Elsevier

Progress in Cardiovascular Diseases

Volume 58, Issue 2, September–October 2015, Pages 152-167
Progress in Cardiovascular Diseases

Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation

https://doi.org/10.1016/j.pcad.2015.08.004Get rights and content

Abstract

Left atrial (LA) structure and function are intimately related to the clinical phenotypes of atrial fibrillation (AF), and have direct implications for the success or otherwise of various therapeutic strategies. In conjunction with intrinsic structural characteristics of the LA, pathological remodelling to a large extent dictates the clinical course of AF. Remodelling is a product of the physiological and structural plasticity of the LA in disease states (including AF itself), and manifests as electrical, physical and structural changes that promote the substrate necessary for AF maintenance. The degree of remodelling impacts upon the efficacy of pharmacological, non-pharmacological and interventional treatments for AF. Evolving therapies seek to specifically target these processes although presently, several remain in the development phase. Catheter ablation (CA) is now firmly established as a highly effective treatment for AF, although increasing its efficacy in the remodelled LA of more severe AF phenotypes remains an ongoing challenge.

Section snippets

LA remodelling

The LA is a complex entity displaying a considerable degree of physiological, electrical and anatomical plasticity in disease states.

“Remodelling” refers to electrical and structural alterations to the atrial tissue leading to impairment of normal atrial function. Many disease processes lead to atrial remodelling, including hypertension (HTN), valvular heart disease (VHD) and cardiomyopathy, however, remodelling in the setting of AF is of particular interest as its occurrence appears to

Mechanisms of electrical remodelling

The mechanisms of electrical remodelling in AF are multifaceted. Electrical remodelling facilitates all three arrhythmia mechanisms: enhanced automaticity, triggered activity and re-entry.3 Enhanced automaticity and triggered activity promote spontaneous rapid depolarisations of atrial myocytes. Re-entry is facilitated by processes which shorten atrial effective refractory period (ERP), reduce action potential duration (APD) and slow conduction velocity.4 These changes increase the period of

Anatomical considerations and implications for AF treatments

Before exploring the crucial role of structural remodelling it is worth appreciating the structural aspects of the LA, and its implications on AF development and treatment. The advent of CA for AF, which by its very nature requires an intimate navigation around the LA endocardium, has significantly advanced our anatomical and electrophysiological understanding of LA structure and function. Nonetheless, despite this detailed biological characterisation of the LA, significant debate still exists

Structural remodelling (Fig 3)

Structural remodelling refers to alterations in the tissue architecture of the LA at both a cellular and macroscopic level the hallmark of which is atrial fibrosis, however inflammation and LA mechanical factors also play a role.

Conclusion

Atrial structure and function have direct implications for the management of AF. Electrical remodelling results in a multitude of complex physiological changes, which create conditions favourable to AF development and sustainment. The identification of key molecular pathways improves our understanding of AF mechanisms, and may also provide opportunities for the development of novel pharmacological therapies, of which more are sorely needed. Intrinsic anatomical aspects of the LA have an

Statement of Conflict of Interest

The authors have no conflicts of interest to disclose.

Acknowledgments

Drs Sandeep Prabhu, Alex JA McLellan and Tomos E Walters receive funding from Australian National Health and Medical Research Council (NHMRC) and National Heart Foundation of Australia. Drs Sandeep Prabhu and Alex JA McLellan also receive funding from the Baker IDI Heart and Diabetes Research Institute. Professor M Kistler is supported by practitioner fellowships from the NHMRC. Drs Meenal Sharma and Alex Voskoboinik have no disclosures. This research is supported in part by the Victorian

References (148)

  • T. Rostock et al.

    Atrial fibrillation begets atrial fibrillation in the pulmonary veins on the impact of atrial fibrillation on the electrophysiological properties of the pulmonary veins in humans

    J Am Coll Cardiol

    (2008)
  • R.J. Hassink et al.

    Morphology of atrial myocardium in human pulmonary veins

    J Am Coll Cardiol

    (2003)
  • M.K. Stiles et al.

