First comes diagnosis then comes treatment: an underappreciated paradigm in atrial fibrillation management

Andreas Bollmann*

Department of Cardiology, University Hospital, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany

* Corresponding author. Tel: +49 391 67 13203; fax: +49 391 67 13202. E-mail address: andreas.bollmann{at}medizin.uni-magdeburg.de

This editorial refers to ‘Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three-decade follow-up’{dagger} by M. Osranek et al., on page 2556

Atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice, has a very complex, incompletely understood pathophysiology with various triggers and substrates interacting in multiple ways. All, genetic pre-disposition, structural changes and fibrosis, progression of heart disease, inflammation, autonomic dysfunction coupled with electrophysiological abnormalities of the atria, and pulmonary vein sleeves, may act, to various degrees, as contributors to initiation and maintenance of the fibrillatory process. Clinically, the atrial remodelling process is accompanied by progression from paroxysmal to persistent AF, failure to restore and maintain sinus rhythm, and also increased risk of thrombogenesis and embolism.1

If one takes a closer look at current ACC/AHA/ESC AF management guidelines,1 one must realize, however, that the focus of clinical evaluation includes characterizing the pattern of the arrhythmia as paroxysmal or persistent, determining its cause, and defining associated cardiac and extracardiac factors. Except for left atrial (LA) dimension, AF pattern, and duration, there is no other atrial-specific variable recommended, which takes, at least partially, into account one or more of the aforementioned contributors. Risk stratification of ischaemic stroke is based on age, the presence of heart disease, hypertension, and diabetes mellitus, as well as left ventricular function, not considering individual coagulation properties or structure and function of the LA appendage, as the most common site for thrombus formation. In other words, characterization of the atrial disease process is largely neglected or at best attempted by clinical variables on which therapeutic guidance is based on. Results of various therapeutic interventions are often disappointing, at least partly due to their empirical application.

As far as stroke and its prevention is concerned, it has been recognized that by the virtue of ageing or the development of cardiac abnormalities, patients move from low risk to intermediate or high-risk groups, which has important implications for the initiation of anticoagulant drugs.1

The Osranek study2 deserves special acknowledgement for the idea to predict outcome in AF with specific cardiac changes which define the degree of atrial remodelling. The authors present data on 46 patients with clinically defined lone AF and report that during a median follow-up of 27 years, 23 patients (50%) experienced cardio- or cerebrovascular events; among them, seven cerebral infarctions occurred. By applying three different statistical models, the authors identify LA volume ≥32 mL/m2 to be independently associated with adverse outcome. Even though the survival free of cerebral infarction for their patients with lone AF was not different from that of the expected survival in the general population and the mortality was even lower than expected, the observation that all cerebral infarctions occurred in patients with LA volumes ≥32 mL/m2 at the time of first AF diagnosis or during follow-up is of special interest.

Despite the well-characterized patient population and the exceptional long follow-up, this study clearly has some limitations. As acknowledged by the authors, the small sample size and event rate made the application of multivariable analysis for prediction of cerebral infarction impossible. Moreover, the influence of different treatment strategies or no treatment at all must be considered an issue. At the time of an adverse event, no patient received anticoagulants and about half of the patients were neither on antiarrhythmics, angiotensin converting enzyme inhibitors, nor beta-blockers (Osranek, personal communication). Subsequently, the question whether initiation of treatment, in this case, warfarin or more aggressive attempts to prevent AF chronification, would have made a difference in outcome, e.g. prevention of stroke, would remain unanswered. Finally, the inclusion of only Caucasian patients with lone AF limits the findings to this particular clinical and ethnic subgroup. However, with these words of caution of mind, this study supports the argument that the degree of atrial changes associated with AF and/or underlying heart disease need to be considered in the decision of whom to treat and what treatment to offer in both anticoagulant and antiarrhythmic therapies.

In that sense, biomarkers such as LA volume may come into play which are defined as ‘characteristic that are objectively measured and evaluated as indicators of normal biologic processes, pathogenic processes, or pharmacological responses to a therapeutic intervention’.3 Biomarkers, which should ideally be non-invasive, include biochemical and functional characteristics or signals.

As highlighted in this2 and previous studies, LA volume seems to be a strong predictor for adverse events and mortality not only in AF, but also after myocardial infarction4 or in dilated cardiomyopathy.5 LA volume is mainly determined by the degree of left ventricular dilation, diastolic dysfunction, the extent of mitral regurgitation,5 and AF pattern (paroxysmal vs. persistent AF), but not AF duration.2

Considering the hallmarks of atrial remodelling that is structural, mechanical, and electrical dysfunction with the associated risk for thrombo-embolism, a list of targets that may offer the potential to better characterize AF and to guide its management is suggested for further study and evaluation in different treatment strategies (Table 1).


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Table 1 Variables to characterize different aspects of the fibrillatory process and thromboembolic risk
 
With the widespread clinical availability and application of echocardiography, detailed characterization of atrial structure and function may take its starting point from LA volume. LA appendage or pulmonary venous flow assessed by Doppler echocardiography,6 as well as P-wave and fibrillatory wave characteristics of the surface ECG,7 also seem to be attractive biomarkers because they have been linked in small studies with disease patterns and response to antiarrhythmic drug therapy and cardioversion. With evolving technologies, genomic and proteomic approaches are on the horizon for broader research and clinical applications.8 In that regard, several gene polymorphisms have already been shown to exhibit an association with risk for AF development, pro-thrombotic and inflammatory state, or pro-arrhythmic risk with antiarrhythmic drug initiation. Furthermore, several plasma markers of cardiac fibrosis or inflammation have been identified and applied for predicting outcome in different cardiovascular diseases, such as coronary artery disease, hypertension, or cardiomyopathy, but are still awaiting their systematic exploration in AF.

