American Heart Journal
Volume 147, Issue 6 , Pages 953-955, June 2004

Atrial fibrillation and atrial cardiomyopathy—two sides of the same coin?

  • Ole Dyg Pedersen, MD

      Affiliations

    • Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark
    • Corresponding Author InformationReprint requests: Ole Dyg Pedersen, MD, Specialist in Cardiology, Department of Cardiology, Bispebjerg University Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark.
    • ,
  • Lars Køber, MD, DSMC

      Affiliations

    • Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
    • ,
  • Christian Torp-Pedersen, DSMC, FESC

      Affiliations

    • Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark

Article Outline

 

See related article on page 1061.

Since Moe et al1 formulated the multiple wavelets re-entry hypothesis of atrial fibrillation (AF), therapy has mainly focused on interfering with the electrical properties of the atria. A series of studies, including 1 in this issue of the journal, demonstrate promising results with a completely different approach, inhibition of the renin angiotensin system. In this editorial, we will review the relation between atrial electrical properties and atrial cardiomyopathy associated with AF to provide understanding of this new approach.

Within the past decade, it has become apparent that the heterogeneous presentation of AF (paroxysmal, persistent, or permanent) is a result of an intimate relation between triggers of AF and perpetuators—factors facilitating maintenance of AF also called the substrate of the arrhythmia.2 AF may occur as a single episode, but in many patients, AF continues to reoccur and finally become persistent or permanent. It is a common clinical experience that short episodes of AF may occur in patients with healthy hearts (normal-size atria) when exposed to a trigger. In these cases, AF persists only for a few minutes or hours, because the arrhythmia is usually self-terminating in a healthy atria. But in patients with diseased atria (more- or less-dilated atria), a trigger may cause persistent or permanent AF. These observations have shifted our attention from the electrical approach to the structural changes associated with AF and focused our interest on the accompanying atrial cardiomyopathy, which apparently is associated with AF.3

In the past few years, it has become evident that prolonged occurrence of AF alters the atrial electrophysiological properties and increases the susceptibility of inducing and maintaining the arrhythmia—a process called “atrial electrical remodeling.” In the classical goat experiment by Wijffels et al,4 it was shown that pacing-induced AF initially only persists as short episodes, but that continuous induction of AF causes episodes to become longer and eventually permanent. The study showed that AF induced by rapid atrial pacing produces shortening of the atrial effective refractory period and reverses the normal physiological rate adaptation of refractoriness. With these changes and probably in part responsible for atrial electrical remodeling, AF is associated with atrial dilation, loss of atrial contraction, and mitral insufficiency—so-called “atrial structural remodeling.” This atrial cardiomyopathy leads to activation of neurohormones and alterations of ionic channels properties.3 The atria of patients with AF display structural abnormalities greater than the changes caused by underlying heart disease. Histological examination has shown patchy fibrosis with juxtaposition of healthy and diseased atrial fibers, which may account for the nonhomogeneity of atrial refractoriness.3 A recent experimental study showed that heart failure facilitates the induction of sustained AF, mediated by extensive interstitial atrial fibrosis.5 These changes are partly reversible after cardioversion to sinus rhythm, but it may take several days and, for some, several weeks or even months to return to a normal level. The electrical remodeling is reversed within 1 week, whereas reversion of the structural remodeling takes several weeks or months and may not be completely reversed.2

Epidemiological data have provided further suggestions of the importance of atrial cardiomyopathy for the development of AF. Epidemiological factors predisposing patients to AF include age, hypertension, diabetes mellitus, heart failure, ischemic heart disease, and mitral valve disease.6 Common to these conditions is that they all increase the loading conditions of the left atrium, and/or is associated with increased atrial size. An increased pressure during left atrial emptying will result in left atrial hypertrophy, then left atrial dilatation, and finally atrial cardiomyopathy. Left atrial dilatation and mitral insufficiency are common findings in patients with long-standing AF, which is primarily thought to originate from the left atrium. This process may occur years before AF develops and may be the reason why atrial structural remodeling is not reversed after cardioversion. In summary, prolonged AF initially causes an electrical remodeling and later causes an atrial myocardial fibrosis and finally ends up with an atrial cardiomyopathy in which permanent AF is common—and various cardiac conditions that stress the atria in time likewise cause an atrial cardiomyopathy and increase the risk of permanent AF. In either case, the end result may be an atrial cardiomyopathy and permanent AF.