    Paroxysmal lone atrial fibrillation is associated with an abnormal atrial substrate: characterizing the "second factor"

    J Am Coll Cardiol

    (2009)
  • J.A. Cabrera et al.

    Morphological evidence of muscular connections between contiguous pulmonary venous orifices: relevance of the interpulmonary isthmus for catheter ablation in atrial fibrillation

    Heart Rhythm

    (2009)
  • A.J.A. McLellan et al.

    Pulmonary vein isolation: the impact of pulmonary venous anatomy on long-term outcome of catheter ablation for paroxysmal atrial fibrillation

    Heart Rhythm

    (2014)
  • M. Kowalski et al.

    Histopathologic characterization of chronic radiofrequency ablation lesions for pulmonary vein isolation

    J Am Coll Cardiol

    (2012)
  • T.J. McGarry et al.

    The anatomical basis of pulmonary vein reconnection after ablation for atrial fibrillation: wounds that never felt a scar?

    J Am Coll Cardiol

    (2012)
  • G.Y.H. Lip et al.

    Improving stroke risk stratification in atrial fibrillation

    The American Journal of Medicine

    (2010)
  • S. Ayirala et al.

    Echocardiographic predictors of left atrial appendage thrombus formation

    J Am Soc Echocardiogr

    (2011)
  • L. Di Biase et al.

    Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study

    J Am Coll Cardiol

    (2012)
  • S. Kumar et al.

    Atrial remodeling in varying clinical substrates within beating human hearts: relevance to atrial fibrillation

    Prog Biophys Mol Biol

    (2012)
  • B. Burstein et al.

    Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation

    J Am Coll Cardiol

    (2008)
  • I.M. de Oliveira et al.

    Fibrosis, myocardial crossings, disconnections, abrupt turns, and epicardial reflections: do they play an actual role in human permanent atrial fibrillation? A controlled necropsy study

    Cardiovasc Pathol

    (2013)
  • W. Schorb et al.

    Angiotensin II is a potent stimulator of map-kinase activity in neonatal rat cardiac fibroblasts

    J Mol Cell Cardiol

    (1995)
  • R. Khatib et al.

    Blockade of the renin–angiotensin–aldosterone system (RAAS) for primary prevention of non-valvular atrial fibrillation: a systematic review and meta analysis of randomized controlled trials

    Int J Cardiol

    (2013)
  • P. Korantzopoulos et al.

    Aldosterone signaling in atrial fibrillation another piece in the puzzle of atrial remodeling

    J Am Coll Cardiol

    (2010)
  • Y. Ito et al.

    Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with long-standing persistent atrial fibrillation

    Am J Cardiol

    (2013)
  • K. Swedberg et al.

    Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure) study

    J Am Coll Cardiol

    (2012)
  • M. Dobaczewski et al.

    Transforming growth factor (TGF)-beta signaling in cardiac remodeling

    J Mol Cell Cardiol

    (2011)
  • Y. Nakatani et al.

    Tranilast prevents atrial remodeling and development of atrial fibrillation in a canine model of atrial tachycardia and left ventricular dysfunction

    J Am Coll Cardiol

    (2013)
  • H. Musa et al.

    Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts

    Heart Rhythm

    (2013)
  • M. Shimano et al.

    Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure

    Heart Rhythm

    (2008)
  • B. Lo et al.

    C-reactive protein is a risk indicator for atrial fibrillation after myocardial revascularization

    Ann Thorac Surg

    (2005)
  • K. Lertsburapa et al.

    Preoperative statins for the prevention of atrial fibrillation after cardiothoracic surgery

    J Thorac Cardiovasc Surg

    (2008)
  • S.S. Chugh et al.

    Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study

    Circulation

    (2014)
  • S.E. Wolowacz et al.

    The cost of illness of atrial fibrillation: a systematic review of the recent literature

    Europace

    (2011)
  • R. Wakili et al.

    Recent advances in the molecular pathophysiology of atrial fibrillation

    J Clin Invest

    (2011)
  • T. Krogh-Madsen et al.

    Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study

    PLoS Comput Biol

    (2012)
  • S. Nattel et al.

    Atrial remodeling and atrial fibrillation: mechanisms and implications

    Circ Arrhythm Electrophysiol

    (2008)
  • R.F. Bosch et al.

    Ionic mechanisms of electrical remodeling in human atrial fibrillation

    Cardiovasc Res

    (1999)
  • E. Grandi et al.

    Human atrial action potential and Ca2 + model: sinus rhythm and chronic atrial fibrillation

    Circ Res

    (2011)
  • S. Nattel et al.

    The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities

    Eur Heart J

    (2012)
  • U. Schotten

    Electrical and contractile remodeling during the first days of atrial fibrillation go hand in hand

    Circulation

    (2003)
  • Z. Wang et al.

    Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation

    Circ Res

    (1992)
  • T. Iwai et al.

    Sodium accumulation during ischemia induces mitochondrial damage in perfused rat hearts

    Cardiovasc Res

    (2002)
  • N. Alp et al.

    Randomised double blind trial of oral versus intravenous flecainide for the cardioversion of acute atrial fibrillation

    Heart

    (2000)
  • M. Gulizia et al.

    A randomized comparison of amiodarone and class IC antiarrhythmic drugs to treat atrial fibrillation in patients paced for sinus node disease: the Prevention Investigation and Treatment: A Group for Observation and Research on Atrial Arrhythmias (PITAGORA) trial

    Am Heart J

    (2008)
  • R.H. Falk

    Proarrhythmia in patients treated for atrial fibrillation or flutter

    Ann Intern Med

    (1992)
  • A. Burashnikov et al.

    Azd1305 exerts atrial predominant electrophysiological actions and is effective in suppressing atrial fibrillation and preventing its reinduction in the dog

    J Cardiovasc Pharmacol

    (2010)
  • P.R. Kowey et al.

    Lb03–05: the effect of the combination of ranolazine and low dose dronedarone on atrial fibrillation burden in patients with paroxysmal atrial fibrillation (HARMONY trial)

  • Cited by (13)

    • Current Evidence-Based Understanding of the Epidemiology, Prevention, and Treatment of Atrial Fibrillation

      2018, Current Problems in Cardiology
      Citation Excerpt :

      Myocardial “sleeves” extending from the PVs are the primary origin of these triggers in >80% of patients with paroxysmal AF.203-205 Because of this common site of initiation, complete electrical PVI is usually the primary endpoint in catheter ablation of AF.49,203,204,206 During a PVI procedure, lesions are created encircling the antrum the PV, which results in nonconducting scar, thereby electrically isolating the PV muscle sleeves and their triggers from the rest of the myocardium.207

    • Association of Systemic Inflammation Score With Atrial Fibrillation: A Case-Control Study With Propensity Score Matching

      2018, Heart Lung and Circulation
      Citation Excerpt :

      Unfortunately, we lacked the medical histories. Therefore, we could not rule out the possibility that some patients might have taken cardiovascular medicine before study inclusion, such as aspirin/clopidogrel which may influence platelet activation, and statins which have a recognised anti-inflammatory role independent of their cholesterol lowering ability [22–24]. Although the drug effect might influence platelets and PLR was not statistically different in our study, platelets are the source of inflammatory mediators and lymphocytes have been shown to regulate the immune response during all progressive stages of atherosclerosis [19].

    • Does Surgical Ablation Energy Source Affect Long-Term Success of the Concomitant Cox Maze Procedure?

      2017, Annals of Thoracic Surgery
      Citation Excerpt :

      In this study, a shorter duration of AF was found to be an independent predictor of SR at 1 and 5 years. This finding may indicate that a lower degree of atrial tissue remodeling is associated with better success [33]. Future studies should focus on understanding such associations further, especially with regard to radiofrequency ablation and establishment of standardized protocols for use of bipolar radiofrequency clamps.

    View all citing articles on Scopus
    View full text