As there is controversy whether atrial remodelling is related to AF or underlying heart disease or both, the management of AF patients should now and even in the future primarily be directed to correct the clinical aetiologies. But, as exemplified in the Osranek study, taking more pathophysiological information into account may identify high-risk patients for adverse outcome. This in turn may prove beneficial for the individual patient if adequate therapies are initiated at the right time.

Although this concept has been clinically accepted in the case of vagal vs. adrenergic paroxysmal AF where beta-blockers may worsen the arrhythmia in the former and provide relief in the latter, it may also be speculated that class I and III antiarrhythmic drugs are more effective in terminating AF or preventing its recurrence in less remodelled atria.9 There is now hope that angiotensin-converting enzyme inhibitors/angiotensin receptor blockers are effective if atrial fibrosis is the dominant pathological substrate.10 It can further be hypothesized that statins are effective if inflammation is prevailing with AF11 or that anticoagulants need to be initiated if LA volume ≥32 mL/m2.2

Unfortunately, it is difficult to clinically assess the degree of electrical and structural remodelling as well as the influence of the various AF promoters for the individual patient. Moreover, attempts to gain this information are rare. In his novel ‘Mount Misery’, Samuel Shem describes the life and work of Dr Roy Bosch as first year resident in psychiatry. Among several ‘hospital laws’, it is provocatively stated that ‘in psychiatry, first comes treatment then comes diagnosis’. Referring to the article by Osranek et al.,2 one should not let this happen in AF management. First should be the search for biomarkers in AF to better characterize the disease process in order to then ‘better guide therapeutic decisions’.2

Acknowledgements

The author wishes to thank Professors Helmut U. Klein (Magdeburg, Germany) and S. Bertil Olsson (Lund, Sweden) for their helpful comments and support in developing and studying the discussed concept.

Conflict of interest: none declared.

Footnotes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

{dagger} doi:10.1093/eurheartj/ehi483 Back

References

  1. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC Jr, Alonso-Garcia A, Blomstrom-Lundqvist C, de Backer G, Flather M, Hradec J, Oto A, Parkhomenko A, Silber S, Torbicki A. ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation 2001;104:2118–2150.[Free Full Text]
  2. Osranek M, Bursi F, Bailey KR, Grossardt BR, Brown RD Jr, Kopecky SL, Tsang TS, Seward JB. Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three decade follow-up. Eur Heart J 2005;26:2556–2561. First published on September 1, 2005, doi:10.1093/eurheartj/ehi483.[Abstract/Free Full Text]
  3. NIH Definitions Working Group. Biomarkers and Surrogate Endpoints in Clinical Research: Definitions and Conceptual Model. Amsterdam: Elsevier; 2000.
  4. Moller JE, Hillis GS, Oh JK, Seward JB, Reeder GS, Wright RS, Park SW, Bailey KR, Pellikka PA. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation 2003;107:2207–2212.[Abstract/Free Full Text]
  5. Rossi A, Cicoira M, Zanolla L, Sandrini R, Golia G, Zardini P, Enriquez-Sarano M. Determinants and prognostic value of left atrial volume in patients with dilated cardiomyopathy. J Am Coll Cardiol 2002;40:1425–1430.[Abstract/Free Full Text]
  6. Bollmann A, Binias K, Grothues F, Sonne K, Esperer H, Nikutta P, Klein H. Left atrial appendage flow in nonrheumatic atrial fibrillation: relationship with pulmonary venous flow and ECG fibrillatory wave amplitude. Chest 2001;119:485–492.[Abstract/Free Full Text]
  7. Bollmann A, Husser D, Stridh M, Soernmo L, Majic M, Klein HU, Olsson SB. Frequency measures obtained from the surface electrocardiogram in atrial fibrillation research and clinical decision-making. J Cardiovasc Electrophysiol 2003;14:S154–S161.[CrossRef][ISI][Medline]
  8. Prentice H, Webster KA. Genomic and proteomic profiles of heart disease. Trends Cardiovasc Med 2004;14:282–288.[CrossRef][ISI][Medline]
  9. Li D, Benardeau A, Nattel S. Contrasting efficacy of dofetilide in differing experimental models of atrial fibrillation. Circulation 2000;102:104–112.[Abstract/Free Full Text]
  10. Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 2001;104:2608–2614.[Abstract/Free Full Text]
  11. Kumagai K, Nakashima H, Saku K. The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model. Cardiovasc Res 2004;62:105–111.[CrossRef][ISI][Medline]

Related articles in EHJ:

Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three-decade follow-up
Martin Osranek, Francesca Bursi, Kent R. Bailey, Brandon R. Grossardt, Robert D. Brown, Jr, Stephen L. Kopecky, Teresa S. Tsang, and James B. Seward
EHJ 2005 26: 2556-2561. [Abstract] [Full Text]  




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