Traditionally, therapy for AF has been directed against the electrical properties, but results have been disappointing. Without antiarrhythmic drug treatment, the 1-year recurrence rate of AF after electrical cardioversion is 80%, and antiarrhythmic treatment offers only a modest protection against recurrence—in the best case reducing the 1-year recurrence rate to 40%. Several antiarrhythmic drugs have been developed for the treatment of AF, all aiming at changing the electrical properties in the atrial myocytes. Class 1 drugs change the conduction properties by blocking sodium channels, and class 3 drugs increase the repolarization time by blocking potassium channels to prevent recurrences. For many years, electrical cardioversion followed by prophylactic treatment with antiarrhythmic drugs has been the primary strategy in the treatment of AF. Unfortunately, none of the marketed antiarrhythmic drugs affect the atrial cardiomyopathy, but they do affect the electrophysiological properties of ventricular myocardium, and thereby may result in serious adverse effects. Skepticism toward the antiarrhythmic strategy has gradually increased with reports of serious adverse events (ie, particularly proarrhythmias—potential life-threatening ventricular arrhythmias).6 Recently the traditional strategy has been challenged in 2 major trials comparing rhythm control (ie, electrical cardioversion and attempts at maintenance of sinus rhythm with antiarrhythmic drugs) against rate control (ie, regulation of the ventricular response, without attempts of cardioversion). Neither study showed that rhythm control offered any benefit in comparison with rate control for major end points such as mortality or thromboembolism. The lack of benefit of rhythm control appears primarily to be caused by a high recurrence rate of AF in the rhythm control group.7, 8

In this era of disappointment in the medical treatment of AF, hope comes from an unexpected corner—inhibition of the renin angiotensin system. In this issue of the journal, Alsheikh-Ali et al demonstrate that angiotensin-converting enzyme (ACE) inhibition in patients with heart failure results in fewer hospital admissions and fewer cardioversions for supraventricular arrhythmias. The result is an extension of previous studies that have demonstrated that ACE inhibition in congestive heart failure and myocardial infarction protects against the development of AF9 and that angiotensin II receptor blockade reduces the occurrence of AF in patients with hypertension.10 The new finding is the clear demonstration of clinical benefit with fewer events of importance for patients.

So, how is this new treatment of AF to be understood: is it a treatment of arrhythmia or a treatment of atrial cardiomyopathy; does it interfere with the trigger for development of AF, the substrate for the continuing of the arrhythmia; or both?

There are mechanistic studies that suggest either beneficial mechanism. Combination therapy of ACE inhibition plus amiodarone or an angiotensin receptor blocker plus amiodarone significantly reduces the recurrence of AF after electrical cardioversion in comparison with amiodarone treatment alone.11, 12 Ueng et al have shown that enalapril reduces the early occurrence of premature atrial beats after electrical cardioversion.11 They also observed that enalapril treatment primarily reduces the early recurrence of AF after electrical cardioversion. Thus, there is reason to believe that ACE inhibition interferes with the trigger of AF, but the trigger and the substrate could be linked by an atrial cardiomyopathy.

Both human and animal studies have shown that prolonged occurrence of AF is associated with increased activity of the renin angiotensin system and changes in cell membrane receptors of this system in the atria. Individuals with AF are known to have up-regulated levels of ACE, but decreased density of angiotensin-II type I receptors and increased density of angiotensin-II type II receptors.13 Specific inhibition of the renin angiotensin system in experimental animal models attenuated or abolished the anatomical changes and the electrical atrial dysfunction, which resulted in a decreased duration of pacing induced AF.5, 14 Involvement of angiotensin II in atrial remodeling has been suggested recently in an experimental animal model. The inhibition of endogenous angiotensin II prevented atrial effective refractory period shortening during rapid atrial pacing in dogs, and infusion of angiotensin II caused a shortening of the atrial effective refractory period.14 In animal models, induction of permanent AF is associated with atrial fibrosis, which could be taken as a sign of atrial cardiomyopathy. ACE inhibition reduces atrial fibrosis, reduces left ventricular hypertrophy, and reduces the hemodynamic load on left atrium, which may reverse atrial cardiomyopathy.

It is therefore apparent that blocking of the renin angiotensin system interferes with both triggers and the substrate of the arrhythmia. Increasing evidence supports that the renin angiotensin system is involved in the pathophysiology of AF once it is present. A long duration of AF results in atrial dilatation and mitral insufficiency. This process may result in activation of the renin angiotensin system, which probably is further activated the more diseased the atria becomes.

Thus, ACE inhibition is known to prevent atrial fibrosis, to reduce triggers of AF, to reduce recurrence of AF after conversion to sinus rhythm, and to reduce occurrence of AF in the setting of heart failure. ACE inhibition is beneficial in known clinical conditions associated with the development of AF. A natural hypothesis is that ACE inhibition interferes with the atrial cardiomyopathy, the apparent end result in all AF. Such a hypothesis would match nicely the development in ventricular disease. Ventricular cardiomyopathy causes arrhythmias, and ACE inhibition reduces arrhythmic (and nonarrhythmic) death, whereas antiarrhythmic treatment has been disappointing. There is currently good reason to believe that ACE inhibition prevents further deterioration of the atria. The question for the future is whether ACE inhibition may be beneficial once the atrial cardiomyopathy is established and permanent AF prevails. Major studies of ACE inhibitors in heart failure provide large databases of patients in sinus rhythm to study occurrence of AF, but only small databases for studies of the recurrence of sinus rhythm in patients with AF. We find that further studies of ACE inhibition in paroxysmal and permanent AF are warranted. Given the available evidence, ACE inhibition could be a treatment as promising as radiofrequency ablation of AF.

Back to Article Outline

References 

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PII: S0002-8703(04)00054-7

doi:10.1016/j.ahj.2004.01.015

American Heart Journal
Volume 147, Issue 6 , Pages 953-955, June 2004

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