL1A1), collagen-3A1 (COL3A1), and fibrillin increased significantly in CHF fibroblasts. Lentivirus-mediated miR29b knockdown in canine atrial fibroblasts (-68%; p<0.01) enhanced COL1A1, COL3A1, and fibrillin mRNA expression by 28% (p<0.01), 19% (p<0.05), and 20% (p<0.05), respectively, versus empty virus-infected fibroblasts and increased COL1A1 protein expression by 90% (p<0.05). In contrast, 3-fold overexpression of miR29b decreased COL1A1, COL3A1, and fibrillin mRNA by 65%, 62%, and 61% (all p<0.001), respectively, versus scrambled control and decreased COL1A1 protein by 60% (p<0.05). MiR29b plasma levels were decreased in patients with CHF or AF (by 53% and 54%, respectively; both p<0.001) and were further decreased in patients with both AF and CHF (by 84%; p<0.001). MiR29b expression was also reduced in the atria of chronic AF patients (by 54% versus sinus rhythm; p<0.05). Adenoassociated viral-mediated knockdown of miR29b in mice significantly increased atrial COL1A1 mRNA expression and cardiac tissue collagen content. CONCLUSIONS MiR29 likely plays a role in atrial fibrotic remodeling and may have value as a biomarker and/or therapeutic target.

MicroRNA29: A Mechanistic Contributor and Potential Biomarker in Atrial Fibrillation

Background —Atrial fibrillation (AF) impairs atrial contractility, inducing "atrial stunning" that promotes thromboembolic stroke Action-potential (AP)-prolonging drugs are reported to normalize atrial hypocontractility caused by atrial-tachycardia remodeling (ATR) Here, we addressed the role of AP-duration (APD) changes in ATR-induced hypocontractility Methods and Results —ATR (7-day tachypacing) decreased APD (perforated-patch recording) by ~50%, atrial contractility (echocardiography, cardiomyocyte video edge-detection) and cellular Ca2+ i -transients ATR AP-waveforms suppressed Ca 2+ i -transients and cell-shortening of control-cardiomyocytes; whereas control AP-waveforms improved Ca 2+ i -transients and cell-shortening in ATR-cells However, ATR-cardiomyocytes clamped with the same control AP-waveform had ~60% smaller Ca 2+ i -transients and cell-shortening than control-cells We therefore sought additional mechanisms of contractile impairment Whole-cell voltage-clamp revealed reduced I CaL ; I CaL -inhibition superimposed on ATR-APs further suppressed Ca 2+ i -transients in control-cells Confocal-microscopy indicated that ATR impaired propagation of the Ca 2+ -release signal to the cell-center in association with loss of t-tubular structures Myofilament-function studies in skinned permeabilized cardiomyocytes showed altered Ca 2+ -sensitivity and force-redevelopment in ATR, possibly due to hypophosphorylation of myosin-binding protein-C and myosin light-chain protein-2a (immunoblot) Hypophosphorylation was related to multiple phosphorylation-system abnormalities: protein-kinase A regulatory-subunits were downregulated whereas autophosphorylation/expression of Ca 2+ /calmodulin-dependent protein-kinase IIδ and protein-phosphatase 1 activity were enhanced Recovery of Ca 2+ -transients and cell-shortening occurred in parallel after ATR-cessation Conclusions —APD-shortening contributes to hypocontractility induced by one-week ATR but accounts for it only partially Additional contractility-suppressing mechanisms include I CaL -reduction, impaired subcellular Ca 2+ -signal transmission, and altered myofilament-function associated with abnormal myosin/myosin-associated protein phosphorylation The complex mechanistic basis of the atrial hypocontractility associated with AF argues for upstream therapeutic-targeting rather than interventions directed towards specific downstream pathophysiological derangements

/pdf/multiple-potential-molecular-contributors-to-atrial-3igzy3jq9e.pdf

Multiple Potential Molecular Contributors to Atrial Hypocontractility Caused by Atrial Tachycardia Remodeling in Dogs

Aims Atrial fibrillation (AF)-induced contractile dysfunction contributes importantly to thrombo-embolic stroke, the most serious AF complication. Atrial cardiomyocytes have a constitutively active acetylcholine-regulated K+-current ( I KAChc) that is enhanced by atrial tachycardia (AT). I KAChc contributes to action potential duration (APD) shortening in AT-remodelled atrial cardiomyocytes; APD regulates contractility by controlling Ca2+-loading and systolic Ca2+-release. This study investigated the potential role of I KAChc in AF-related contractile dysfunction.

Methods and results Dogs were divided into two groups: (i) unpaced control (CTL); (ii) AT (400 bpm for at least 7 days). Tertiapin-Q (TQ), a selective I KAChc blocker, was used to define I KAChc contributions to contractility. Single-cell left atrial (LA) intracellular Ca2+-transients (CaTrs), cell-shortening (CS), and whole LA tissue tension-generation were measured. Atrial tachycardia increased I KAChc. Whole LA contractility was decreased in AT (0.17 ± 0.05 g) compared with CTL (0.40 ± 0.09 g), with significant reversal (0.30 ± 0.06 g) after TQ administration. Ca2+-transient amplitude and CS in single-cell were decreased by AT compared with CTL (167 ± 14 vs. 88 ± 10 nM; 10.3 ± 1.3 vs. 1.7 ± 0.3 µm, respectively; P < 0.001). The AT-induced reductions in single-cell CaTr amplitude and CS were partly reversed by TQ administration (88 ± 10 vs. 112 ± 16 nM; P < 0.001; 1.7 ± 0.3 vs. 3.6 ± 0.7 µm; P < 0.01). We then measured CaTr and CS with carbachol and/or TQ to vary I KACh at various extracellular [Ca2+]. The CaTr–CS relationship was linear and AT results fell on the regression line, indicating that AT-remodelling effects on contractility are attributable to reduced CaTr.

Conclusion Up-regulated I KAChc contributes to AF-related contractile dysfunction and could be a novel target to prevent hypocontractility-related thrombo-embolic complications.

Reza Wakili

Papers

Recent advances in the molecular pathophysiology of atrial fibrillation

MicroRNA29: A Mechanistic Contributor and Potential Biomarker in Atrial Fibrillation

Multiple Potential Molecular Contributors to Atrial Hypocontractility Caused by Atrial Tachycardia Remodeling in Dogs

Role of constitutively active acetylcholine-mediated potassium current in atrial contractile dysfunction caused by atrial tachycardia remodelling.

Provocative Testing for Arrhythmias